Entry - *107741 - APOLIPOPROTEIN E; APOE

Location	Phenotype View Clinical Synopses	Phenotype MIM number	Inheritance	Phenotype mapping key
19q13.32	{?Alzheimer disease, protection against, due to APOE3-Christchurch}	607822	AD	3
	{?Macular degeneration, age-related}	603075	AD	3
	{Coronary artery disease, severe, susceptibility to}	617347		3
	Alzheimer disease 2	104310	AD	3
	Hyperlipoproteinemia, type III	617347		3
	Lipoprotein glomerulopathy	611771		3
	Sea-blue histiocyte disease	269600	AR	3

A quick reference overview and guide (PDF)">

TEXT

▼ Description

Apolipoprotein E is the recognition site for receptors involved in the clearance of remnants of very low density lipoproteins and chylomicrons (summary by Blum, 2016).

▼ Cloning and Expression

Rall et al. (1982) published the full amino acid sequence of apoE. Mature apoE is a 299-amino acid polypeptide.

Utermann et al. (1979) described 2 phenotypes, apoE(IV+) and apoE(IV-), differentiated by analytical isoelectric focusing. They concluded that this polymorphism of apolipoprotein E in human serum is determined by 2 autosomal codominant alleles, apoE(n) and apoE(d).

Further complexities of the genetics of the apolipoprotein E system were discussed by Utermann et al. (1980). Apolipoprotein E (apoE) of very low density lipoprotein (VLDL) from different persons shows 1 of 2 complex patterns, termed alpha and beta (Zannis et al., 1981). Three subclasses of each pattern were found and designated alpha-II, alpha-III and alpha-IV and beta-II, beta-III and beta-IV. From family studies, Zannis et al. (1981) concluded that a single locus with 3 common alleles is responsible for these patterns. The alleles were designated epsilon-II, -III, and-IV. The authors further concluded that beta class phenotypes represent homozygosity for one of the epsilon alleles, e.g., beta-II results from homozygosity for the epsilon-II allele. In contrast, the alpha phenotypes are thought to represent compound heterozygosity, i.e., heterozygosity for 2 different epsilon alleles: alpha II from epsilon II and III; alpha III from epsilon III and IV. The frequency of the epsilon II, III, and IV alleles was estimated at 0.11, 0.72, and 0.17, respectively. ApoE subclass beta-IV was found to be associated with type III hyperlipoproteinemia.

The 3 major isoforms of human apolipoprotein E (apoE2, -E3, and -E4), as identified by isoelectric focusing, are coded for by 3 alleles (epsilon 2, 3, and 4). The E2 (107741.0001), E3 (107741.0015), and E4 (107741.0016) isoforms differ in amino acid sequence at 2 sites, residue 112 (called site A) and residue 158 (called site B). At sites A/B, apoE2, -E3, and -E4 contain cysteine/cysteine, cysteine/arginine, and arginine/arginine, respectively (Weisgraber et al., 1981; Rall et al., 1982). The 3 forms have 0, 1+, and 2+ charges to account for electrophoretic differences (Margolis, 1982). (The nomenclature of the apolipoprotein E isoforms, defined by isoelectric focusing, has gone through an evolution.) E3 is the most frequent ('wildtype') isoform. As reviewed by Smit et al. (1990), E4 differs from E3 by a cys-to-arg change at position 112 and is designated E4(cys112-to-arg). Four different mutations giving a band at the E2 position with isoelectric focusing have been described: E2(arg158-to-cys), E2(lys146-to-gln), E2(arg145-to-cys) and E2-Christchurch(arg136-to-ser). E2(arg158-to-cys) is the most common of the 4.

Hazzard et al. (1981) reported on the large O'Donnell kindred, studied because of a proband with type III HLP. They studied specifically the VLDL isoapolipoprotein E distributions. The findings confirmed earlier work indicating that the ratio of E3 to E2 is determined by two apoE3 alleles, designated d and n, which produce 3 phenotypes, apoE3-d, apoE3-nd, and apoE3-n, corresponding to the low, intermediate, and high ratios.

ApoE, a main apoprotein of the chylomicron, binds to a specific receptor on liver cells and peripheral cells. The E2 variant binds less readily. Weisgraber et al. (1982) showed that human E apoprotein of the E2 form, which contains cysteine (rather than arginine) at both of the 2 variable sites, binds poorly with cell surface receptors, whereas E3 and E4 bind well. They postulated that a positively charged residue at variable site B is important for normal binding. To test the hypothesis, they treated E2 apoE with cysteamine to convert cysteine to a positively charged lysine analog. This resulted in a marked increase in the binding activity of the E2 apoE.

Vogel et al. (1985) showed that large amounts of apoE can be produced by E. coli transformed with a plasmid containing a human apoE cDNA. The use in studies of structure-function relationships through production of site-specific mutants was noted. Wardell et al. (1989) demonstrated that the defect is a 7-amino acid insertion that represents a tandem repeat of amino acid residues 121-127 resulting in the normal protein having 306 amino acids rather than the normal 299.

Chappell (1989) studied the binding properties of lipoproteins in 9 subjects with dysbetalipoproteinemia who were either homozygous or heterozygous for APOE substitutions at atypical sites: at residue 142 in 6, at 145 in 2, and at 146 in 1.

▼ Mapping

Olaisen et al. (1982) found linkage of C3 (120700) and apoE with a lod score of 3.00 in males at a recombination fraction of 13%. Since the C3 locus is on chromosome 19, apoE can be assigned to that chromosome also. The authors stated that preliminary evidence suggested that the apoE locus is close to the secretor locus (182100). Berg et al. (1984) studied apoE-C3 linkage with a C3 restriction fragment length polymorphism. Low positive lod scores were found when segregation was from a male (highest score at recombination fraction 0.17). Using DNA probes, Das et al. (1985) mapped the apoE gene to chromosome 19 by Southern blot analysis of DNA from human-rodent somatic cell hybrids. Humphries et al. (1984) used a common TaqI RFLP near the APOC2 gene to demonstrate close linkage to APOE in 7 families segregating for APOE protein variants. No recombination was observed in 20 opportunities. Apparent linkage disequilibrium was observed. On the other hand, Houlston et al. (1989), using a robust PCR-based method for apoE genotyping, found no strong linkage disequilibrium between the APOE and APOC2 loci. Gedde-Dahl et al. (1984) found linkage between Se and APOE with a peak lod score of 3.3 at recombination fraction of 0.08 in males and 1.36 at 0.22 in females, and linkage between APOE and Lu with a lod score 4.52 at zero recombination (sexes combined). The C3-APOE linkage gave lod score 4.00 at theta 0.18 in males and 0.04 at theta 0.45 in females. Triply heterozygous families confirmed that APOE is on the Se side and on the Lu side of C3. Lusis et al. (1986) used a reciprocal whole arm translocation between the long arm of 19 and the short arm of chromosome 1 to map APOC1, APOC2, APOE and GPI to the long arm and LDLR, C3 and PEPD to the short arm. Furthermore, they isolated a single lambda phage that carried both APOC1 and APOE separated by about 6 kb of genomic DNA. Since family studies indicate close linkage of APOE and APOC2, the 3 must be in a cluster on 19q.

▼ Gene Function

The E2 isoform shows defective binding of remnants to hepatic lipoprotein receptors (Schneider et al., 1981; Rall et al., 1982) and delayed clearance from plasma (Gregg et al., 1981).

Using a yeast 1-hybrid screen with the proximal region of the APOE promoter as bait, Salero et al. (2001) isolated cDNAs encoding the ZIC1 (600470) and ZIC2 (603073) transcription factors. Electrophoretic mobility shift and mutational analyses identified binding sites in the -136 to -125, -65 to -54, and -185 to -174 regions of the APOE promoter. Luciferase reporter analysis showed that the ZIC proteins stimulate potent transcriptional activation of APOE through these binding sites.

Using a variety of structural tools, Morrow et al. (2002) determined that the 22-kD N terminus of APOE4 forms a stable folding intermediate (called a molten globule structure) more readily than does APOE3 or APOE2. They concluded that the differential abilities of the APOE isoforms to form a molten globule may contribute to the isoform-specific effects of APOE in disease.

Van den Elzen et al. (2005) defined the pathways mediating markedly efficient exogenous lipid antigen delivery by apolipoproteins to achieve T-cell activation. Apolipoprotein E binds lipid antigens and delivers them by receptor-mediated uptake into endosomal compartments containing CD1 (e.g., 188370) in antigen-presenting cells. Apolipoprotein E mediates the presentation of serum-borne lipid antigens and can be secreted by antigen-presenting cells as a mechanism to survey the local environment to capture antigens or to transfer microbial lipids from infected cells to bystander antigen-presenting cells. Thus, van den Elzen et al. (2005) concluded that the immune system has co-opted a component of lipid metabolism to develop immunologic responses to lipid antigens.

▼ Evolution

Fullerton et al. (2000) studied sequence haplotype variation in 5.5 kb of genomic DNA encompassing the whole of the APOE locus and adjoining flanking regions in 96 individuals from 4 populations (48 chromosomes from each group): blacks from Jackson, Mississippi, Mayans from Campeche, Mexico, Finns from North Karelia, Finland, and non-Hispanic whites from Rochester, Minnesota. They identified 22 diallelic sites defining 31 distinct haplotypes. Sequence analysis of the chimpanzee APOE gene showed that it is most closely related to human E4-type haplotypes. The evolutionary history of allelic divergence within humans was inferred from the pattern of haplotype relationships. Sequence analysis suggested that haplotypes defining the E3 and E2 alleles were derived from the ancestral E4 and that the E3 group of haplotypes had increased in frequency, relative to E4, in the past 200,000 years. Substantial heterogeneity was found within all 3 classes of sequence haplotypes, and there were important interpopulation differences in the sequence variation underlying the protein isoforms that may be relevant to interpreting conflicting reports of phenotypic associations with variation in the common protein isoforms.

▼ Population Genetics

Gerdes et al. (1992) and Gerdes et al. (1996) reported the frequency of apoE polymorphisms in the Danish population and in Greenland Inuit, respectively, in relation to the findings in 45 other study populations around the world.

Corbo and Scacchi (1999) analyzed the APOE allele distribution in the world. They pointed out that the APOE3 allele is the most frequent in all human groups, especially in populations with a long-established agricultural economy such as those of the Mediterranean basin, where the allele frequency is 0.849-0.898. The frequency of the APOE4 allele, the ancestral allele, remains higher in populations such as Pygmies (0.407) and Khoi San (0.370), aborigines of Malaysia (0.240) and Australia (0.260), Papuans (0.368), some Native Americans (0.280), and Lapps (0.310) where an economy of foraging still exists, or food supply is (or was until shortly before the time of the report) scarce and sporadically available. The APOE2 frequency fluctuates with no apparent trend (0.145-0.02) and is absent in Native Americans. Corbo and Scacchi (1999) suggested that the APOE4 allele, based on some functional properties, may be a 'thrifty' allele. The exposure of APOE4 to the environmental conditions at the time of the report (Western diet, longer life spans) may have rendered it a susceptibility allele for coronary artery disease and Alzheimer disease. The absence of the association of APOE4 with either disorder in sub-Saharan Africans, and the presence of the association in African Americans, seems to confirm this hypothesis.

▼ Molecular Genetics

Data on gene frequencies of apoE allelic variants were tabulated by Roychoudhury and Nei (1988).

In a comprehensive review of apoE variants, de Knijff et al. (1994) found that 30 variants had been characterized, including the most common variant, apoE3.

Hyperlipoproteinemia Type III

De Knijff et al. (1994) stated that 14 apoE variants had been found to be associated with familial dysbetalipoproteinemia (hyperlipoproteinemia type III; 617347), characterized by elevated plasma cholesterol and triglyceride levels and an increased risk for atherosclerosis.

Most patients with familial dysbetalipoproteinemia are homozygous for the E2 isoform (107741.0001). Only rarely does the disorder occur with the heterozygous phenotypes E3E2 or E4E2 (Breslow et al., 1982).

In the kindred with apolipoprotein E deficiency studied by Ghiselli et al. (1981), the defect was shown by Cladaras et al. (1987) to involve an acceptor splice site mutation in intron 3 of the APOE gene (107741.0005).

Smit et al. (1987) described 3 out of 41 Dutch dysbetalipoproteinemic patients who were apparent E3/E2 heterozygotes rather than the usual E2/E2 homozygotes. All 3 genetically unrelated patients showed an uncommon E2 allele that contained only 1 cysteine residue. The uncommon allele cosegregated with familial dysbetalipoproteinemia which in these families seemed to behave as a dominant. Smit et al. (1990) showed that these 3 unrelated patients had (E2K146Q; 107741.0011).

Feussner et al. (1996) reported a 20-year-old man with a combination of type III hyperlipoproteinemia and heterozygous familial hypercholesterolemia (FH; 143890). Multiple xanthomas were evident on the elbows, interphalangeal joints and interdigital webs of the hands. Lipid-lowering therapy caused significant decrease of cholesterol and triglycerides as well as regression of the xanthomas. Flat xanthomas of the interdigital webs were also described in 3 out of 4 previously reported patients with combination of these disorders of lipoprotein metabolism. Feussner et al. (1996) stated that these xanthomas may indicate compound heterozygosity (actually double heterozygosity) for type III hyperlipoproteinemia and FH.

Role in Cardiovascular Disease

Eto et al. (1989) presented data from Japan indicating that both the E2 allele and the E4 allele are associated with an increased risk of ischemic heart disease as compared with the E3 allele. Boerwinkle and Utermann (1988) studied the simultaneous effect of apolipoprotein E polymorphism on apolipoprotein E, apolipoprotein B, and cholesterol metabolism. Since both apoB and apoE bind to the LDL receptor and since the different isoforms show different binding affinity, these effects are not unexpected.

In 5 of 19 Australian men, aged 30 to 50, who were referred for coronary angioplasty (26%), van Bockxmeer and Mamotte (1992) observed homozygosity for E4. This represented a 16-fold increase compared with controls. Payne et al. (1992), O'Malley and Illingworth (1992), and de Knijff et al. (1992) expressed doubts concerning a relationship between E4 and atherosclerosis.

In a case-control study of 338 centenarians compared with adults aged 20 to 70 years of age, Schachter et al. (1994) found that the E4 allele of apoE, which promotes premature atherosclerosis, was significantly less frequent in centenarians than in controls (p = less than 0.001), while the frequency of the E2 allele, associated previously with types III and IV hyperlipidemia, was significantly increased (p = less than 0.01).

To study the effect of birth weight on apoE genetic determinants of circulating lipid levels, Garces et al. (2002) evaluated apoE genotypes and plasma lipid and apolipoprotein concentrations in 933 children (491 males and 442 females), aged 6 to 8 years (mean 6.7 years), with known birth weights. A greater effect of the apoE polymorphism on total cholesterol (TC), LDL cholesterol (LDL-C), and apoB levels was found in the lower tertile than in the upper tertiles of birth weight in both genders. A decrease in TC, LDL-C and apoB associated with the E2 allele became more marked the lower the birth weight and could be explained by the significant positive interaction between birth weight and the E2 allele shown by linear regression analysis. Garces et al. (2002) suggested that the interaction of apoE genotype and birth weight may be an important determinant for atherosclerosis.

In a large cohort of patients with angiographically documented coronary artery disease, Ye et al. (2003) found that the APOE -219T allele (107741.0030) and the E4 allele had independent effects on CAD severity. The frequency of the E4 allele and the -219T allele both increased linearly with increasing number of diseased vessels. The -219T/T genotype conferred an odds ratio of 1.598 in favor of increased disease severity, and the -219T/T haplotype in combination with the E4 haplotype conferred an odds ratio of 1.488. The findings suggested that the -219T and E4 polymorphisms, which may affect the quantity and quality of apoE, respectively, have independent and possibly additive effects on CAD severity.

In 802 patients undergoing transthoracic echocardiography, Novaro et al. (2003) evaluated the association between apoE alleles and calcific valvular lesions of the heart. The authors found that the genotype distribution of patients with aortic stenosis (AS) differed significantly from those without AS (p = 0.03), with increasing prevalences of the apoE4 allele (27% in those without vs 40% in those with AS, p = 0.01). In multivariate analyses adjusting for age, gender, LDL cholesterol levels, and coronary artery disease, increasing age and the apoE4 allele were significant predictors of AS (OR = 1.94, 95% CI = 1.01-3.71, p = 0.046). There was no difference in genotype distribution or prevalence of apoE4 between those with or without mitral annular calcification, however, and the apoE4 allele was not predictive of mitral annular calcification.

Witsch-Baumgartner et al. (2004) determined common APOE and DHCR7 (602858) genotypes in 137 unrelated patients with Smith-Lemli-Opitz syndrome (270400) and 108 of their parents (59 mothers and 49 fathers). There was a significant correlation between patients' clinical severity scores and maternal APOE genotypes (p = 0.028) but not between severity scores and patients' or paternal APOE genotypes. Presence of the maternal APOE2 allele was associated with a more severe phenotype, and the association persisted after stratification for DHCR7 genotype. Witsch-Baumgartner et al. (2004) suggested that the efficiency of cholesterol transport from the mother to the embryo is affected by maternal APOE genotype, and that APOE plays a role in modulation of embryonic development and malformations.

Frikke-Schmidt et al. (2007) presented evidence that combinations of SNPs in APOE and LPL (609708) identify subgroups of individuals at substantially increased risk of ischemic heart disease beyond that associated with smoking, diabetes, and hypertension.

Kathiresan et al. (2008) studied SNPs in 9 genes in 5,414 subjects from the cardiovascular cohort of the Malmo Diet and Cancer Study. All 9 SNPs, including rs4420638 of APOE, had previously been associated with elevated LDL or lower HDL. Kathiresan et al. (2008) replicated the associations with each SNP and created a genotype score on the basis of the number of unfavorable alleles. With increasing genotype scores, the level of LDL cholesterol increased, whereas the level of HDL cholesterol decreased. At 10-year follow-up, the genotype score was found to be an independent risk factor for incident cardiovascular disease (myocardial infarction, ischemic stroke, or death from coronary heart disease); the score did not improve risk discrimination but modestly improved clinical risk reclassification for individual subjects beyond standard clinical factors.

Sea-Blue Histiocyte Disease

Nguyen et al. (2000) reported 2 kindreds in which the sea-blue histiocyte syndrome (269600) was associated with an apoE variant (del149Leu; 107741.0031) in the absence of severe dyslipidemia.

In 2 brothers with splenomegaly, thrombocytopenia, and hypertriglyceridemia, Faivre et al. (2005) identified the del149leu mutation in the APOE gene. Their mother, who also had the mutation, had only isolated hypertriglyceridemia.

Lipoprotein Glomerulopathy

In 3 Japanese patients with lipoprotein glomerulopathy (LPG; 611771), Oikawa et al. (1997) identified heterozygosity for a mutation in the APOE gene (R145P; 107741.0032).

In a Japanese man with LPG, Matsunaga et al. (1999) detected a heterozygous mutation in the APOE gene (R25C; 107741.0033). Rovin et al. (2007) identified the R25C mutation in 2 American males of European descent with LPG.

Alzheimer Disease 2

Saunders et al. (1993) reported an increased frequency of the E4 allele in a small prospective series of possible-probable Alzheimer disease patients presenting to the memory disorders clinic at Duke University, in comparison with spouse controls. Corder et al. (1993) found that the APOE*E4 allele is associated with the late-onset familial and sporadic forms of Alzheimer disease. In 42 families with the late-onset form of Alzheimer disease (AD2; 104310), the gene had been mapped to the same region of chromosome 19 as the APOE gene. Corder et al. (1993) found that the risk for AD increased from 20 to 90% and mean age of onset decreased from 84 to 68 years with increasing number of APOE*E4 alleles. Homozygosity for APOE*E4 was virtually sufficient to cause AD by age 80.

Lannfelt et al. (1995) compared allelic frequency of apolipoprotein E4 in 13 dizygotic twin pairs discordant for Alzheimer disease and found the expected increased frequency of the epsilon-4 allele in Alzheimer compared to healthy cotwins. In a well-known American kindred with late-onset Alzheimer disease, descended from a couple who immigrated to the United States from France in the 18th century, Borgaonkar et al. (1993) found evidence confirming a dosage effect of the E4 allele of 6 affected individuals; 4 E4/E4 homozygotes had onset in their 60s, whereas 2 E4/E3 heterozygotes had onset at ages 77 and 78, respectively. Apolipoprotein E is found in senile plaques, congophilic angiopathy, and neurofibrillary tangles of Alzheimer disease. Strittmatter et al. (1993) compared the binding of synthetic amyloid beta peptide to purified APOE4 and APOE3, the most common isoforms. Both isoforms in oxidized form bound the amyloid beta peptide; however, binding to APOE4 was observed in minutes, whereas binding to APOE3 required hours. Strittmatter et al. (1993) concluded that binding of amyloid beta peptide by oxidized apoE may determine their sequestration and that isoform-specific differences in apoE binding or oxidation may be involved in the pathogenesis of the lesions of Alzheimer disease.

In a study of 91 patients with sporadic Alzheimer disease and 74 controls, Poirier et al. (1993) found a significant association between E4 and sporadic AD. The association was more pronounced in women. Scott (1993) pointed to the need for caution in the application of knowledge gained through screening of E4 in relation to this very common disorder.

Talbot et al. (1994) presented data suggesting that the E2 allele may confer protection against Alzheimer disease and that its effect is not simply the absence of an E4 allele. Corder et al. (1994) presented data demonstrating a protective effect of the E2 allele, in addition to the dosage effect of the E4 allele in sporadic AD. Although a substantial proportion (65%) of AD is attributable to the presence of E4 alleles, risk of AD is lowest in subjects with the E2/E3 genotype, with an additional 23% of AD attributable to the absence of an E2 allele. The opposite actions of the E2 and E4 alleles were interpreted by Corder et al. (1994) to provide further support for the direct involvement of APOE in the pathogenesis of AD.

Sanan et al. (1994) demonstrated that the E4 isoform binds to the beta amyloid (A-beta) peptide more rapidly than the E3 isoform. Soluble SDS-stable complexes of E3 or E4, formed by coincubation with the A-beta peptide, precipitated after several days of incubation at 37 degrees C, with E4 complexes precipitating more rapidly than E3 complexes.

Hyman et al. (1996) demonstrated homozygosity for the E4 genotype in an 86-year-old man with no history of neurologic disease and whose autopsy did not reveal any neurofibrillary tangles and only rare mature senile plaques. This suggested to the authors that inheritance of apoE4 does not necessarily result in the development of dementia or Alzheimer disease.

Myers et al. (1996) examined the association of apolipoprotein E4 with Alzheimer disease and other dementias in 1,030 elderly individuals in the Framingham Study cohort. They found an increased risk for Alzheimer disease as well as other dementias in patients who were homozygous or heterozygous for E4. However they pointed out that most apoE4 carriers do not develop dementia and about one-half of Alzheimer disease is not associated with apoE4.

Kawamata et al. (1994) examined the E4 frequency in 40 patients with late-onset sporadic Alzheimer disease, 13 patients with early-onset sporadic Alzheimer disease, 19 patients with vascular dementia, and 49 nondemented control subjects. In the late-onset sporadic Alzheimer group, the allele frequency was 0.25, considerably higher than the frequency in controls, 0.09. In contrast, there was no increased frequency in early-onset sporadic Alzheimer disease or in patients with vascular dementia. Olichney et al. (1996) found that the apolipoprotein E4 allele is strongly associated with increased neuritic plaques but not neocortical or fibrillary tangles in both Alzheimer disease and the Lewy body variant.

Kawamata et al. (1994) speculated that the lower magnitude of the raised frequency of E4 in the Japanese group compared to that of North American families may be due to a lower E4 frequency in the normal Japanese population and lower morbidity from Alzheimer disease in Japan. Nalbantoglu et al. (1994) performed apolipoprotein analysis on 113 postmortem cases of sporadic Alzheimer disease and 77 control brains in Montreal. In this population, the odds ratio associating E4 with Alzheimer disease was 15.5 and the population attributable risk was 0.53. Yoshizawa et al. (1994) examined the apolipoprotein genotypes in 83 Japanese patients with Alzheimer disease. They found a significant increase in apoE4 frequency in late-onset sporadic Alzheimer disease and a mild increase of apoE4 frequency in late- and early-onset familial Alzheimer disease. In contrast, they found no association between apoE4 and early-onset sporadic Alzheimer disease.

Lucotte et al. (1994) examined the apoE4 frequency in 132 French patients with onset of Alzheimer disease after 60 years of age. They found that homozygosity for the E4 allele was associated with a younger age of disease occurrence than was heterozygosity or absence of the E4 allele. Osuntokun et al. (1995) found no association between E4 and Alzheimer disease in elderly Nigerians, in contrast to the strong association reported in their previous study of African Americans in Indianapolis. Levy-Lahad et al. (1995) found that the epsilon 4 allele did not affect the age of onset in either Alzheimer disease type 4 present in Volga Germans (600753) or Alzheimer disease type 3 (607822). This suggested to them that some forms of early onset familial Alzheimer disease are not influenced by the apolipoprotein E system.

By genotype analysis of 109 carriers of the E280A PSEN1 mutation (104311.0009), including 52 individuals with AD, Pastor et al. (2003) found that those with at least 1 APOE4 allele were more likely to develop AD at an earlier age than those without an APOE4 allele, indicating an epistatic effect.

Wijsman et al. (2005) noted the wide range in age at onset of Alzheimer disease in Volga German families with the N141I mutation in PSEN2 (600759.0001). To examine evidence for a genetic basis for the variation in age at onset, the authors performed a Bayesian oligogenic segregation and linkage analysis on 9 Volga German families known to have a least 1 affected PSEN2 mutation carrier. The analysis was designed to estimate the effects of APOE and PSEN2 and the number and effects of additional loci and the environment (family effects) affecting age at onset of AD. The analysis showed that APOE plays a small but significant role in modifying the age at onset in these Volga German families. There was evidence of a dose-dependent relationship between the number of E4 alleles and age at onset. Wijsman et al. (2005) calculated an approximately 83% posterior probability of at least one modifier locus in addition to APOE; the fraction of the variance in age at onset attributable to PSEN2, APOE, other loci, and family effects was approximately 70%, 2%, 6.5%, and 8.5%, respectively.

Bennett et al. (1995) examined the APOE genotype in family history-positive and family history-negative cases of Alzheimer disease and found a distortion of the APOE allele frequencies similar to those with previous studies. However, they also examined the allele distribution of at-risk sibs and found an excess of the E4 allele which did not differ from that of affected sibs. In these families, they found no evidence for linkage between the APOE4 locus and Alzheimer disease. They concluded that the APOE locus is neither necessary nor sufficient to cause Alzheimer disease and speculated that it may modify the preclinical progression, and therefore the age of onset, in people otherwise predisposed to develop Alzheimer disease.

Head injury is an epidemiologic risk factor for Alzheimer disease and deposition of A-beta occurs in approximately one-third of individuals dying after severe head injury. Nicoll et al. (1995) found that the frequency of APOE4 in individuals with A-beta deposition following head injury (0.52) was higher than in most studies of Alzheimer disease, while in those head-injured individuals without A-beta deposition, the APOE4 frequency (0.16) was similar to controls without Alzheimer disease (P = less than 0.00001). Thus, environmental and genetic risk factors for Alzheimer disease may act additively.

In a review of apolipoprotein E and Alzheimer disease, Strittmatter and Roses (1995) pointed out that isoform-specific differences have been identified in the binding of apoE to the microtubule-associated protein tau (MAPT; 157140), which forms the paired helical filament and neurofibrillary tangles, and to amyloid beta peptide (APP; 104760), a major component of the neuritic plaque. Identification of apoE in the cytoplasm of human neurons and isoform-specific binding of apoE to the microtubule-associated protein tau and MAP-2 (157130) make it possible that apoE may affect microtubule function in the Alzheimer brain. Blennow et al. (1994) demonstrated a significant reduction of CSF apolipoprotein E in Alzheimer disease compared to that of controls. They suggested that the increased reutilization of apolipoprotein E lipid complexes in the brain in Alzheimer disease may explain the low CSF concentration.

The observation that the APOE4 allele is neither necessary nor sufficient for the expression of AD emphasizes the significance of other environmental or genetic factors that, either in conjunction with APOE4 or alone, increase the risk of AD. Kamboh et al. (1995) noted that among the candidate genes that might affect the risk for Alzheimer disease is alpha-1-antichymotrypsin (AACT; 107280) because, like APOE protein, AACT binds to beta-amyloid peptide with high affinity in the filamentous deposits found in the AD brain. Additionally, it serves as a strong stimulatory factor in the polymerization of beta-amyloid peptide into amyloid filaments. Kamboh et al. (1995) demonstrated that a common polymorphism in the signal peptide of AACT (107280.0005) confers a significant risk for AD and that the APOE4 gene dosage effect associated with AD risk is significantly modified by the AACT polymorphism. They identified the combination of the AACT 'AA' genotype with the APOE4/4 genotype as a potential susceptibility marker for AD, as its frequency was 1/17 in the AD group compared to 1/313 in the general population controls. It is noteworthy that one form of Alzheimer disease (designated Alzheimer type 3, 607822), like AACT, maps to 14q; however, AACT and AD3 are located at somewhat different sites on 14q.

Tang et al. (1996) compared relative risks by APOE genotypes in a collection of cases and controls from 3 ethnic groups in a New York community. The relative risk for Alzheimer disease associated with APOE4 homozygosity was increased in all ethnic groups: African American RR = 3.0; Caucasian RR = 7.3; and Hispanic RR = 2.5 (compared with the RR with APOE3 homozygosity). The risk was also increased for APOE4 heterozygous Caucasians and Hispanics, but not for African Americans. The age distribution of the proportion of Caucasian and Hispanics without AD was consistently lower for APOE4 homozygous and APOE4 heterozygous individuals than for those with other APOE genotypes. In African Americans this relationship was observed only in APOE4 homozygotes. Differences in risk among APOE4 heterozygous African Americans suggested to the authors that other genetic or environmental factors may modify the effect of APOE4 in some populations.

In a study of 85 Scottish persons with early onset Alzheimer disease, St Clair et al. (1995) found highly significant enrichment for both homozygous and heterozygous APOE epsilon-4 allele carriers in both familial and sporadic cases with a pattern closely resembling that in late-onset AD.

As reviewed earlier, the APOE4 allele is associated with sporadic and late-onset familial Alzheimer disease. Gene dose has an effect on risk of developing AD, age of onset, accumulation of senile plaques in the brain, and reduction of choline acetyltransferase (118490) in the hippocampus of AD patients. Poirier et al. (1995) examined the effect of APOE4 allele copy number on pre- and postsynaptic markers of cholinergic activity. APOE4 allele copy number showed an inverse relationship with residual brain CHAT activity and nicotinic receptor binding sites in both the hippocampal formation and the temporal cortex of AD subjects. AD subjects lacking the APOE4 allele showed CHAT activities close to or within the age-matched normal control range. Poirier et al. (1995) then assessed the effect of the APOE4 allele on cholinomimetic drug responsiveness in 40 AD patients who completed a double-blind, 30-week clinical trial of the cholinesterase inhibitor tacrine. Results showed that more than 80% of APOE4-negative AD patients showed marked improvement after 30 weeks, whereas 60% of APOE4 carriers had poor responses.

Polvikoski et al. (1995) reported on an autopsy study involving neuropathologic analysis and DNA analysis of frozen blood specimens performed in 92 of 271 persons who were at least 85 years of age, who had been living in Vantaa, Finland, on April 1, 1991, and who had died between that time and the end of 1993. All subjects had been tested for dementia. Apolipoprotein E genotyping was done with a solid-phase minisequencing technique. The percentage of cortex occupied by methenamine silver-stained plaques was used as an estimate of the extent of beta-amyloid protein deposition. They found that the APOE4 allele was significantly associated with Alzheimer disease. Even in elderly subjects without dementia, the apolipoprotein E4 genotype was related to the degree of deposition of beta-amyloid protein in the cerebral cortex.

In late-onset familial AD, women have a significantly higher risk of developing the disease than do men. Studying 58 late-onset familial AD kindreds, Payami et al. (1996) detected a significant gender difference for the APOE4 heterozygous genotype. In women, APOE4 heterozygotes had higher risk than those without APOE4; there was no significant difference between APOE4 heterozygotes and APOE4 homozygotes. In men, APOE4 heterozygotes had lower risk than APOE4 homozygotes; there was no significant difference between APOE4 heterozygotes and those without APOE4. A direct comparison of APOE4 heterozygous men and women revealed a significant 2-fold increased risk in women. These results were corroborated in studies of 15 autopsy-confirmed AD kindreds from the National Cell Repository at Indiana University Alzheimer Disease Center.

Mahley (1988) provided a review documenting the expanding role of apoE as a cholesterol transport protein in cell biology. The pronounced production and accumulation of apoE in response to peripheral nerve injury and during the regenerative process indicates, for example, that apoE plays a prominent role in the redistribution of cholesterol to the neurites for membrane biosynthesis during axon elongation and to the Schwann cells for myelin formation. Poirier (1994) reviewed the coordinated expression of apoE and its receptor, the apoE/apoB LDL receptor (606945), in the regulation of transport of cholesterol and phospholipids during the early and intermediate phases of reinnervation, both in the peripheral and in the central nervous system. He proposed that the linkage of the E4 allele to Alzheimer disease (104300) may represent dysfunction of the lipid transport system associated with compensatory sprouting and synaptic remodeling central to the Alzheimer disease process.

Tomimoto et al. (1995) found only 3 cases with focal accumulation of apolipoprotein E in dystrophic axons and accompanying macrophages in 9 cases of cerebral vascular disease and 4 control subjects. The results suggested to the authors that apolipoprotein E may have a role in recycling cholesterol in other membrane components in the brain, but that this phenomenon is restricted to the periphery of infarctions and may be less prominent than in the peripheral nervous system.

Egensperger et al. (1996) determined the apoE allele frequencies in 35 subjects with neuropathologically confirmed Lewy body parkinsonism with and without concomitant Alzheimer lesions, 27 patients with AD, and 54 controls. They concluded that the apoE4 allele does not function as a risk factor which influences the development of AD lesions in PD.

Myers et al. (1996) examined the association of apolipoprotein E4 with Alzheimer disease and other dementias in 1,030 elderly individuals in the Framingham Study cohort. They found an increased risk for Alzheimer disease as well as other dementias in patients who were homozygous or heterozygous for E4. However, they pointed out that most apoE4 carriers do not develop dementia, and about one-half of Alzheimer disease is not associated with apoE4.

In aggregate, the association studies on apoE in Alzheimer disease suggest epsilon-4 accelerates the neurodegenerative process in Alzheimer disease. However, in 3 independent studies, Kurz et al. (1996), Growdon et al. (1996), and Asada et al. (1996) found no differences in the clinical rate of decline of newly diagnosed Alzheimer disease patients with or without the epsilon-4 allele.

Bickeboller et al. (1997) confirmed the increased risk for AD associated with the APOE4 allele in 417 patients compared with 1,030 control subjects. When compared to the APOE3 allele, the authors demonstrated an increased risk associated with the APOE4 allele (odds ratio = 2.7) and a protective effect of the APOE2 allele (odds ratio = 0.5). An effect of E4 allele dosage on susceptibility was confirmed: the odds ratio of E4/E4 versus E3/E3 = 11.2; odds ratio of E3/E4 versus E3/E3 = 2.2. In E3/E4 individuals, sex-specific lifetime risk estimates by age 85 years (i.e., sex-specific penetrances by age 85 years) were 0.14 for men and 0.17 for women. Houlden et al. (1998) found that the APOE genotype is only a risk factor for early-onset AD families with no lesion detectable in the presenilin or APP gene.

Meyer et al. (1998) presented data on an elderly population which suggested that apoE genotype influences the age-specific risk of Alzheimer disease but that, regardless of apoE genotype, more than half of the population will not develop AD by age 100. ApoE genotype did not appear to influence whether subjects will develop AD, but the study did confirm that the apoE4 alleles influence when susceptible individuals will develop AD. The findings could be explained by a gene or genes independent of apoE that condition vulnerability.

Wiebusch et al. (1999) conducted a case-control study of 135 pathologically confirmed AD cases and 70 non-AD controls (age of death greater than or equal to 60 years) in whom they genotyped for APOE epsilon-4 and BCHE-K (177400.0005). The allelic frequency of BCHE-K was 0.13 in controls and 0.23 in cases, giving a carrier odds ratio of 2.1 (95% confidence interval (CI) 1.1-4.1) for BCHE-K in confirmed AD. In an older subsample of 27 controls and 89 AD cases with ages of death greater than or equal to 75 years, the carrier odds ratio increased to 4.5 (95% CI 1.4-15) for BCHE-K. The BCHE-K association with AD became even more prominent in carriers of APOE epsilon-4. Only 3 of 19 controls compared with 39 of 81 cases carried both, giving an odds ratio of 5.0 (95% CI 1.3-19) for BCHE-K carriers within APOE epsilon-4 carriers. The authors concluded that the BCHE-K polymorphism is a susceptibility factor for AD and enhances the AD risk from APOE epsilon-4 in an age-dependent manner.

Myeloperoxidase (MPO; 606989) is a potent oxidant found in immune cells that has been detected in activated microglial macrophages and within amyloid plaques. Using statistical analysis, Reynolds et al. (2000) examined the relationship between APOE and MPO polymorphisms in the risk of AD in a genetically homogeneous Finnish population. They found that the presence of the MPO A allele in conjunction with APOE4 significantly increased the risk of AD in men, but not in women (odds ratio for men with both alleles = 11.4 vs APOE4 alone = 3.0). Reynolds et al. (2000) also found that estrogen receptor-alpha (133430) binds to the MPO A promoter, which may explain the gender differences.

Goldstein et al. (2001) genotyped 71 African American patients with presumed AD and found that each copy of the E4 allele was associated with a 3.6-year earlier onset of disease. The results fit a clear linear dose-response relationship, with mean age of onset being 77.9 years with no E4 alleles, 74.3 years with 1 allele, and 70.7 years with 2 alleles.

Mortensen and Hogh (2001) tested 139 subjects without dementia with the Wechsler Adult Intelligence Scale and several performance tests at the ages of 50, 60, 70, and 80 years and found that there was a significant association between APOE4 genotype and decline in performance tests in women between 70 and 80 years, but not in men. These findings corroborated previous findings of gender differences in the association of APOE genotype and risk of AD.

Multiple reports have linked APOE promoter polymorphisms to AD, both in association with and independent of APOE alleles, yielding overall conflicting results. Wang et al. (2000) analyzed 3 promoter polymorphisms in 237 patients and 274 controls and found a strong association between -491 AA genotype and AD, in both E4 and non-E4 carriers. They also confirmed the well-described association between APOE4 and AD. Wang et al. (2000) proposed a mechanistic model of disease in which the level of expression of APOE in addition to the specific isoform of APOE influences the deposition of beta-amyloid.

Ghebremedhin et al. (2001) examined 729 routine autopsy brains for the classic neuropathologic findings in AD, namely intracellular neurofibrillary tangles (NFT) and extracellular senile plaques (SP), to determine the effect of APOE genotype on the development of lesions. Presence of the APOE4 allele was significantly associated with both NFT and SP, but was differentially modified by age and gender: the effect of the E4 allele on NFT was noted at ages 80 and above, but not between ages 60 to 79, in both genders, whereas the association between the E4 allele and SP for women was found only between ages 60 to 79 years, but not above 80 years, with no age difference in men.

Bonay and Avila (2001) presented evidence that apoE, particularly apoE4, adds to neuroblastoma cells in culture and stimulates sulfate incorporation on cell and extracellular matrix glycosaminoglycans. They hypothesized that elevated levels of sulfated glycosaminoglycans could facilitate the assembly of beta-amyloid and tau proteins in the plaques and tangles of AD.

Lambert et al. (2001) measured amyloid-beta load immunohistochemically in regions 8 and 9 of Brodman's area in 74 people with Alzheimer disease. The amount of deposited amyloid-beta-40 was significantly increased in Alzheimer disease brain samples carrying at least one APOE4 allele, compared with samples that did not (p = 0.005). There was also an increase in amyloid-beta-40 load in individuals carrying the -491AA genotype independent of E4 status. On the basis of these findings, Lambert et al. (2001) suggested that the association between increased amyloid-beta load and alleles of the APOE promoter polymorphisms is independent of APOE genotype.

Zubenko et al. (2001) described a prospective, longitudinal, double-blind assessment of the age-specific risk of AD encountered by 325 asymptomatic first-degree relatives of AD probands who carried the D10S1423 234-bp allele (see 606187), the APOE4 allele, or both, after 11.5 years of systematic follow-up. They found that with the best-fitting model, only individuals who carried both risk alleles exhibited a risk ratio that differed significantly from 1. After controlling for these genotypes, female gender was also significantly associated with increased risk of developing AD.

Peskind et al. (2001) suggested that the effects of APOE genotype on the hypothalamic-pituitary-adrenal (HPA) axis may be involved in the pathobiology of AD. They examined APOE genotype and CSF cortisol levels in 64 subjects with Alzheimer disease and 34 controls and found that higher cortisol levels were associated with increased frequency of the E4 allele and decreased frequency of the E2 allele. They noted that previous animal studies had shown a correlation between glucocorticoid elevation and hippocampal dendritic atrophy and neuronal loss, and postulated that increased cortisol levels in patients with AD may lower the threshold for neuronal degeneration. Sass et al. (2001) requested that Peskind et al. (2001) provide specific information on the protocol they used for CSF cortisol measurement. Wilkinson et al. (2001) explicitly described the modifications they made to the commercial cortisol assay protocol used to detect the low concentrations of cortisol in the CSF in their study.

Scarmeas et al. (2002) followed 87 patients with early-stage AD for up to 10 years to determine whether APOE genotype was related to the incidence of psychiatric symptomatology. They found that the presence of 1 E4 allele conferred a 2.5-fold risk and the presence of 2 E4 alleles conferred a 5.6-fold risk for development of delusions. The associations were significant even after controlling for variables. No association was found for depressive symptoms or behavioral disturbances.

In a longitudinal study of 55 patients with Alzheimer disease, Mori et al. (2002) determined that the rate of hippocampal atrophy was significantly greater in those with an APOE4 allele, and that the rate became more severe as the number of E4 alleles increased. However, their data did not support the findings of previous studies that the E4 allele is associated with an increased rate of cognitive decline.

Dal Forno et al. (2002) genotyped 125 patients with Alzheimer disease for the APOE allele and followed the participants for 10 years. They found that the APOE4 allele was associated with shorter survival in men, but not in women.

Among 1,732 patients with Alzheimer disease, Lambert et al. (2002) found that the -491AA and -219TT APOE genotypes were associated with increased risk for Alzheimer disease (odds ratio for -491AA was 1.7 and for -219TT was 1.6), with age accentuating the effect of the -219TT genotype. The authors concluded that because these polymorphisms appear to influence ApoE levels, the results suggest that APOE expression is an important determinant of AD pathogenesis.

Using logistic and linear regression statistical analysis to examine clinical, pathologic, and genetic data from 128 older persons (51 with probable AD and 77 without dementia), Bennett et al. (2003) determined that the E4 allele was strongly associated with the likelihood of clinical AD (odds ratio = 3.46) and decreased level of cognitive function. However, controlling for the effect of AD pathology, including neuritic plaques and neurofibrillary tangles, attenuated the associations, rendering them no longer significant. Bennett et al. (2003) concluded that the E4 allele is associated with the clinical manifestations of AD through an association with the pathologic hallmarks of AD rather than via some other mechanism.

In a study of 966 Swedish patients 75 years of age or older, Qiu et al. (2003) found that 204 were diagnosed with AD during a 6-year period. Presence of the APOE4 allele, high systolic blood pressure (140 mm Hg or greater), and low diastolic blood pressure (less than 70 mm Hg) were each associated with an increased risk of AD. APOE4 allele combined with low diastolic pressure greatly increased the risk of AD independent of antihypertensive drug use. Antihypertensive medication significantly reduced the risk of AD regardless of APOE4 status and counteracted the combined risk effect of the APOE4 allele and high blood pressure on the disease.

Among 563 AD patients and 118 controls, Prince et al. (2004) found that presence of the APOE4 allele was strongly associated with reduced CSF levels of beta-amyloid-42 in both patients and controls. The findings suggested an involvement of ApoE in beta-amyloid metabolism.

In a postmortem analysis of 296 AD brains, including 149 with 1 E4 allele, 38 with 2 E4 alleles, and 109 non-E4 carriers, Tiraboschi et al. (2004) found that patients with 2 E4 alleles had significantly more neuritic plaques and neurofibrillary tangles in all neocortical regions compared to those with 1 or no E4 alleles. There were no significant differences in neocortical cholinergic activity, as measured by tissue CHAT (118490) activity, between those with and without the E4 allele. Patients with the E2 allele had significantly decreased numbers of neuritic plaques in all neocortical regions, consistent with a putative protective effect of the E2 allele in AD. Tiraboschi et al. (2004) suggested that a single E4 allele does not influence neuropathologic severity in AD.

Huang et al. (2004) reported that 203 of 907 Swedish individuals over the age of 75 years developed AD over a period of 6 years. Analysis of the APOE allele genotype showed that individuals with at least 2 affected first-degree relatives or sibs had a significantly increased risk of disease development only in the presence of the E4 allele.

Bray et al. (2004) applied highly quantitative measures of allele discrimination to cortical RNA from individuals heterozygous for the APOE E2, E3, and E4 alleles. A small, but significant, increase in the expression of E4 allele was observed relative to that of the E3 and E2 alleles (p less than 0.0001). Similar differences were observed in brain tissue from confirmed late-onset Alzheimer disease subjects, and between cortical regions BA10 (frontopolar) and BA20 (inferior temporal). Stratification of E4/E3 allelic expression ratios according to heterozygosity for the -219G-T promoter polymorphism (107741.0030) revealed significantly lower relative expression of haplotypes containing the -219T allele (p = 0.02). Bray et al. (2004) concluded that, in human brain, most of the cis-acting variance in APOE expression may be accounted for by the E4 haplotype, but there are additional small cis-acting influences associated with the promoter genotype.

Tsuang et al. (2005) found a higher frequency of the E4 allele among 74 patients with the Lewy body variant of AD (see 127750) compared to 57 patients with AD without Lewy bodies (47.3% vs 35.1%, respectively). The findings suggested an association between the E4 allele and the development of Lewy bodies.

In a study of 140 elderly Nigerian patients with dementia, of which 123 were diagnosed with AD, Gureje et al. (2006) found no association between the APOE4 allele and dementia or AD.

Among 184 healthy individual with normal cognition aged 21 to 88 years, Peskind et al. (2006) found that the concentration of CSF beta-amyloid-42, but not beta-amyloid-40, decreased with age. Those with an APOE4 allele showed a sharp and significant decline in CSF beta-A-42 beginning in the sixth decade compared to those without the APOE4 allele. The findings were consistent with APOE4-modulated acceleration of pathogenic beta-A-42 deposition starting in late middle age in persons with normal cognition, and suggested that early treatment for AD in susceptible individuals may be necessary in midlife or earlier.

Among 100 patients with AD, van der Flier et al. (2006) found an association between presence of the E4 allele and the typical amnestic phenotype, characterized by initial presentation of forgetfulness and difficulties with memory. Those with the memory phenotype were 3 times more likely to carry an E4 allele compared to AD patients who displayed a nonmemory phenotype, with initial complaints including problems with calculation, agnosia, and apraxia. The memory phenotype was almost exclusively observed in homozygous E4 carriers.

Borroni et al. (2007) also reported an association between the memory phenotype of AD and presence of the E4 allele. Among 319 late-onset AD patients, 77.6% of E4 allele carriers presented with the memory phenotype compared to 64.6% of noncarriers.

Among 51 patients with probable AD and 31 patients with frontotemporal dementia (FTD; 600274), Agosta et al. (2009) found that presence of the E4 allele was associated with greater brain atrophy on imaging studies. AD E4 allele carriers showed greater atrophy in the bilateral parietal cortex and right hippocampus, whereas FTD E4 allele carriers demonstrated greater atrophy in the bilateral medial, dorsolateral, and orbital frontal cortex, anterior insula, and cingulate cortex with right predominance. The regional effect was consistent with the hypothesis that APOE may affect morphologic expression uniquely in different neurodegenerative diseases, and that E4 carriers are at greater risk for clinical progression.

ApoE acts normally to scaffold the formation of high-density lipoprotein particles, which promote the proteolytic degradation of soluble forms of amyloid-beta. The expression of apoE is transcriptionally regulated by the ligand-activated nuclear receptors PPAR-gamma (601487) and liver X receptor (LXR; see 602423), which form obligate heterodimers with retinoid X receptors (RXRs). Transcriptional activity is regulated by ligation of either member of the pair. PPAR-gamma:RXR and LXR:RXR act in a feed-forward manner to induce the expression of apoE, its lipid transporters ABCA1 (600046) and ABCG1 (603076), and the nuclear receptors themselves. Agonists of these receptors also act on macrophages and microglia to stimulate their conversion into 'alternative' activation states and promote phagocytosis.

Theendakara et al. (2013) found that expression of APOE4, but not APOE3, caused a marked reduction in the ratio of the NAD-dependent deacetylase SIRT1 (604479), which is neuroprotective, relative to SIRT2 (604480), which is neurotoxic. The effect was observed in cultured mouse and human neural cells and in brains of patients with AD.

Reiman et al. (1996) found that in late middle age, cognitively normal subjects who were homozygous for the APOE4 allele had reduced glucose metabolism in the same regions of the brain as in patients with probable Alzheimer disease. These findings provided preclinical evidence that the presence of the APOE4 allele is a risk factor for Alzheimer disease. Positron-emission tomography (PET) was used in these studies; Reiman et al. (1996) suggested that PET may offer a relatively rapid way of testing treatments to prevent Alzheimer disease in the future.

Role in Alzheimer Disease 3

In a woman from the very large Colombian family with early-onset Alzheimer disease (AD3; 607822) caused by a glu280-to-ala mutation in the PSEN1 gene (E280A; 104311.0009) who carried that mutation but who did not develop mild cognitive impairment until her seventies, Arboleda-Velasquez et al. (2019) detected homozygosity for an arginine-to-serine substitution at amino acid 136 (R136S) on the APOE3 allele of APOE.

Role in Cognitive Decline with Aging

Blesa et al. (1996) found an apoE epsilon-4 frequency of 0.315 in patients with age-related memory decline without dementia, similar to the 0.293 allele frequency found in an Alzheimer disease group. This contrasted to the frequency of 0.057 found in their control group. Payami et al. (1997) reported the results of a prospective case-control study that enlisted 114 Caucasian subjects who were physically healthy and cognitively intact at age 75 years and who were followed, for an average of 4 years, with neurologic, psychometric, and neuroimaging examinations. Excellent health at entry did not protect against cognitive decline. Incidence of cognitive decline rose sharply with age. E4 and a family history of dementia (independent of E4) were associated with an earlier age at onset of dementia. Subjects who had E4 or a family history of dementia had a 9-fold-higher age-specific risk for dementia than did those who had neither. From these observations, Payami et al. (1997) suggested that the rate of cognitive decline increases with age and that APOE and other familial/genetic factors influence the onset age throughout life.

Yaffe et al. (2000) studied 2,716 women 65 years of age or older by cognitive testing on 2 or more visits. They analyzed change in score on the Modified Mini-Mental State Examination as a function of estrogen use, APOE genotype, and baseline common and internal carotid artery wall thickening. A total of 297 (11%) women were current estrogen users, and 336 (12%) were past estrogen users. Over the 6-year average follow-up, baseline current users declined 1.5 points, whereas women who had never used estrogen declined 2.7 points (P = 0.023). Compared with APOE4-negative women, APOE4-positive women had a greater adjusted hazard ratio of cognitive impairment. There was an interaction between estrogen use and APOE4 presence. Among APOE4-negative women, current estrogen use reduced the risk of adjusted cognitive impairment by almost half compared with the risk of those who had never used estrogen, whereas it did not reduce the risk among APOE4-positive women. Compared with never having used estrogen, current estrogen use was associated with less internal and common carotid wall thickening in APOE4-negative women but not in APOE4-positive women. Differences remained after adjusting for age, education, race, and stroke. Yaffe et al. (2000) concluded that estrogen use was associated with less cognitive decline among women who did not have the APOE4 allele but not among women who had at least one APOE4 allele.

Cohen et al. (2001) examined 25 healthy women with normal cognition above the age of 50 in a longitudinal 2-year study and found that a single APOE4 allele was associated with a significant decrease in hippocampal volume (mean 2.3% decrease per year), as measured by MRI, compared to the APOE4-negative group (mean 0.77% decrease per year). These results suggested that brain structural changes may be associated with the E4 genotype and that the changes may precede the development of cognitive deficits.

In a 6-year longitudinal study of 611 participants aged 65 years or older, Wilson et al. (2002) found that presence of the APOE E4 allele was associated with a more rapid decline in cognitive functions, particularly episodic memory, which is an early and defining clinical characteristic of AD. To identify the determinants of normal age-related cognitive change, Deary et al. (2002) genotyped 466 healthy subjects who had taken the Moray House Test (MHT) to measure cognitive ability in 1932 at age 11 and the Mini-Mental State Examination (MMSE) at age 80. Possession of the APOE4 allele was found to be unrelated to differences in mental ability in youth, but was significantly associated with decreased mental ability in old age and the change in ability score from youth.

In a cohort of 180 asymptomatic individuals with a mean age of 60 years, Caselli et al. (2004) found that carriers of an E4 allele showed greater declines in memory performance over a median period of 33 months compared to those without an E4 allele. Among 494 individuals with mild cognitive impairment, Farlow et al. (2004) found an association between the E4 allele and worse scores on cognition tests as well as smaller total hippocampal volume. Among 6,202 Caucasian middle-aged individuals (47 to 68 years), Blair et al. (2005) found that carriers of the E4 allele had greater cognitive decline over a 6-year period compared to those without an E4 allele. Results for 1,693 African American patients were inconclusive.

Among 136 patients with mild cognitive impairment, 35 of whom developed AD, Devanand et al. (2005) found no association between APOE4 carrier status and development of AD or further cognitive decline. After controlling for known demographic and clinical risk factors, E4 carrier status was associated with conversion to AD only in patients older than 70 years.

Using EEG to study 89 patients with mild cognitive impairment and 103 with AD, Babiloni et al. (2006) found that the amplitude of alpha sources in occipital, temporal, and limbic areas was lower in patients with the E4 allele compared to those not carrying the E4 allele.

Caselli et al. (2009) presented evidence that the APOE E4 allele affects age-related memory performance independently of mild cognitive impairment and dementia. A longitudinal study of 815 individuals, including 317 E4 carriers (79 homozygous subjects and 238 heterozygous subjects) and 498 E4 noncarriers, showed that carriers of the E4 allele had a decline in memory beginning in their fifties compared to noncarriers (p = 0.03). Noncarriers showed a decline in memory beginning in their seventies. The findings indicated that carriers of the E4 allele may have increased age-related memory decline and decreased visuospatial function.

In a prospective population-based study of 516 individuals aged 85 years from the Netherlands, van Vliet et al. (2009) found an association between high serum calcium and decreased cognitive function in APOE E3/E4 carriers and to a lesser extent in E3/E3 carriers, but not in E2/E3 carriers. The p value for interaction between APOE genotype and serum calcium levels corrected for confounders was 0.025; the p value for interaction between APOE genotype and serum calcium level in relation to global cognitive function over time was 0.011. The findings suggested that APOE genotype modulates an association between serum calcium and cognitive function in old age.

Possible Role in Multiple Sclerosis

Chapman et al. (2001) reported on 205 patients with multiple sclerosis (MS; 126200) and found that the APOE4 allele was associated with significantly faster progression of disability. The effect was significant after adjustment for sex and age of onset. Although the E4 allele was associated with slightly earlier disease onset, there was no support for the E4 allele being a risk factor for development of MS.

Noting that the APOE4 allele has been associated with earlier age of onset in AD, but not disease progression, and with faster disease progression in MS, but not age of onset, Chapman et al. (2001) suggested that these apparent effects are influenced by whether the diagnosis is made late in disease course (as in AD) or relatively early in disease course (as in MS). The authors hypothesized that the APOE4 genotype influences neuronal disease in general via alterations in the efficacy of neuronal maintenance and repair, and that the apparent effects of the genotype on these 2 parameters are related to the threshold at which the disease manifests itself clinically.

In MS, a reduction in concentration of N-acetylaspartate (NAA), which has been shown to be contained almost exclusively in mature neurons, reflects neuronal loss, axonal loss, and generalized neuronal dysfunction. Moreover, the degree of reduction of NAA has been correlated with disease severity and extent of tissue destruction. In 72 patients with relapsing-remitting MS, Enzinger et al. (2003) showed by proton magnetic resonance spectroscopy (MRS) that patients with the APOE4 allele had a higher degree of disability and a significantly lower NAA:creatine ratio than patients without the E4 allele. During follow-up in 44 patients, the drop in the NAA:creatine ratio of E4 carriers was significantly larger and was paralleled by a higher number of relapses and a faster disease progression. Enzinger et al. (2003) concluded that the findings indicated more extensive axonal damage associated with the APOE4 allele.

Kantarci et al. (2004) presented evidence suggesting that the APOE2 allele is associated with lesser disease severity in women with MS, as indicated by a longer time to reach an expanded disability status scale (EDSS) score of 6. In contrast, Zwemmer et al. (2004) reported no favorable role for the E2 allele in a study of 250 women with MS. In fact, they found a trend in the opposite direction: time to an EDSS score of 6 was shorter (6.8 years) in E2 carriers than in noncarriers (10.0 years). In addition, E2 carriers had a higher lesion load on MRI compared to noncarriers. In a response, Weinshenker and Kantarci (2004) noted that the study by Zwemmer et al. (2004) had a higher number of more severe primary progressive cases (22% of subjects) than that reported by Kantarci et al. (2004) (6.4% of subjects), which may explain the discrepancy.

Enzinger et al. (2004) noted that decreases in brain size and volume in patients with MS are related to neuroaxonal injury and loss, and are a useful surrogate marker of tissue damage and disease progression. In a study of 99 patients with MS, the authors found that patients who carried an E4 allele had more relapses during the study period and had a 5-fold higher rate of annual brain volume loss compared to patients without the E4 allele. Over time, E4 carriers also had an increase in individual lesions on MRI, termed 'black holes.' Among all genotype groups, the lowest annual loss of brain volume occurred in patients with an E2 allele. Among 76 patients with relapsing-remitting MS, de Stefano et al. (2004) found that carriers of the E4 allele showed significantly lower total brain volumes compared to MS patients without the E4 alleles. There was no difference in lesion volume between the 2 groups. The authors suggested that the E4 allele is linked to impaired mechanisms of cell repair and severe tissue destruction in MS.

Among 125 Greek MS patients, Koutsis et al. (2007) found that E4 carriers had a 6-fold increase in the relative risk of verbal learning deficits compared to noncarriers. The effect was specific and was not observed in other cognitive domains.

Among 1,006 Australian patients with relapsing-remitting MS or secondary progressive MS, van der Walt et al. (2009) found no association between APOE allele status or promoter region heterogeneity at positions -219G-T (rs405509; 107741.0030) or +113C-G (rs440446) and clinical disease severity, cognition, or cerebral atrophy.

Ghaffar et al. (2010) found no differences in 11 cognitive outcome variables, including attention, processing speed, verbal and visual memory, and executive functions in a comparison of 50 MS patients with the E4 allele and 50 MS patients without the E4 allele who were well-matched regarding education and disease course and duration. The presence of cognitive impairment overall was 41%.

Role in Recovery From Traumatic Brain Injury

Among 89 patients with head injury, Teasdale et al. (1997) found that patients with the E4 allele (107741.0016) were more likely than those without the E4 allele to have an unfavorable outcome 6 months after head injury. The authors discussed the role of the apoE protein in response to acute brain injury. In a prospective study of 69 patients with severe blunt trauma to the head, Friedman et al. (1999) found an odds ratio of 5.69 for more than 7 days of unconsciousness and 13.93 for a suboptimal neurologic outcome at 6 months for individuals with an APOE4 allele compared to those without that allele.

In 110 patients with traumatic brain injury (TBI), Crawford et al. (2002) tested memory and other cognitive variables and found that patients with the APOE4 allele had more difficulty with memory than matched patients without the E4 allele. In those with the E4 allele, performance was poor regardless of severity of injury, whereas in those without the E4 allele, performance worsened with more severe injury. Crawford et al. (2002) noted that TBI may result in greater damage to the medial temporal lobe structures involved in memory and suggested a role for the APOE protein in neuronal repair.

In 87 patients with mild to moderate TBI, Liberman et al. (2002) used neuropsychologic testing to examine whether the APOE4 genotype affected short-term recovery. At 6 weeks, E4-positive patients had lower mean scores on 11 of 13 tests, but the differences from the E4-negative group were smaller than the differences observed at 3 weeks. Although Liberman et al. (2002) stated that the findings are consistent with delayed recovery among E4-positive TBI patients, perhaps due to interactions with beta-amyloid, they cautioned against the generalizability of the results.

Among 60 patients with TBI with a mean follow-up of 31 years, Koponen et al. (2004) found that presence of the E4 allele increased the risk for dementia, but there was no association between the E4 allele and development of other psychiatric illnesses, including depression, anxiety, psychosis, or personality disorders.

Possible Role in Other Neurologic Disorders

Saunders et al. (1993) found no association of E4 with other amyloid-forming diseases, i.e., Creutzfeldt-Jakob disease (CJD; 123400), familial amyloidotic polyneuropathy, and Down syndrome (190685). On the other hand, Amouyel et al. (1994) concluded that E4 is a major susceptibility factor for CJD. They found a relative risk of CJD between subjects with at least one E4 allele and subjects with none to range between 1.8 and 4.2, depending on the control group used. A variation in disease duration was also noted, depending on apoE genotype, with an increase in duration of illness in E2 allele carriers.

Frisoni et al. (1994) assessed the apoE allele frequency in 51 elderly control subjects, 23 subjects with vascular dementia, and 93 patients with Alzheimer disease. There was increased frequency of the E4 allele both in Alzheimer disease and in vascular dementia with respect to both elderly and young control subjects. There was no difference in the proportion of E2, E3, and E4 frequency in Alzheimer disease and vascular dementia patients. Slooter et al. (1996) compared E4 allele frequency between 185 patients with Alzheimer disease and those with other types of dementia. The authors found little predictive value in distinguishing Alzheimer patients from those with other forms of dementia using APOE genotyping. In contrast, Mahieux et al. (1994) found an increase of E4 in Alzheimer disease, but not in vascular dementia. They speculated that the difference between their results and those of Frisoni et al. (1994) may be attributable to the small size of the groups or to the different mean ages of the populations that they studied.

McCarron et al. (1999) performed a metaanalysis that demonstrated a significantly higher frequency of E4 carriers in individuals with ischemic cerebrovascular disease than in control subjects (odds ratio, 1.73).

Tabaton et al. (1995) found that although apolipoprotein E immunoreactivity was associated with neurofibrillary tangles in an autopsy study of 12 patients with progressive supranuclear palsy (601104), the apolipoprotein E allele frequency was similar to that of age-matched controls. Farrer et al. (1995) demonstrated that the number of epsilon-4 alleles was inversely related to the age at onset of Pick disease (172700). Their results suggested that epsilon-4 may be a susceptibility factor for dementia and not specifically for AD.

Mui et al. (1995) found no association between apolipoprotein E4 and the incidence or the age of onset of sporadic or autosomal dominant amyotrophic lateral sclerosis (105400). Garlepp et al. (1995) found an increased frequency of the epsilon 4 allele in patients with inclusion body myositis (147421) compared with that in patients with other inflammatory muscle diseases or that in the general population.

In a study of apoE genotypes in schizophrenic patients coming to autopsy, Harrington et al. (1995) found that schizophrenia is associated with an increased E4 allele frequency. The E4 allele frequency in schizophrenia was indistinguishable from that found in either Alzheimer disease or Lewy body dementia (127750). From the age range at autopsy (from 19 to 95 years), they determined that the epsilon-4 frequency was not associated with increased age.

Betard et al. (1994) analyzed allele frequencies of apoE in 166 autopsied French-Canadian patients with dementia. The E4 frequency was highest in Lewy body dementia (0.472); presenile Alzheimer disease (0.405); senile Alzheimer disease (0.364); and Alzheimer disease with cerebrovascular disease (0.513). In contrast, the E4 allele frequency was 0.079 in autopsied cases of individuals with vascular dementia but no changes of Alzheimer disease. Subjects with vascular dementia demonstrated an increased relative E2 allele frequency of 0.211 compared to 0.144 in elderly controls. In contradistinction to the findings of Betard et al. (1994), Lippa et al. (1995) found much lower frequency of E4, 0.22, when they were careful to exclude Lewy body patients that had concurrent Alzheimer disease by the Cerat criterion. They did, however, find that a neuritic degeneration in CA2-3 was slightly greater in those Lewy body disease patients with the apoE4 allele than those with the E3/3 genotype. Hyman et al. (1995) found that senile plaques in the Alzheimer disease of Down syndrome were abnormally large, whereas those of APOE4-related Alzheimer disease were unusually numerous. The findings suggested that the pathology in Down syndrome is due to increased amyloid production and deposition, whereas that in APOE4, disease is related to an increased probability of senile plaque initiation. Royston et al. (1994) assessed the apoE genotype in elderly Down syndrome patients and found that the epsilon-2 variant was associated both with increased longevity and a significantly decreased frequency of Alzheimer-type dementia. They noted that none of their elderly Down patients was homozygous for the epsilon-4 allele.

In a case-control study of apoE genotypes in Alzheimer disease associated with Down syndrome, van Gool et al. (1995) showed that the frequencies of apoE type 2, 3, or 4 were not significantly different in Down syndrome cases with Alzheimer disease compared with aged-matched Down syndrome controls. The apoE4 frequency in Down syndrome cases with Alzheimer disease was significantly lower than in any other Alzheimer disease populations studied thus far, suggesting that apoE4 does not significantly affect the pathogenesis of Alzheimer disease in Down syndrome patients.

Kehoe et al. (1999) showed that the APOE epsilon-2/epsilon-3 genotype is associated with significantly earlier age of onset of Huntington disease (143100) in males than in females. This sex difference was not apparent for any other APOE genotypes.

Greenberg et al. (1995) found that the presence of apolipoprotein E4 significantly increased the odds ratio for moderate or severe cerebral amyloid angiopathy (CAA; see 605714), even after controlling for the presence of Alzheimer disease. Yamada et al. (1996) reported a lack of association between the E4 allele and CAA in elderly Japanese patients. Nicoll et al. (1996, 1997) did not find an association between the E4 allele and CAA-related hemorrhage. However, they did find a high frequency of the E2 allele in patients with CAA-related hemorrhage, regardless of the presence of AD. The authors suggested that patients with the E2 allele may be protected from parenchymal AD but may be susceptible to the rupture of amyloid-laden vessels.

In a postmortem study, Greenberg et al. (1998) found an association between apolipoprotein E2 and vasculopathy in cerebral amyloid angiopathy. Of 75 brains with complete amyloid replacement of vessel walls, only 23 had accompanying signs of hemorrhage in cracks of the vessel wall. The frequency of apolipoprotein E2 was significantly higher in the group with vasculopathy. The authors suggested that apolipoprotein E2 and E4 might promote hemorrhage through separate mechanisms: E4 by enhancing amyloid deposition and E2 by promoting rupture.

O'Donnell et al. (2000) identified a specific apolipoprotein E genotype as a risk factor for early recurrence of cerebral amyloid angiopathy: carriers of the E2 (107741.0001) or E4 (107741.0016) allele had an increased risk for early recurrence compared to individuals with the E3/E3 (107741.0015) genotype.

Fetal iodine deficiency disorder (FIDD; 228355) is the principal form of endemic cretinism, and the most common cause of preventable mental deficiency in the world. Not everyone at risk develops FIDD and familial aggregation is common, suggesting that genetic factors may be involved. The APOE gene encodes a lipoprotein that possesses a thyroid hormone-binding domain, and the APOE genotype might affect the efficiency with which thyroid hormone influences neuronal cell growth during the first and second trimesters of fetal development. For this reason, Wang et al. (2000) compared APOE genotypes in 91 FIDD cases with those of 154 local control subjects, recruited from 3 iodine deficiency areas in central China. They also genotyped 42 FIDD family cases and 158 normal individuals from the families of local controls, and 375 population controls from Shanghai. APOE4 genotypes were significantly enriched in FIDD probands from each of the 3 iodine deficiency areas; the E4 allele frequency was 16% versus 6% in controls. They suggested that this phenomenon may affect population selection and contribute to the low frequency of the APOE4 allele in Chinese compared with Caucasian populations.

Using nocturnal polysomnography in a study of 791 middle-aged adults, Kadotani et al. (2001) found that the probability of moderate to severe sleep-disordered breathing (apnea/hypopnea) was significantly higher in persons with apoE4, independent of age, sex, body mass index, and ethnicity. See sleep apnea (107650).

In a study of 1,775 individuals, Gottlieb et al. (2004) found an age-dependent association between the E4 allele and obstructive sleep apnea. E4 carriers younger than 65 years had an odds ratio of 3.08 for sleep apnea, whereas E4 carriers 65 years of age or older had an odds ratio of 1.25. The association was stronger in those with hypertension or cardiovascular disease.

Among 18 older adult APOE4 carriers with obstructive sleep apnea, O'Hara et al. (2005) found an association between greater numbers of respiratory events and lower memory performance. No association was found in 18 older adult noncarriers with sleep apnea. The authors suggested that sleep apnea may partly account for the association of the E4 allele and cognitive decline in community-dwelling older adults and postulated that hypoxia may have a role in neuronal vulnerability to oxidative stress.

In a study of 79 patients with Parkinson disease, 22 of whom were demented, Marder et al. (1994) found that the E4 allele frequency was 0.13 in patients without dementia and 0.068 in those with dementia as opposed to a control value of 0.102. The authors concluded that the biologic basis for dementia in Parkinson disease differs from that of Alzheimer disease.

Zareparsi et al. (2002) examined the effect of the APOE genotypes on age at onset of Parkinson disease using a population of 521 unrelated Caucasian patients with idiopathic Parkinson disease from movement disorder clinics in Oregon and Washington. They found that age at onset was significantly earlier in E3E4/E4E4 patients (mean onset 56.1 years) than in E3E3 patients (mean onset 59.6 years) (p = 0.003). This earlier onset was not influenced by effects of recruitment site, family history, or gender on onset of Parkinson disease.

Li et al. (2004) presented evidence suggesting that the E4 allele increases disease risk for familial PD and is associated with earlier age at disease onset independent of cognitive impairment; however, the effect was not as strong as that observed in AD. In a review and metaanalysis of 22 studies, Huang et al. (2004) concluded that the E2 allele, but not the E4 allele, was positively associated with sporadic Parkinson disease.

Frikke-Schmidt et al. (2001) genotyped over 9,000 individuals and found no association between APOE genotype and ischemic cerebrovascular disease, defined as the sudden onset of focal neurologic symptoms. However, they did find an association between the genotype E4E3 and 'other dementia,' which included vascular dementia, alcohol-induced dementia, and unclassifiable dementia. They confirmed the findings of previous studies that APOE genotypes E4E3 and E4E4 are significant risk factors for AD. The increases in all dementia risks were independent of plasma lipid and lipoprotein levels.

Broderick et al. (2001) examined data from a tissue plasminogen activator (t-PA; 173370) trial and concluded that the efficacy of intravenous t-PA in patients with acute ischemic stroke, as measured by favorable outcome at 3 months, may be enhanced in those with an APOE E2 phenotype.

Verpillat et al. (2002) determined the APOE genotype frequencies in 94 unrelated patients with frontotemporal dementia (600274) and 392 age- and sex-matched controls without cognitive deficits or behavioral disturbances (after excluding 6 patients with autosomal dominant inheritance and mutation in the MAPT gene). Homozygosity for the E2E2 genotype was significantly associated with frontotemporal dementia (odds ratio = 11.3, P = 0.033, exact test) but was based on very few subjects (3 patients and 1 control). The result was even more significant in the group with a positive familial history (odds ratio = 23.8, P = 0.019, exact test). For the metaanalysis of the APOE polymorphism in frontotemporal dementia, Verpillat et al. (2002) pooled 10 case-control studies with available genotype or allele information (total of 364 patients and 2,671 controls), but the E2E2 genotype did not reach statistical significance. Because of heterogeneity, Verpillat et al. (2002) analyzed on one hand the neuropathologically-confirmed studies, and on the other hand the clinical-based studies. A significant increase in the E2 allele frequency was found in the neuropathologically-confirmed patients, and heterogeneity disappeared (Mantel-Haenszel statistics). The authors concluded that the APOE E2 allele may be a risk factor for frontotemporal dementia, but that the data should be interpreted with caution due to the rarity of the E2E2 genotype.

Matsumoto et al. (2003) provided evidence suggesting that patients with primary dystonia who have the APOE4 genotype have an earlier age at disease onset than APOE4 noncarriers with dystonia, which they suggested was caused in part by a defect in neuronal repair in those with the APOE4 allele.

In a large population-based study of 9,294 French individuals, Dufouil et al. (2005) found a decreased risk for the development of non-AD dementia among those who used lipid lowering agents and maintained normal lipid levels. The odds for non-AD dementia were increased in subjects with hyperlipidemia. The findings were not modified by APOE genotype.

Among 32 patients with a clinical diagnosis of frontotemporal dementia, including 15 patient with primary progressive aphasia, Acciarri et al. (2006) found increased frequency of the E2 and E4 alleles and significantly decreased frequency of the E3 allele compared to 87 control individuals. The E2E4 genotype in particular was significantly associated with primary progressive aphasia.

Among 87 patients with medically intractable temporal lobe epilepsy necessitating temporal lobectomy, Busch et al. (2007) found that the presence of the E4 allele was associated with significantly reduced verbal and nonverbal memory in those with a long duration of epilepsy (greater than 22 years), particularly in those with an earlier age at onset. Busch et al. (2007) suggested that medically refractory seizures are similar to traumatic brain injury and that neuronal recovery after seizures may be impaired by the presence of the E4 allele. Surgery had no significant effects on the results.

In a metaanalysis including 8 published studies comprising 696 patients with subarachnoid hemorrhage, Lanterna et al. (2007) found that patients with the E4 allele had approximately 2-fold increased risk of negative outcome and delayed ischemia compared to those without the allele.

Gozal et al. (2007) found that the E4 allele was more common in nonobese children with obstructive sleep apnea (107650) compared to controls, and particularly in those who developed neurocognitive deficits.

In a metaanalysis of 1,500 cases of schizophrenia versus 2,702 controls, Allen et al. (2008) found that the odds ratio for the APOE4 versus the APOE3 genotype was 1.16 (95% CI, 1.00-1.34; p = 0.043).

Silva et al. (2013) studied a total of 44 unrelated FMR1 premutation (309550.0004) carriers, 22 with fragile X-associated tremor/ataxia syndrome (FXTAS; 300623) and 22 without, and genotyped them for the ApoE locus. All ApoE4 homozygous genotype carriers detected and 6 of the 7 ApoE4/3 genotype carriers (85.7%) were patients presenting with FXTAS, whereas only 40% of the ApoE3/3 genotype carriers belonged to the FXTAS group. These results showed that the presence of the ApoE4 allele increases the risk of developing FXTAS (OR = 12.041; p = 0.034). Silva et al. (2013) concluded that the presence of at least 1 ApoE4 allele acts as a genetic factor predisposing individuals to develop FXTAS.

Possible Role in Ocular Disorders

Primary open-angle glaucoma (POAG; 137760) is an optic neuropathy that has a high worldwide prevalence and that shows strong evidence of complex inheritance. The myocilin gene (MYOC; 601652) has been shown to have mutations in patients with POAG. Apolipoprotein E plays an essential role in lipid metabolism, and the APOE gene has been involved in the neuronal degeneration that occurs in Alzheimer disease. Copin et al. (2002) reported that 2 APOE-promoter single nucleotide polymorphisms (SNPs) previously associated with Alzheimer disease also modified the POAG phenotype. APOE(-219G) is associated with increased optic nerve damage, as reflected by increased cup:disc ratio and visual field alteration. In addition, APOE(-491T), interacting at a highly significant level with a SNP in the MYOC promoter, MYOC(-1000G), is associated with increased intraocular pressure (IOP) and with limited effectiveness of IOP-lowering treatments in patients with POAG. Together, these findings establish APOE as a potent modifier for POAG, which could explain the linkage to chromosome 19q previously observed by use of a genome scan for this condition (Wiggs et al., 2000) and an increased frequency of glaucoma in patients with Alzheimer disease (Bayer et al., 2002). The findings also shed new light on potential mechanisms of optic nerve damage and of IOP regulation in POAG. Bunce et al. (2003) criticized the statistical approach used by Copin et al. (2002) and concluded that without supportive clinical data, evidence is lacking that APOE SNPs either are associated with a more severe phenotype or interact at a highly significant level with a SNP in the MYOC promoter.

Zetterberg et al. (2007) studied the association of AD-associated APOE polymorphisms in 242 patients with POAG and 187 controls. They found no differences between patients and controls with regard to APOE genotypes.

Because clinical studies had shown an association between glaucoma and AD (Bayer et al., 2002), which is also a complex trait, Ressiniotis et al. (2004) examined DNA from 137 unrelated patients with POAG and 75 control subjects. In this cohort, APOE genotype did not constitute a risk factor for developing POAG, even in patients with normal tension glaucoma. The authors concluded that APOE polymorphisms did not appear to be contributory to POAG.

The inheritance of specific ApoE alleles is linked to the incidence of age-related macular degeneration (ARMD; see 603075). ApoE appears to be a ubiquitous component of drusen, which are the hallmark of ARMD irrespective of clinical phenotype. Anderson et al. (2001) found ApoE located at the same anatomic locus at which drusen are situated and suggested that the retinal pigment epithelium is the most likely local biosynthetic source of ApoE at that site. They concluded that age-related alteration of lipoprotein biosynthesis and/or processing at the level of the retinal pigment epithelium and/or Bruch membrane might be a significant contributing factor in drusen formation and ARMD pathogenesis.

Schultz et al. (2003) found no evidence to support an association between ARMD in medium to large families and the E4 or E2 alleles of ApoE. They also found no evidence for an association of ApoE polymorphisms in a set of unrelated patients with ARMD. They did, however, find a trend for a decreased risk of ARMD associated with ApoE4 in a set of unrelated patients with a family history of ARMD.

Baird et al. (2006) studied progression of ARMD in a cohort of 238 individuals from a single center. Individuals with an E2 genotype (526C-T; 107741.0001) of the APOE gene showed a strong association with disease with a significant 4.8-fold increased relative risk compared to individuals with an E4 genotype (388T-C; 107741.0016) (odds ratio, 4.8) and a nearly significant 3-fold increased relative risk compared to individuals with an E3 (107741.0015) genotype. This finding was present only in females who progressed with ARMD, which suggested that there may be a gender-specific role in progression of ARMD in individuals with an E2 allele.

Bojanowski et al. (2006) investigated the association between apoE2 (158C), apoE3, and apoE4 (112R) variants and ARMD in 133 clinically screened controls, 94 volunteers with a younger mean age, 120 patients with advanced ARMD, and 40 archived ocular ARMD slides. They also tested the effects of recombinant apoE variants on the expression of a chemokine (CCL2; 158105), a chemokine receptor (CX3CR1; 601470), and a cytokine (VEGF; 192240) in cultured human retinal pigment epithelial (RPE) cells and analyzed the serum cholesterol profiles of the clinically screened subjects. The apoE4 distribution differed significantly between ARMD patients and controls. The arg112 allele frequency was 10.9% in the ARMD group when compared with 16.5% in the younger controls and 18.8% in the clinically screened controls. The pathologically diagnosed archived ARMD cases had the lowest allele frequency of 5%. No significant differences in apoE2 distribution were observed among the groups. A metaanalysis of 8 cohorts, including 4,289 subjects, showed a strong association between ARMD and 112R, but not 158C. In vitro studies found that recombinant apoE suppressed CCL2 and VEGF expression in RPE cells. However, the E4 isoform showed more suppression than E3 in both cases. Bojanowski et al. (2006) concluded that these results further confirm the association between apoE4 and a decreased risk of ARMD development. They suggested that the underlying mechanisms may involve differential regulation of both CCL2 and VEGF by the apoE isoforms.

Possible Role in Other Disorders

Infante-Rivard et al. (2003) studied the transmission of the 3 APOE alleles from heterozygous parents to newborns with intrauterine growth restriction (IUGR), defined as birth weight below the 10th centile for gestational age and sex, based on Canadian standards. They found a significantly reduced transmission of the E2 allele. The E2 allele had been associated with a lower risk of cardiovascular disease and babies born with growth restriction had been reported to be at higher risk for such disease later in life; the data seemed to reconcile these 2 observations.

To investigate the association of APOE and TGFB1 (190180) with obesity, Long et al. (2003) analyzed several SNPs of each gene in 1,873 subjects from 405 white families to test for linkage or association with 4 obesity phenotypes including BMI, fat mass, percentage fat mass (PFM), and lean mass, with the latter 3 being measured by dual energy x-ray absorptiometry. A significant linkage disequilibrium (p less than 0.01) was observed between pairs of SNPs within each gene except for SNP5 and SNP6 in TGFB1 (p greater than 0.01). Within-family association was observed in the APOE gene for SNP1 and PFM (p = 0.001) and for the CGTC haplotype with both fat mass (p = 0.012) and PFM (p = 0.006). For the TGFB1 gene, within-family association was found between lean mass and SNP5 (p = 0.003), haplotype C+C (p = 0.12), and haplotype T+C (p = 0.012). Long et al. (2003) concluded that the large study size, analytical method, and inclusion of the lean mass phenotype improved the power of their study and explained discrepancies in previous studies, and that both APOE and TGFB1 are associated with obesity phenotypes in their population.

In a review of genetic determinants of human longevity, Christensen et al. (2006) pointed out that polymorphism in the APOE gene has consistently been found to be associated with survival and longevity (Gerdes et al., 2000).

Price et al. (2006) noted that hepatitis C virus (HCV; see 609532) RNA is associated with low and very low density lipoproteins, and that HCV uptake through LDLR into hepatocyte cell lines can be blocked by anti-APOB and anti-APOE. They evaluated APOE genotypes in 420 northern Europeans with evidence of HCV exposure. Both APOE2 and APOE4 alleles were associated with reduced likelihood of chronic infection, and no APOE2 homozygotes were HCV seropositive. Price et al. (2006) concluded that APOE2 and APOE4 alleles favor HCV clearance.

Burt et al. (2008) examined a large cohort of human immunodeficiency virus (HIV; see 609423)-positive European and African American subjects and found that those homozygous for APOE4 had an accelerated disease course and progression to death compared with those homozygous for APOE3. The increased risk was independent of CD4 (186940)-positive T-cell count, delayed-type hypersensitivity reactivity, and CCL3L1 (601395)-CCR5 (601373) type. APOE4 alleles showed a weak association with higher viral load. No association was observed with APOE4 homozygosity and HIV-associated dementia or with an increased risk of acquiring HIV infection. Expression of recombinant APOE4 or APOE3 in HeLa cells also expressing CD4 and CCR5 revealed that the presence of APOE4 enhanced HIV fusion/cell entry of both R5 (macrophage-tropic) and X4 (T lymphocyte-tropic) HIV strains in vitro. Burt et al. (2008) concluded that APOE4 is a determinant of AIDS pathogenesis.

▼ Animal Model

Because apolipoprotein E is a ligand for receptors that clear remnants of chylomicrons and very low density lipoproteins, lack of apoE would be expected to cause accumulation in plasma of cholesterol-rich remnants whose prolonged circulation should be atherogenic. Zhang et al. (1992) demonstrated that this was indeed the case: apoE-deficient mice generated by gene targeting (Piedrahita et al., 1992) had 5 times normal plasma cholesterol and developed foam cell-rich depositions in their proximal aortas by age 3 months. These spontaneous lesions progressed and caused severe occlusion of the coronary artery ostium by 8 months. Plump et al. (1992) independently found the same in apoE-deficient mice created by homologous recombination in ES cells. The findings in the mouse model are comparable to those in 3 human kindreds with inherited apoE deficiency (Ghiselli et al., 1981; Mabuchi et al., 1989; Kurosaka et al., 1991). Commenting on the articles of Plump et al. (1992) and Zhang et al. (1992), Brown and Goldstein (1992) pointed out that molecular genetics has given us the opportunity to satisfy Koch's postulates for multifactorial metabolic diseases. Further use of the apoE gene-targeted mice was made by Linton et al. (1995), who showed that the severe hyperlipidemia and atherosclerosis in these mice could be prevented by bone marrow transplantation. Although the majority of apoE in plasma is of hepatic origin, the protein is synthesized by a variety of cell types, including macrophages. Because macrophages derive from hematopoietic cells, bone marrow transplantation seemed a possible therapeutic approach. ApoE-deficient mice given transplants of normal bone marrow showed apoE in the serum and a normalization of serum cholesterol levels. Furthermore, they showed virtually complete protection from diet-induced atherosclerosis.

To unravel the metabolic relationship between apoE and apoC1 in vivo, van Ree et al. (1995) generated mice deficient in both apolipoproteins. This enabled subsequent production of transgenic mice with variable ratios of normal and mutant apoE and apoC1 on a null background. They found that double inactivation of the ApoE and ApoC1 (107710) loci in mice, as well as single inactivations at either one of these loci, also affected the levels of RNA expression of other members of the Apoe-c1-c2 cluster. Homozygous Apoe-c1 knockout mice were hypercholesterolemic and, with serum cholesterol levels more than 4 times the control value, resembled mice solely deficient in apoE.

Kashyap et al. (1995) noted that apolipoprotein E-deficient mice, generated using homologous recombination for targeted gene disruption in embryonic stem cells, developed marked hyperlipidemia as well as atherosclerosis. Kashyap et al. (1995) found that intravenous infusion of a recombinant adenovirus containing the human APOE gene resulted in normalization of the lipid and lipoprotein profile with markedly decreased total cholesterol, VLDL, IDL, and LDL, as well as increased HDL. A marked reduction in the extent of aortic atherosclerosis was observed after one month.

Plump et al. (1992) and Zhang et al. (1992) created apoE-deficient mice by gene targeting in embryonic stem cells. These mice displayed severe hypercholesterolemia even on a low-fat, low cholesterol diet. A key regulator of cholesterol-rich lipoprotein metabolism, apoE, is synthesized by numerous extrahepatic tissues. It is synthesized, for example, in macrophages. To assess the contribution of macrophage-derived apoE to hepatic clearance of serum cholesterol, Boisvert et al. (1995) performed bone marrow transplantation on hypercholesterolemic apoE-deficient 'knockout' mice. Serum cholesterol levels dropped dramatically in the bone marrow-treated mice largely due to a reduction in VLDL cholesterol. The extent of atherosclerosis in the treated mice was also greatly reduced. Wildtype apoE mRNA was detected in the liver, spleen, and brain of the treated mice indicating that gene transfer was successfully achieved through bone marrow transplantation. Masliah et al. (1995) observed an age-dependent loss of synaptophysin-immunoreactive nerve terminals and microtubule-associated protein 2-immunoreactive dendrites in the neocortex and hippocampus of apoE-deficient (knockout) mice. They suggested that apoE may play a role in maintaining the stability of the synapto-dendritic apparatus.

Sullivan et al. (1997) found that when the mouse apolipoprotein E gene was replaced by the human APOE3 gene in transgenic mice, diet-induced hypercholesterolemia and atherosclerosis were considerably enhanced.

To assess the effects of human APOE isoforms on deposition of amyloid-beta protein in vivo, Holtzman et al. (1999) bred apoE3 and apoE4 hemizygous (+/-) transgenic mice expressing human APOE by astrocytes to mice homozygous (+/+) for a mutant amyloid precursor protein, V717F (104760.0003), transgene that developed age-dependent Alzheimer disease neuropathology. All mice had a mouse apoE null (-/-) background. By 9 months of age, the mice heterozygous for the human V717F mutant had developed deposition of amyloid-beta protein, but the quantity of amyloid-beta deposits was significantly less than that seen in heterozygous mice expressing mouse apoE. In contrast to effects of mouse apoE, similar levels of human apoE3 and apoE4 markedly suppressed early amyloid-beta deposition at 9 months of age in the V717F heterozygous transgenic mice, even when compared with mice lacking apoE. These findings suggested that human APOE isoforms decrease amyloid-beta aggregation or increase amyloid-beta clearance relative to an environment in which mouse apoE or no apoE is present.

To determine the effect of APOE on deposition of amyloid-beta and Alzheimer disease pathology, Holtzman et al. (2000) compared APP(V717F) transgenic mice expressing mouse, human, or no APOE. A severe, plaque-associated neuritic dystrophy developed in the transgenic mice expressing mouse or human APOE. Although significant levels of amyloid-beta deposition also occurred in APP(V717F) transgenics that completely lacked APOE, neuritic degeneration was virtually absent. Expression of APOE3 and APOE4 in APP(V717F) transgenics who had knockout of APOE resulted in fibrillar amyloid-beta deposits and neuritic plaques by 15 months of age, and more than 10-fold more fibrillar deposits were observed in APOE4-expressing APP(V717F) transgenic mice. The data demonstrated a critical and isoform-specific role for APOE in neuritic plaque formation, a pathologic hallmark of Alzheimer disease.

Raber et al. (2000) tested the spatial memory of transgenic mice carrying human forms of amyloid precursor protein and either apoE3 or apoE4 and found that it was impaired in mice with apoE4 but not in those with apoE3, even though the levels of beta-amyloid in their brains were comparable. As no plaques were detectable in APP and APP/apoE mice at 6 months of age, Raber et al. (2000) concluded that the differential effects of apoE isoforms on human amyloid precursor protein/amyloid beta-induced cognitive impairments are independent of plaque formation. Learning deficits were more significant in female than in male mice. These sex-dependent differences may relate to the increased susceptibility of women to APOE4-associated cognitive deficits.

Mitchell et al. (2000) investigated the therapeutic efficacy of liver repopulation in ApoE knockout mice. Knockout mice were transplanted with Fas/CD95-resistant hepatocytes, which constitutively express ApoE, and were subsequently submitted to weekly injections of nonlethal doses of the Fas agonist antibody Jo2. After 8 weeks of treatment, mice exhibited up to 30% of the normal level of plasma ApoE. ApoE secretion was accompanied by a drastic and significant decrease in total plasma cholesterol and a markedly reduced progression of atherosclerosis.

Mice homozygous for human APOE2 (107741.0001), regardless of age or gender, develop type III hyperlipoproteinemia (HLP; 606945.0001), whereas homozygosity for APOE2 results in HLP in no more than 10% of humans, predominantly in adult males. By generating mice homozygous for human APOE2 and heterozygous for human LDLR and mouse Ldlr, Knouff et al. (2001) detected increased stability of mRNA in liver associated with a truncation of the 3-prime-UTR of LDLR. Plasma lipoprotein levels were normal in the LDLR heterozygotes. Knouff et al. (2001) concluded that moderate and controlled overexpression of the LDLR completely ameliorates the type III HLP phenotype of APOE2 homozygous mice.

Tangirala et al. (2001) determined that human APOE3 expressed in Ldlr-null mice accumulated in artery walls. Expression induced significant regression of advanced pre-existing atherosclerotic lesions. Regression of lesions was accompanied by the loss of macrophage-derived foam cells and a trend toward increased extracellular matrix of lesions, but there was no change in plasma total cholesterol levels or lipoprotein composition. APOE also had antioxidant properties as measured by reduced levels of isoprostanes in urine, LDLs, and artery walls.

Lesuisse et al. (2001) investigated whether increased expression of apoE can, in a dominant fashion, influence amyloid deposition. They expressed human apoE4 via the mouse prion protein promoter, resulting in high expression in both astrocytes and neurons; only astrocytes efficiently secreted human apoE4 (at least 5-fold more than endogenous). Mice hyperexpressing human apoE4 developed normally and lived normal life spans. The coexpression of human apoE4 with a mutant APP or mutant APP and mutant presenilin did not lead to proportional changes in the age of appearance, relative burden, character, or distribution of amyloid-beta deposits. The authors concluded that the mechanisms by which apoE influences amyloid-beta deposition may involve an aspect of its normal function that is not augmented by hyperexpression.

Yamauchi et al. (2003) crossed ApoE-deficient mice with mice carrying a transgene for the globular domain of adiponectin (605441). When expressed on the ApoE-deficient background, the globular domain of adiponectin reduced the atherosclerotic lesions even though plasma glucose and lipid levels remained the same. The protection from atherosclerosis was associated with decreased expression of class A scavenger receptor (see 153622) and tumor necrosis factor alpha (191160).

Chen et al. (2001) determined that ApoE is expressed in mouse kidneys, specifically in the mesangial cells and at lower levels in glomerular epithelial cells. They found that ApoE-null mice showed increased mesangial cell proliferation and matrix formation compared with wildtype mice. ApoE-null mice also had reduced levels of perlecan (142461), the major heparin sulfate proteoglycan (HSPG) of the mesangial matrix. The addition of ApoE3 to isolated mouse mesangial cells in culture completely blocked mesangial cell proliferation stimulated by serum, PDGF (190040), or LDL. ApoE3 also induced HSPG formation and inhibited mesangial cell apoptosis induced by oxidized LDL. ApoE2 and ApoE4 were less effective.

To study lipoprotein metabolism, Magoori et al. (2003) generated mice lacking both apoE and Lrp5 (603506). On a normal diet, the double knockout mice older than 4 months of age had 60% higher plasma cholesterol levels than the levels observed with apoE deficiency alone. LRP5 deficiency alone had no significant effects on the plasma cholesterol levels. Analysis showed that the VLDL and low LDL fractions were markedly increased in the double knockout mice. Atherosclerotic lesions in the double knockout mice at age 6 months were severe, with destruction of the internal elastic lamina.

Huang et al. (2001) found that apoE undergoes proteolytic cleavage in AD brains and in cultured neuronal cells, resulting in the accumulation of C-terminal-truncated fragments of apoE that are neurotoxic. Harris et al. (2003) showed that this fragmentation is caused by proteolysis of apoE by a chymotrypsin-like serine protease that cleaves apoE4 more efficiently than apoE3. They found that transgenic mice expressing the C-terminal-cleaved product, apoE4 (del272-299), at high levels in the brain died at 2 to 4 months of age. The cortex and hippocampus of these mice displayed AD-like neurodegenerative alterations, including abnormally phosphorylated tau and silver-positive neurons that contained cytosolic straight filaments with diameters of 15 to 20 nm, resembling preneurofibrillary tangles. Transgenic mice expressing lower levels of the truncated apoE4 survived longer but showed impaired learning and memory at 6 to 7 months of age. Thus, C-terminal-truncated fragments of apoE4, which occur in AD brains, are sufficient to elicit AD-like neurodegeneration and behavioral deficits in vivo. Harris et al. (2003) concluded that inhibiting their formation might inhibit apoE4-associated neuronal deficits. Using various truncation and mutant constructs, Chang et al. (2005) demonstrated that the neurotoxicity associated with ApoE4 fragments was mediated by both the lipid-binding region, spanning amino acids 241-272, and the receptor-binding region, spanning amino acids 135-150, which caused mitochondrial dysfunction and neurotoxicity.

Lund et al. (2004) found aberrant DNA methylation patterns prior to the onset of atherosclerosis in Apoe null mice. Both hyper- and hypomethylation were found in aortas and peripheral blood mononuclear cells of 4-week-old mutant mice with no detectable atherosclerotic lesions. Sequencing and expression analysis of 60 leukocyte polymorphisms revealed that epigenetic changes involved transcribed genes as well as repeated interspersed elements. Furthermore, Lund et al. (2004) showed that atherogenic lipoproteins promoted global DNA hypermethylation in a human monocyte cell line.

Ricci et al. (2004) showed that atherosclerosis-prone ApoE-null mice simultaneously lacking Jnk2 (602896) (ApoE -/- Jnk2 -/- mice), but not ApoE -/- Jnk1 (601158) -/- mice, developed less atherosclerosis than do ApoE-null mice. Pharmacologic inhibition of Jnk activity efficiently reduced plaque formation. Macrophages lacking Jnk2 displayed suppressed foam cell formation caused by defective uptake and degradation of modified lipoproteins and showed increased amounts of the modified lipoprotein-binding and -internalizing scavenger receptor A (see 153622), whose phosphorylation was markedly decreased. Macrophage-restricted deletion of Jnk2 was sufficient to decrease atherogenesis. Thus, Ricci et al. (2004) concluded that JNK2-dependent phosphorylation of SRA promotes uptake of lipids in macrophages, thereby regulating foam cell formation, a critical step in atherogenesis.

DeMattos et al. (2004) generated transgenic mice with a mutation in the amyloid precursor protein (APP) (V717F; 104760.0003) that were also null for apoE, apoJ (185430), or null for both apo genes. The double apo knockout mice showed early-onset beta-amyloid deposition beginning at 6 months of age and a marked increase in amyloid deposition compared to the other mice. The amyloid plaques were compact and diffuse, were thioflavine S-positive (indicating true fibrillar amyloid), and were distributed throughout the hippocampus and some parts of the cortex, contributing to neuritic plaques. The findings suggested that apoE and apoJ are not required for amyloid fibril formation. The double apo knockout mice also had increased levels of intracellular soluble beta-amyloid compared to the other mice. Insoluble beta-42 was similar to the apoE-null mice, suggesting that ApoE has a selective effect on beta-42. As APP is produced and secreted by neurons in the CNS and apoE and clusterin are produced and secreted primarily by astrocytes in the CNS, the interaction between the apolipoproteins and beta-amyloid occurs in the interstitial fluid of the brain, an extracellular compartment that is continuous with the CSF. DeMattos et al. (2004) found that apoE-null and apoE/apoJ-null mice had increased levels of beta-amyloid in the CSF and interstitial space, suggesting that apoE, and perhaps apoJ, play a role in regulating extracellular CNS beta-amyloid clearance independent of beta-amyloid synthesis. The data suggested that, in the mouse, apoE and apoJ cooperatively suppress beta-amyloid deposition.

Steffens et al. (2005) investigated the effects of delta-9-tetrahydrocannabinol (THC) in a mouse model of established atherosclerosis. Oral administration of THC (1 mg/kg(-1) per day) resulted in significant inhibition of disease progression. This effective dose is lower than the dose usually associated with psychotropic effects of THC. Furthermore, Steffens et al. (2005) detected CB2 receptor (605051) (the main cannabinoid receptor expressed on immune cells) in both human and mouse atherosclerotic plaques. Lymphoid cells isolated from THC-treated mice showed diminished proliferation capacity and decreased interferon-gamma (147570) secretion. Macrophage chemotaxis, which is a crucial step for the development of atherosclerosis, was also inhibited in vitro by THC. All these effects were completely blocked by a specific CB2 receptor antagonist. Steffens et al. (2005) concluded that oral treatment with a low dose of THC inhibited atherosclerosis progression in the apolipoprotein E knockout mouse model, through pleiotropic immunomodulatory effects on lymphoid and myeloid cells, and that THC or cannabinoids with activity at the CB2 receptor may be valuable targets for treating atherosclerosis.

In cultured rat neuroblastoma cells, Ye et al. (2005) found that lipid-poor Apoe4 increased beta-amyloid production to a greater extent than lipid-poor Apoe3 due to more pronounced stimulation of APP recycling by Apoe4 compared to Apoe3. The difference in beta-amyloid production was abolished by blocking the LDL receptor (606945) protein pathway. The findings indicated that there are isoform-specific effects of ApoE on beta-amyloid production.

Dodart et al. (2005) generated mice carrying the APP V717F mutation (104760.0003) and found that intracerebral hippocampal delivery of the human ApoE E4 gene in V717F-mutant mice that lacked mouse Apoe resulted in increased beta-amyloid deposition compared to similar mice that received human ApoE E3 or E4. In V717F-mutant mice expressing mouse Apoe, administration of human ApoE E4 did not result in increased beta-amyloid burden, and administration of human ApoE E2 resulted in decreased beta-amyloid burden, reflecting the dominant effect of the human E2 isoform. Dodart et al. (2005) noted that the findings were consistent with ApoE isoform-dependent human neuropathologic findings. However, the lentiviral vectors used to deliver ApoE isoforms appeared to result in a loss of hippocampal granule neurons, suggesting a neurotoxic effect.

Malek et al. (2005) described a mouse model that combined 3 known ARMD (603075) risk factors: advanced age, high fat cholesterol-rich (HF-C) diet, and apoE genotype. Eyes of aged, targeted replacement mice expressing human apoE2, apoE3, or apoE4 and maintained on an HF-C diet showed apoE isoform-dependent pathologies of differential severity: apoE4 mice were the most severely affected. They developed a constellation of changes that mimicked the pathology associated with human ARMD. These alterations included diffuse subretinal pigment epithelial deposits, drusenoid deposits, thickened Bruch membrane, and atrophy, hypopigmentation, and hyperpigmentation of the retinal pigment epithelium. In extreme cases, apoE4 mice also developed choroidal neovascularization, a hallmark of exudative ARMD. Neither age nor HF-C diet alone was sufficient to elicit these changes. The findings implicated the human apoE4 allele as a susceptibility gene for ARMD.

Seitz et al. (2005) reported that, in addition to the transcript (ApoE S1) that translates into ApoE, there are 3 additional transcripts in mice. Two of these transcripts, ApoE S2 and ApoE S3, which are predicted to be transmembrane proteins, were transcribed from the sense strand. ApoE AS1 was transcribed from the antisense strand and was complementary to exon 4 of ApoE S1. The antisense transcript fell within the region of the human APOE*E4 allele that has been linked to the familial onset form of Alzheimer disease. Although ApoE S3 and ApoE AS1 were transcribed in ApoE-knockout mice, ApoE S1 and ApoE S2 were not transcribed. In spinal cord-injured C57BL/6 mice, both ApoE S1 and ApoE S3 transcripts were upregulated 10-fold, and the antisense ApoE AS1 was upregulated 100-fold compared with normal levels. Seitz et al. (2005) suggested that these alternate transcripts may be involved in the molecular pathogenesis of CNS disease and perhaps in ApoE expression in general, since ApoE S2 and AS1 are also transcribed in humans.

In mouse hybrid cells and cultured rat hippocampal cells in vitro, Wang et al. (2006) found that ApoE expression was differentially regulated by estrogen receptor (ESR)-alpha (ESR1; 133430) and ESR-beta (ESR2; 601663). Pharmacologic activation of ESR1 significantly upregulated ApoE mRNA and protein expression, whereas ESR2 activation resulted in significant downregulation. Similar results were observed in the hippocampus of ovariectomized rats in vivo.

Using different Apoe transgenic mice, including mice with ablation and/or inhibition of cyclophilin A (CypA; 123840), Bell et al. (2012) showed that expression of Apoe4 and lack of murine Apoe, but not Apoe2 and Apoe3, leads to blood-brain barrier breakdown by activating a proinflammatory CypA-Nfkb (164011)-Mmp9 (120361) pathway in pericytes. This, in turn, leads to neuronal uptake of multiple blood-derived neurotoxic proteins, and microvascular and cerebral blood flow reductions. Bell et al. (2012) showed that the vascular defects in Apoe-deficient and Apoe4-expressing mice precede neuronal dysfunction and can initiate neurodegenerative changes. Astrocyte-secreted Apoe3, but not Apoe4, suppressed the CypA-Nfkb-Mmp9 pathway in pericytes through a lipoprotein receptor. Bell et al. (2012) concluded that CypA is a key target for treating APOE4-mediated neurovascular injury and the resulting neuronal dysfunction and degeneration.

Dutta et al. (2012) showed that after myocardial infarction or stroke, Apoe-null mice developed larger atherosclerotic lesions with a more advanced morphology. This disease acceleration persisted over many weeks and was associated with markedly increased monocyte recruitment. Seeking the source of surplus monocytes in plaques, Dutta et al. (2012) found that myocardial infarction liberated hematopoietic stem and progenitor cells from bone marrow niches via sympathetic nervous system signaling. The progenitors then seeded the spleen, yielding a sustained boost in monocyte production.

Shi et al. (2017) generated P301S (157140.0012) tau transgenic mice on either a human ApoE knockin or ApoE knockout (KO) background and showed that P301S/E4 mice have significantly higher tau levels in the brain and a greater extent of somatodendritic tau redistribution by 3 months of age compared with P301S/E2, P301S/E3, and P301S/EKO mice. By 9 months of age, P301S mice with different ApoE genotypes displayed distinct phosphorylated tau protein (p-tau) staining patterns. P301S/E4 mice developed markedly more brain atrophy and neuroinflammation than P301S/E2 or P301S/E3 mice, whereas P301S/EKO mice were largely protected from these changes. In vitro, E4-expressing microglia exhibited higher innate immune reactivity after lipopolysaccharide treatment. Coculturing P301S tau-expressing neurons with E4-expressing mixed glia resulted in a significantly higher level of tumor necrosis factor-alpha (TNFA; 191160) secretion and markedly reduced neuronal viability compared with neuron/E2 and neuron/E3 cocultures. Neurons cocultured with EKO glia showed the greatest viability with the lowest level of secreted TNFA. Treatment of P301S neurons with recombinant ApoE (E2, E3, E4) also led to some neuronal damage and death compared with the absence of ApoE, with ApoE4 exacerbating the effect. In individuals with a sporadic primary tauopathy, the presence of an ApoE4 allele was associated with more severe regional neurodegeneration. In individuals who were positive for amyloid-beta pathology with symptomatic Alzheimer disease, who usually have tau pathology, E4 carriers demonstrated greater rates of disease progression. Shi et al. (2017) concluded that ApoE affects tau pathogenesis, neuroinflammation, and tau-mediated neurodegeneration independently of amyloid-beta pathology. ApoE4 exerts a toxic gain of function whereas the absence of ApoE is protective.

▼ History

Utermann et al. (1979) found that homozygosity for the apoE(n) results in primary dysbetalipoproteinemia but only some persons develop gross hyperlipidemia (hyperlipoproteinemia type III; 617347). Vertical transmission is pseudodominance due to high frequency of the apoE(d) gene (Utermann et al., 1979). Dysbetalipoproteinemia is already expressed in childhood. Utermann et al. (1979) concluded that primary dysbetalipoproteinemia is a frequent monogenic variant of lipoprotein metabolism, but not a disease. Coincidence of the genes for this dyslipoproteinemia with any of the genes for monogenic or polygenic forms of familial hyperlipemia results in hyperlipoproteinemia type III.

▼ ALLELIC VARIANTS ( 34 Selected Examples):

Table View ClinVar

.0001 HYPERLIPOPROTEINEMIA, TYPE III, DUE TO APOE2, AUTOSOMAL RECESSIVE

APOE, ARG158CYS

RCV000019428...

The E2 isoform of apolipoprotein E (APOE2) differs from the APOE3 and APOE4 isoforms by having a cysteine at residue 158 rather than arginine (Rall et al., 1982; Gill et al., 1985). Rall et al. (1982) noted that there is more than one genotype within the homozygous E2 phenotype on isoelectric focusing. Other isoforms that give a band at the E2 position with isoelectric focusing include E2(lys146-to-gln) (107741.0011) and E2(arg145-to-cys; 107741.0004). Type III hyperlipoproteinemia is typically associated with homozygosity for the change in apolipoprotein E2 from arg158 to cys.

The common E2 isoform carrying arg158-to-cys (R158C) was found in 98 of 100 E2 alleles by Emi et al. (1988).

By generating mice with a human APOE*2 allele in place of the mouse Apoe gene via targeted gene replacement in embryonic stem cells, Sullivan et al. (1998) demonstrated that a single amino acid difference (R158C) in the APOE protein is sufficient to cause type III hyperlipoproteinemia and spontaneous atherosclerosis in mice. Mice expressing human APOE2 (2/2) had virtually all the characteristics of type III hyperlipoproteinemia. Both their plasma cholesterol and triglyceride levels were 2 to 3 times those in normolipidemic mice that expressed human APOE3 (3/3) generated in an identical manner. The 2/2 mice were markedly defective in clearing beta-migrating VLDL particles and spontaneously developed atherosclerotic plaques, even on a regular diet. An atherogenic diet, high in fat and cholesterol, exacerbated development of atherosclerosis and xanthomas in the 2/2 mice.

In 72 patients with type III hyperlipidemia (617347) and the APOE 2/2 genotype, Evans et al. (2005) found a significantly higher frequency for at least 1 minor allele of the APOA5 -1131T-C and S19W (606368.0002) SNPs in patients than in controls (53% vs 19.7%, respectively; p = 0.0001). Evans et al. (2005) concluded that genetic variation in the APOA5 gene is an important cofactor in the development of type III hyperlipidemia.

.0002 HYPERLIPOPROTEINEMIA, TYPE III, AND ATHEROSCLEROSIS ASSOCIATED WITH APOE5

APOE, GLU3LYS

RCV000019429

Yamamura et al. (1984) and Yamamura et al. (1984) identified patients with hyperlipidemia and/or atherosclerosis from 3 Japanese families whose apo VLDL produced a band more basic than the APOE4 position on isoelectric focusing. They designated this band APOE5. Tajima et al. (1988) performed DNA sequencing analysis of the APOE5 allele and identified a G-to-A substitution in the third exon of the gene resulting a glu3-to-lys (E3K) substitution in mature APOE. The rest of the sequence was the same as the common APOE3.

Using isoelectric focusing with immunoblotting in the study of blood specimens from 1,269 Japanese subjects, Matsunaga et al. (1995) found that the epsilon-5 allele had a frequency of 0.001.

.0003 HYPERLIPOPROTEINEMIA, TYPE III, DUE TO APOE2-CHRISTCHURCH

APOE, APOE2 AND ARG136SER

RCV000019430...

This variant was described by Wardell et al. (1987) and Emi et al. (1988). Wardell et al. (1987) studied the primary structure of apoE in 7 patients with type III hyperlipoproteinemia (617347) with the apoE2/E2 phenotype on isoelectric focusing. Six of the patients had identical 2-dimensional tryptic peptide maps; these differed from the normal by the altered mobility of a single peptide. Amino acid analysis and sequencing showed that these patients had the most common form of apoE2 (R158C; 107741.0001). The seventh patient had a unique peptide map with the new peptide resulting from a substitution of arginine-136 to serine (R136S). He was heterozygous for this and for the common R158C mutation resulting in APOE2. Wardell et al. (1987) designated the R136S-carrying allele APOE2-Christchurch.

.0004 HYPERLIPOPROTEINEMIA, TYPE III, ASSOCIATED WITH APOE2

APOE, ARG145CYS

RCV000019432...

This variant was described by Rall et al. (1982) and Emi et al. (1988). Rall et al. (1982) demonstrated heterogeneity in type III hyperlipoproteinemia (617347). They studied 3 subjects who were phenotypically homozygous for apoE2 but showed considerable differences in the binding activity to the fibroblast receptor. The subject with the poorest binding apoE2 was genotypically homozygous for an apoE allele (epsilon 2); cysteine was found at sites A and B. The subject with the most actively binding apoE2 was genotypically homozygous for an apoE allele (epsilon 2*); cysteine was found at site A and at a new site, site C, residue 145, which in apoE2 has arginine. Epsilon 2*, furthermore, specifies a protein with arginine at site B (residue 158). The third subject, whose apoE2 displayed binding activity intermediate between the activities of the other 2, was genotypically heterozygous, having 1 epsilon 2 allele and 1 epsilon 2* allele.

.0005 HYPERLIPOPROTEINEMIA, TYPE III, ASSOCIATED WITH APOE DEFICIENCY

APOE, IVS3AS, A-G, -1

RCV000019433

Cladaras et al. (1987) showed that one form of familial apoE deficiency (617347) results from a point mutation in the 3-prime splice junction of the third intron of the APOE gene. The change, an A-to-G substitution in the penultimate 3-prime nucleotide of the third intron, abolished the correct 3-prime splice site, thus creating 2 abnormally spliced mRNA forms. Both mRNAs contain chain termination codons within the intronic sequence. The clinical features of the patient were described by Ghiselli et al. (1981) and Schaefer et al. (1986).

.0006 HYPERLIPOPROTEINEMIA, TYPE III, ASSOCIATED WITH APOE3-LEIDEN

APOE, 21-BP DUP, CODONS 121-127

RCV000019434

Havekes et al. (1986) found type III hyperlipoproteinemia (617347) in a dominant pedigree pattern in a family with a variant of E3 that they called E3(Leiden). By isoelectric focusing, the affected persons appeared to be homozygous for normal apoE3, but the variant E3 showed defective binding to LDL receptor, and on sodium dodecyl sulfate polyacrylamide gel electrophoresis showed mobility intermediate to those of normal E3 and normal E2. The mother and 5 of 8 sibs had type III HLP; 4 of the 5 had xanthomatosis. The affected persons were heterozygotes E3/E3(Leiden). Wardell et al. (1989) demonstrated a 7-amino acid insertion that is a tandem repeat of residues 121-127. In a screening of patients with familial dysbetalipoproteinemia, de Knijff et al. (1991) found 5 probands showing heterozygosity for the APOE*3-Leiden allele. Genealogic studies revealed that these probands shared common ancestry in the 17th century. In 1 large kindred spanning 3 generations, 37 additional heterozygotes were detected. Although severity varied, all carriers showed characteristics of dysbetalipoproteinemia such as: (a) elevated levels of cholesterol in VLDL and IDL fractions; (b) elevated ratios of cholesterol levels in these density fractions over total plasma levels of triglycerides; and (c) strongly increased plasma levels of apoE. Multiple linear regression analysis showed that most of the variability in expression of familial dysbetalipoproteinemia in APOE*3-Leiden allele carriers can be explained by age.

In a discussion of mouse models of atherosclerosis, Breslow (1996) referred to the development of a transgenic mouse carrying the APOE-Leiden mutation. When fed a very high cholesterol diet containing cholic acid, these mice had cholesterol levels of 1,600 to 2,000 mg/dl and developed fatty streak and fibrous plaque lesions.

.0007 HYPERLIPOPROTEINEMIA, TYPE III, AND ATHEROSCLEROSIS ASSOCIATED WITH APOE7

APOE-SUITA

APOE, GLU244LYS AND GLU245LYS

RCV000019435

In patients whose plasma VLDL particles exhibited 4 additional units of positive charge compared to APOE3 on isoelectric focusing, Maeda et al. (1989) and Tajima et al. (1989) found that 2 contiguous glutamic acid residues, glu244 and glu245, were changed to lysine residues, lys244 and lys245. This involved a change from GAC-GAG to AAC-AAG. This isoform was designated APOE7.

Using isoelectric focusing with immunoblotting in the study of blood specimens from 1,269 Japanese subjects, Matsunaga et al. (1995) found that the epsilon-7 allele (E7) had a frequency of 0.007.

This variant has also been designated APOE-SUITA. Yamamura et al. (1984) had identified the apoE-Suita isoform in 4 unrelated patients with hyperlipidemia and/or atherosclerosis.

.0008 HYPERLIPOPROTEINEMIA, TYPE III, AUTOSOMAL DOMINANT, ASSOCIATED WITH APOE3

APOE, APOE3, CYS112ARG AND ARG142CYS

RCV000019438...

In a family reported by Havel et al. (1983), Rall et al. (1989) found that the members with type III hyperlipoproteinemia (617347) were compound heterozygotes for 2 different APOE3 alleles, one coding for the normal APOE3 and one for a previously undescribed variant APOE3 with 2 changes: arginine replacing cysteine at residue 112 and cysteine replacing arginine at residue 142. The variant APOE3 was defective in its ability to bind to lipoprotein receptors, a functional defect probably contributing to expression of type III HLP in this kindred. Type III HLP typically is associated with homozygosity for apolipoprotein E2 (arg158 to cys); see 107741.0001. Dominant expression of type III HLP associated with apoE phenotype E3/3 is caused by heterozygosity for a common apoE variant, apoE3 (cys112-to-arg; arg142-to-cys). To determine the functional characteristics of the variant protein, Horie et al. (1992) used recombinant DNA techniques to produce the variant in bacteria. They also produced a non-naturally occurring variant, apoE(arg142cys), that had only the cysteine substituted at residue 142. They demonstrated that the cys142 variant was responsible for the defective binding to lipoprotein receptors because both showed the same defect. The arg112,cys142 variant predominates 3:1 over normal apoE3 in the very low density lipoproteins of plasma from an affected subject. Horie et al. (1992) concluded that unique properties of the arg112,cys142 variant provided an explanation for its association with dominant expression of type III HLP.

.0009 HYPERLIPOPROTEINEMIA DUE TO APOE1

APOE, GLY127ASP AND ARG158CYS

RCV000019428...

Weisgraber et al. (1984) found an electrophoretic variant of apoE in a Finnish hypertriglyceridemic subject. The variant was designated E1 (gly127-to-asp, arg158-to-cys). Family studies showed 'vertical transmission.' The relation of E1 to hypertriglyceridemia was unclear.

.0010 HYPERLIPOPROTEINEMIA, TYPE III, DUE TO APOE1-HARRISBURG

APOE, LYS146GLU

RCV000019440

Mann et al. (1989) described heterozygosity for this mutation (K146E) in the APOE gene as the basis of familial dysbetalipoproteinemia (617347) in 5 affected members of a family. The mutation led to type III hyperlipoproteinemia in 4 of the 5. The mutation was designated APOE1-Harrisburg.

A second family with type III hyperlipoproteinemia due to the identical mutation was reported by Moriyama et al. (1992). Mann et al. (1995) determined the structural defect in the ApoE-1 molecule resulting from this mutation and studied its functional implications using in vivo kinetic studies in the original proband and in normal subjects, and using in vitro binding assays with human fibroblasts and the proteoglycan heparin. They concluded that the functional dominance of the mutation resulted from the abnormal in vitro binding characteristics and the altered in vivo metabolism of the mutant protein.

.0011 HYPERLIPOPROTEINEMIA, TYPE III, DUE TO APOE2

APOE, APOE2, LYS146GLN

RCV001804151

As in APOE1-Harrisburg, a heterozygous mutation at position 146 (K146Q) in the APOE gene leads to dysbetalipoproteinemia (617347), suggesting that this residue plays a crucial role in removal of chylomicrons and VLDL in vivo. See Rall et al. (1983). In the Netherlands, Smit et al. (1990) found that all 40 patients with familial dyslipoproteinemia and the E2E2 phenotype were homozygous for the E2(arg158-to-cys) mutation. On the other hand, all 3 unrelated patients with the E3E2 phenotype showed the rare E2(lys146-to-gln) mutation due to an A-to-C substitution at nucleotide 3847 of the APOE gene. This mutation was not found in 13 normolipidemic persons with the E2E2 phenotype or 120 with the E3E2 phenotype selected from a random population sample. Family studies showed predisposition to type III hyperlipoproteinemia with high penetrance. Thus, this is a highly penetrant dominant form of the disease; E2(arg158-to-cys) is a low penetrant, recessive form. Dominant inheritance has been observed also with E1(Harrisburg), E3(Leiden), and E3(cys112-to-arg; arg142-to-cys). Some of the reduced penetrance of the E2 allele in causing familial dysbetalipoproteinemia is based on the fact that all E2 as phenotyped by isoelectric focusing is not genetically a single entity.

.0012 APOE2-DUNEDIN

HYPERLIPOPROTEINEMIA, TYPE IV/V, DUE TO APOE2-DUNEDIN

APOE, APOE2, ARG228CYS

RCV000019442...

In identical twin brothers with the E2/2 phenotype but with type IV/V hyperlipoproteinemia, Wardell et al. (1990) found compound heterozygosity for the arg158-to-cys mutation and a second unusual mutation, a substitution of cysteine for arginine at position 228, represented as APOE2(228Arg-Cys).

.0013 HYPERLIPOPROTEINEMIA, TYPE III, DUE TO APOE4-PHILADELPHIA

APOE, GLU13LYS AND ARG145CYS

RCV000019432...

In a 24-year-old white female with severe type III hyperlipoproteinemia (617347), Lohse et al. (1991) found 2 rare point mutations in the APOE gene. One was a C-to-T mutation which converted arginine (CGT) at position 145 of the mature protein to cysteine (TGT), creating the APOE2* isoprotein (see 107741.0004), which is slightly more acidic than APOE3. A second G-to-A substitution at amino acid 13 led to the exchange of lysine (AAG) for glutamic acid (GAG), thereby adding 2 positive charge units to the APOE3 protein and producing the APOE5 isoprotein. Both substitutions together, inherited on the same allele, resulted in an isoprotein focusing in the APOE4 position. Both mutations resulted in loss of restriction enzyme cleavage sites. The proband was homozygous for both mutations. Lohse et al. (1992) extended their analyses to include 9 additional family members of the Philadelphia kindred spanning 4 generations. DNA and protein analysis demonstrated that the originally described proposita, called by them propositus, was a true homozygote for the apolipoprotein E4(Philadelphia) allele and that 6 of the 9 family members were heterozygous for the mutant allele and the normal E3 allele or, in 1 case, the E4 allele. Heterozygosity led to the expression of a moderate form of type III HLP without clinical manifestations. The simultaneous presence of unaffected persons, heterozygotes, and a homozygote makes it possible to conclude that the mutation shows incomplete dominance.

.0014 HYPERLIPOPROTEINEMIA, TYPE III, ASSOCIATED WITH APOE DEFICIENCY

HYPERLIPOPROTEINEMIA, TYPE III, ASSOCIATED WITH APOE3(WASHINGTON)

APOE, TRP210TER

RCV000019445...

Lohse et al. (1992) studied a kindred with apolipoprotein E deficiency (617347) and a truncated low molecular weight apoE mutant, designated apoE-3(Washington). Gel electrophoresis demonstrated complete absence of the normal apoE isoproteins and the presence of a small quantity of a lower molecular weight apoE. Plasma apoE levels in the proband were approximately 4% of normal. This marked deficiency of apoE resulted in delayed uptake of chylomicron and very low density lipoprotein (VLDL) remnants by the liver, elevated plasma cholesterol levels, mild hypertriglyceridemia, and the development of type III hyperlipoproteinemia. Sequence analysis demonstrated a G-to-A transition which converted amino acid 210 of the mature protein, tryptophan (TGG), to a premature chain termination codon (TAG), thus leading to the synthesis of a truncated E apolipoprotein of 209 amino acids with a molecular mass of 23.88 kD. The nucleotide substitution also resulted in the formation of a new restriction site for MaeI. Using this enzyme, they were able to establish that the proband was a homozygote and that her 2 offspring were heterozygotes. They stated that only a single kindred with apoE deficiency had been reported previously; that was the kindred reported by Ghiselli et al. (1981) and elucidated at the molecular level by Cladaras et al. (1987); see 107741.0005.

.0015 APOE3 ISOFORM

APOE, CYS112 AND ARG158

RCV000019447...

Weisgraber et al. (1981) and Rall et al. (1982) identified one of the 3 major apolipoprotein E isoforms, apolipoprotein E3. The variant has cys112 and arg158. This is the most common variant, with frequencies of 40 to 90% in various populations.

.0016 ALZHEIMER DISEASE 2 DUE TO APOE4 ISOFORM

APOE, CYS112ARG

RCV000019438...

Weisgraber et al. (1981), Das et al. (1985), and Paik et al. (1985) identified the apolipoprotein E4 (apoE4) isoform, in which there is a cys112-to-arg (C112R) substitution. This variant is found in 6 to 37% of individuals from different populations. Individuals carrying the apolipoprotein E4 allele display low levels of apolipoprotein E and high levels of plasma cholesterol, low density lipoprotein-cholesterol, apolipoprotein B, lipoprotein (a), and are at higher risk for coronary artery disease than other individuals.

Saunders et al. (1993) reported an increased frequency of the E4 allele in a small prospective series of possible-probable AD patients presenting to the memory disorders clinic at Duke University, in comparison with spouse controls. Corder et al. (1993) found that the APOE*E4 allele is associated with the late-onset familial and sporadic forms of Alzheimer disease. In 42 families with the late-onset form of Alzheimer disease (AD2; 104310), the gene had been mapped to the same region of chromosome 19 as the APOE gene. Corder et al. (1993) found that the risk for AD increased from 20 to 90% and mean age of onset decreased from 84 to 68 years with increasing number of APOE*E4 alleles. Homozygosity for APOE*E4 was virtually sufficient to cause AD by age 80.

Enzinger et al. (2004) noted that decreases in brain size and volume in patients with multiple sclerosis (126200) are related to neuroaxonal injury and loss, and are a useful surrogate marker of tissue damage and disease progression. In a study of 99 patients with MS, the authors found that patients who carried an E4 allele had more relapses during the study period and had a 5-fold higher rate of annual brain volume loss compared to patients without the E4 allele. Over time, E4 carriers also had an increase in individual lesions on MRI, termed 'black holes.' Among all genotype groups, the lowest annual loss of brain volume occurred in patients with an E2 allele. Among 76 patients with relapsing-remitting MS, de Stefano et al. (2004) found that carriers of the E4 allele showed significantly lower total brain volumes compared to MS patients without the E4 alleles. There was no difference in lesion volume between the 2 groups. The authors suggested that the E4 allele is linked to impaired mechanisms of cell repair and severe tissue destruction in MS.

Among 89 patients with head injury, Teasdale et al. (1997) found that patients with the E4 allele were more likely than those without the E4 allele to have an unfavorable outcome 6 months after head injury. The authors discussed the role of the apoE protein in response to acute brain injury. In a prospective study of 69 patients with severe blunt trauma to the head, Friedman et al. (1999) found an odds ratio of 5.69 for more than 7 days of unconsciousness and 13.93 for a suboptimal neurologic outcome at 6 months for individuals with an APOE4 allele compared to those without that allele.

Montagne et al. (2020) showed that individuals bearing APOE4 were distinguished from those without APOE4 by breakdown of the blood-brain barrier in hippocampus and medial temporal lobe. This finding was apparent in cognitively unimpaired APOE4 carriers and was more severe in those with cognitive impairment, but it was not related to amyloid-beta or tau pathology measured in cerebrospinal fluid or by positron emission tomography. High baseline levels of soluble PDGFR-beta (PDGFRB; 173410), a blood-brain barrier pericyte injury biomarker, in cerebrospinal fluid predicted future cognitive decline in APOE4 carriers but not in noncarriers, even after controlling for amyloid-beta and tau status, and correlated with increased activity of the blood-brain barrier-degrading cyclophilin A (PPIA; 123840)-matrix metalloproteinase-9 (MMP9; 120361) pathway in cerebrospinal fluid. Montagne et al. (2020) concluded that breakdown of the blood-brain barrier contributes to APOE4-associated cognitive decline independently of Alzheimer disease pathology and might be a therapeutic target in APOE4 carriers.

.0017 HYPERLIPOPROTEINEMIA, TYPE III, ASSOCIATED WITH APOE DEFICIENCY, AUTOSOMAL RECESSIVE

APOE, 1-BP DEL, 2919G

RCV000019444

Feussner et al. (1992) identified in German subjects with autosomal recessive familial dysbetalipoproteinemia (617347) a 1-bp deletion (G) at the last nucleotide of codon 30 at position 2919 of exon 3 (or the first 2 nucleotides of codon 31 at nucleotide positions 2920 or 2921). This frameshift mutation (called APOE0) creates a termination at codon 60 resulting in a truncated protein. Individuals heterozygous for this mutation display reduced plasma apolipoprotein E levels. Subjects homozygous for this allele have undetectable plasma apolipoprotein E levels concomitant with severe forms of familial dysbetalipoproteinemia.

.0018 HYPERLIPOPROTEINEMIA, TYPE III, DUE TO APOE3(-)-KOCHI

APOE, ARG145HIS

RCV000019449...

This arg145-to-his amino acid change in the APOE gene was identified in a Japanese subject with familial dysbetalipoproteinemia (617347) by Suehiro et al. (1990). The variant was designated E3(-) because it is slightly more acidic than apolipoprotein E3 (107741.0015). This variant was designated APOE3(-)-Kochi.

.0019 HYPERLIPOPROTEINEMIA, TYPE III, DUE TO APOE2-FUKUOKA

APOE, ARG224GLN

RCV000019428...

In a Japanese woman with hyperlipoproteinemia type III (107741), Moriyama et al. (1996) identified heterozygosity for a G-to-A transition at exon 4 leading to a change from arginine-224 to glutamine. This substitution resulted in a protein with 1 additional negatively charged unit compared to APOE3. The isoform carrying the R224Q variant was designated APOE2-Fukuoka.

.0020 APOE5 VARIANT

APOE, GLU13LYS

RCV000019429...

In 2 apparently unrelated French Canadian individuals who did not have hyperlipoproteinemia type III, whose VLDL fraction showed a more cathodic migration than apoE4 on isoelectric focusing, Mailly et al. (1991) identified a heterozygous variant in the APOE gene: a G-to-A transition resulting in a glu13-to-lys substitution. The isoform carrying the mutation was designated apoE5.

.0021 HYPERLIPOPROTEINEMIA, TYPE III, ASSOCIATED WITH APOE2

APOE, APOE2, VAL236GLU

RCV000019428...

In Dutch subjects with hypertriglyceridemia (617347), van den Maagdenberg et al. (1993) identified mutations in the APOE gene: the common APOE2 variant arg158-to cys (107741.0001) and a T-to-A transition leading to a substitution of glutamic acid for valine-236 in an APOE2 allele.

.0022 HYPERLIPOPROTEINEMIA, TYPE III, ASSOCIATED WITH APOE3

APOE, CYS112ARG AND ARG251GLY

RCV000019438...

Van den Maagdenberg et al. (1993) identified in Dutch subjects with hypertriglyceridemia (617347) 2 substitutions in an APOE3 allele: cys112arg and arg251gly. The authors designated the allele APOE3(Cys112-Arg; Arg251-Gly).

.0023 APOE4(-)-FREIBURG

APOE, LEU28PRO AND CYS112ARG

RCV000019438...

Wieland et al. (1991) identified an apolipoprotein E4 variant in German-Caucasian subjects that was not associated with hyperlipidemia. The variant was designated E4(-) because it is slightly more acidic than E4 (107741.0016). This variant has a leu28-to-pro substitution (CTG-to-CCG).

.0024 APOE3(-)-FREIBURG

APOE, THR42ALA

RCV000019457

In German-Caucasian subjects, Wieland et al. (1991) identified an apolipoprotein E3 variant designated E3(-) that is slightly more acidic than E3. This variant has a thr42-to-ala substitution (ACA-to-GCA) and was not associated with hyperlipidemia.

.0025 APOE5 VARIANT

APOE, PRO84ARG AND CYS112ARG

RCV000019438...

In an individual of European descent who had been reported by Ordovas et al. (1987), Wardell et al. (1991) identified an apolipoprotein E5 variant not associated with hyperlipidemia. This variant has a pro84-to-arg substitution (CCG-to-CGG) and was designated APOE5(84Pro-Arg; 112Cys-Arg).

.0026 APOE3 VARIANT

APOE, ALA99THR AND ALA152PRO

RCV000019459

In an American subject, McLean et al. (1984) identified an apolipoprotein E3 variant not associated with hyperlipidemia. This variant has ala99-to-thr and ala152-to-pro substitutions (GCG-to-ACG and GCC-to-CCC, respectively).

.0027 APOE2 VARIANT

APOE, ARG134GLN

RCV000019460

De Knijff et al. (1994) cited unpublished data identifying an apolipoprotein E2 variant in Dutch subjects with no hyperlipidemia. This variant has an arg134-to-gln substitution (CGG-to-CAG). The mutation is located in the receptor-binding domain.

.0028 APOE4 VARIANT

APOE, ARG274HIS

RCV000019461

In a Dutch individual (P.D.), van den Maagdenberg et al. (1993) identified an apolipoprotein E4 variant not associated with hyperlipidemia. This variant has an arg274-to-his substitution and was designated APOE4- (Cys112-Arg; Arg274-His). E4- denotes an aberrant isoelectric band that focused on a slightly more cathodic position compared to the standard E4 band.

.0029 APOE4(+)

APOE, SER296ARG

RCV000019462

In a Dutch individual (H.G.), van den Maagdenberg et al. (1993) identified an apolipoprotein E4 variant with a ser296-to-arg substitution (AGC-to-CGC), APOE4+(Ser296-Arg), not associated with hyperlipidemia. The variant was designated E4(+) because it is slightly more basic than E4.

.0030 CORONARY ARTERY DISEASE, SEVERE, SUSCEPTIBILITY TO

APOE, -219G-T (rs405509)

RCV001804152

In a large multicenter case-control study of myocardial infarction using 567 cases and 678 controls, Lambert et al. (2000) identified an increased risk of myocardial infarction among patients carrying the -219T allele, a promoter polymorphism. The odds ratio was 1.29, with a 95% confidence interval of 1.09 to 1.52 and a P value of less than 0.003. The effect of the allele was independent of the presence of other promoter polymorphisms or mutations including the APOE epsilon-2/epsilon-3/epsilon-4 polymorphism. Moreover, the -219T allele greatly decreased the APOE plasma concentrations in a dose-dependent manner (P less than 0.008). Lambert et al. (2000) concluded that the -219G-T polymorphism of the APOE regulatory region is a genetic susceptibility risk factor for myocardial infarction and constitutes another common risk factor for both neurodegenerative and cardiovascular diseases.

In a large cohort of patients with angiographically documented coronary artery disease, Ye et al. (2003) found that the APOE -219T allele and the E4 allele had independent effects on CAD severity. The frequency of the E4 allele and the -219T allele both increased linearly with increasing number of diseased vessels. The -219T/T genotype conferred an odds ratio of 1.598 in favor of increased disease severity, and the -219T/T haplotype in combination with the E4 haplotype conferred an odds ratio of 1.488. The findings suggested that the -219T and E4 polymorphisms, which may affect the quantity and quality of apoE, respectively, have independent and possibly additive effects on CAD severity.

.0031 SEA-BLUE HISTIOCYTE DISEASE

APOE, 3-BP DEL, 499CTC

RCV000202536...

Nguyen et al. (2000) reported 2 kindreds in which the sea-blue histiocyte syndrome (269600) was associated with an apoE variant in the absence of severe dyslipidemia. Both patients presented with mild hypertriglyceridemia and splenomegaly. After splenectomy both patients developed severe hypertriglyceridemia. Pathologic evaluation of the spleen revealed the presence of sea-blue histiocytes. An APOE mutation was found: a 3-bp deletion resulting in the loss of leucine-149 in the receptor-binding region of APOE (delta149 leu). Although the probands were unrelated, they were of French Canadian ancestry, suggesting the possibility of a founder effect.

In 2 brothers with splenomegaly, thrombocytopenia, and hypertriglyceridemia, Faivre et al. (2005) identified the delta149 leu mutation in the APOE gene. Their mother, who also had the mutation, had only isolated hypertriglyceridemia. One brother had a large beta band in the VLDL fraction and an elevated VLDL cholesterol-to-plasma triglyceride ratio; Faivre et al. (2005) suggested that the more severe phenotype might be explained by the presence of an APOE2 allele (107741.0001) in this patient.

.0032 LIPOPROTEIN GLOMERULOPATHY

APOE, ARG145PRO

RCV000019466

In 3 Japanese patients with lipoprotein glomerulopathy (LPG; 611771), Oikawa et al. (1997) identified heterozygosity for a G-to-C transversion in exon 4 of the APOE gene that resulted in substitution of proline for arginine at codon 145 (R145P). Two of the patients were related as parent and child; the third patient was unrelated to them. Oikawa et al. (1997) termed the mutation 'APOE Sendai' for the proband's city of origin.

Ishigaki et al. (2000) introduced APOE Sendai into ApoE-deficient hypercholesterolemic mice using adenovirus-mediated gene transfer and observed insufficient correction of hypercholesterolemia and a marked and temporal induction of plasma triglyceride levels. In vitro binding studies demonstrated reduced affinity of APOE-Sendai for the low density lipoprotein receptor (LDLR; 606945), suggesting that dysbetalipoproteinemia in LPG is caused by the APOE mutation. Histologic examination revealed marked intraglomerular depositions of APOE-containing lipoproteins.

.0033 LIPOPROTEIN GLOMERULOPATHY

APOE, ARG25CYS

RCV000019468...

In a Japanese man with lipoprotein glomerulopathy (LPG; 611771), Matsunaga et al. (1999) detected a heterozygous C-to-T transition in exon 3 of the APOE gene that resulted in substitution of cysteine for arginine at codon 25 of the mature protein (R25C). The authors designated the mutation APOE Kyoto. The proband's mother, who also carried the mutation, was clinically unaffected.

Rovin et al. (2007) identified APOE Kyoto in 2 American males of European descent with LPG.

.0034 ALZHEIMER DISEASE 3, PROTECTION AGAINST, DUE TO APOE3-CHRISTCHURCH (1 family)

APOE, APOE3, ARG136SER

RCV000019430...

In a woman from the very large Colombian family with early-onset Alzheimer disease caused by a glu280-to-ala mutation in the PSEN1 gene (E280A; 104311.0009) who carried that mutation but who did not develop mild cognitive impairment until her seventies, Arboleda-Velasquez et al. (2019) detected homozygosity for an arginine-to-serine substitution at amino acid 136 (R136S) on the APOE3 allele of APOE. The mutation was detected by whole-exome sequencing and confirmed by Sanger sequencing. The R136S mutation in APOE is known as the Christchurch mutation (see also 107741.0003); the authors referred to the APOE allele in this individual as APOE3ch. Unlike the over 1,200 members of this kindred who manifest mild cognitive impairment by the median age of 44 and dementia by age 49, this individual developed only mild cognitive impairment in her 70s. She was found to have high brain amyloid burden, but limited tau burden and limited neurodegenerative measurements. Extensive analysis identified homozygosity for APOE3ch as the most likely genetic modifier. A post hoc analysis of 117 other members of the kindred revealed no other homozygous APOE3ch carriers. Four closely related family members carried the PSEN1 variant with 1 copy of APOE3ch; all progressed to mild cognitive impairment by the mean age of 45.

Quiroz et al. (2024) analyzed data from 27 participants with 1 copy of the APOE3 Ch variant among 1,077 carriers of the PSEN1 E280A variant in a kindred of over 6,000 with autosomal dominant Alzheimer disease from Antioquia, Colombia, to estimate the age at onset of cognitive impairment and dementia in this group as compared to persons without the APOE3 Ch variant. Among carriers of PSEN1 E280A who were heterozygous for the APOE3 Ch variant, the median age at the onset of cognitive impairment was 52 years (95% CI, 51 to 58), in contrast to a matched group of PSEN1 E280A carriers without the APOE3 Ch variant, among whom the median age of onset was 47 years (95% CI, 47 to 49). Both age of onset of mild cognitive impairment and dementia were delayed in those with the APOE3 Ch variant. In 2 participants with the APOE3 Ch and PSEN1 E280A variants who underwent brain imaging, 18F-fluorodeoxyglucose positron-emission tomographic (PET) imaging showed relatively preserved metabolic activity in areas typically involved in Alzheimer disease. In 1 of these participants, who underwent 18F-flortaucipir PET imaging, tau findings were limited as compared with persons with PSEN1 E280A in whom cognitive impairment occurred at the typical age in this kindred. Autopsy material obtained from 4 individuals with the APOE3 Ch and PSEN1 E280A variants showed greater amyloid plaque burden and a relatively limited tau burden as compared with that seen in material obtained from those who had the PSEN1 E280A variant but not the APOE3 Ch variant.

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Contributors:

Ada Hamosh - updated : 09/25/2024

Ada Hamosh - updated : 11/03/2020
Ada Hamosh - updated : 11/22/2019
Ada Hamosh - updated : 12/27/2017
Carol A. Bocchini - updated : 02/14/2017
Patricia A. Hartz - updated : 12/4/2014
Ada Hamosh - updated : 11/13/2013
Ada Hamosh - updated : 10/7/2013
Ada Hamosh - updated : 8/10/2012
Ada Hamosh - updated : 6/5/2012
Ada Hamosh - updated : 5/15/2012
Cassandra L. Kniffin - updated : 4/18/2011
Cassandra L. Kniffin - updated : 6/25/2010
Cassandra L. Kniffin - updated : 1/6/2010
Paul J. Converse - updated : 8/27/2009
Paul J. Converse - updated : 8/6/2009
Cassandra L. Kniffin - updated : 7/21/2009
Cassandra L. Kniffin - updated : 6/17/2009
Marla J. F. O'Neill - updated : 2/12/2009
Ada Hamosh - updated : 8/6/2008
Cassandra L. Kniffin - updated : 6/19/2008
Jane Kelly - updated : 6/5/2008
Ada Hamosh - updated : 4/1/2008
Cassandra L. Kniffin - updated : 2/7/2008
Victor A. McKusick - updated : 12/20/2007
Victor A. McKusick - updated : 11/12/2007
Jane Kelly - updated : 10/29/2007
Cassandra L. Kniffin - updated : 9/20/2007
Cassandra L. Kniffin - updated : 6/15/2007
George E. Tiller - updated : 5/22/2007
Cassandra L. Kniffin - updated : 1/4/2007
Jane Kelly - updated : 10/6/2006
Marla J. F. O'Neill - updated : 9/8/2006
Victor A. McKusick - updated : 7/12/2006
Victor A. McKusick - updated : 6/6/2006
Cassandra L. Kniffin - updated : 4/24/2006
Cassandra L. Kniffin - updated : 4/18/2006
Cassandra L. Kniffin - updated : 1/4/2006
Marla J. F. O'Neill - updated : 11/30/2005
Marla J. F. O'Neill - updated : 11/15/2005
Cassandra L. Kniffin - updated : 11/7/2005
Ada Hamosh - updated : 11/2/2005
Cassandra L. Kniffin - updated : 9/1/2005
Cassandra L. Kniffin - updated : 7/12/2005
Ada Hamosh - updated : 6/2/2005
Cassandra L. Kniffin - updated : 3/4/2005
Ada Hamosh - updated : 12/10/2004
Marla J. F. O'Neill - updated : 11/3/2004
Cassandra L. Kniffin - updated : 9/17/2004
Marla J. F. O'Neill - updated : 9/13/2004
Patricia A. Hartz - updated : 8/16/2004
Jane Kelly - updated : 7/26/2004
Natalie E. Krasikov - updated : 7/7/2004
Cassandra L. Kniffin - updated : 6/21/2004
Natalie E. Krasikov - updated : 3/30/2004
Cassandra L. Kniffin - updated : 1/29/2004
Victor A. McKusick - updated : 12/8/2003
Victor A. McKusick - updated : 10/7/2003
Cassandra L. Kniffin - updated : 9/5/2003
Jane Kelly - updated : 8/19/2003
Michael B. Petersen - updated : 7/2/2003
Cassandra L. Kniffin - updated : 6/20/2003
Victor A. McKusick - updated : 5/23/2003
Cassandra L. Kniffin - updated : 5/15/2003
Patricia A. Hartz - updated : 4/28/2003
Cassandra L. Kniffin - updated : 3/4/2003
Cassandra L. Kniffin - updated : 2/11/2003
Cassandra L. Kniffin - updated : 1/8/2003
Cassandra L. Kniffin - updated : 9/6/2002
Cassandra L. Kniffin - updated : 6/13/2002
Victor A. McKusick - updated : 6/12/2002
Cassandra L. Kniffin - updated : 6/12/2002
Cassandra L. Kniffin - updated : 5/28/2002
George E. Tiller - updated : 5/7/2002
Sonja A. Rasmussen - updated : 4/18/2002
Jane Kelly - updated : 4/3/2002
Victor A. McKusick - updated : 8/10/2001
John A. Phillips, III - updated : 8/8/2001
Victor A. McKusick - updated : 6/21/2001
Paul J. Converse - updated : 5/16/2001
Ada Hamosh - updated : 4/26/2001
George E. Tiller - updated : 11/14/2000
Victor A. McKusick - updated : 10/20/2000
Victor A. McKusick - updated : 9/15/2000
Ada Hamosh - updated : 9/13/2000
Victor A. McKusick - updated : 5/1/2000
Victor A. McKusick - updated : 4/18/2000
Ada Hamosh - updated : 3/27/2000
Ada Hamosh - updated : 2/1/2000
Orest Hurko - updated : 12/2/1999
Michael J. Wright - updated : 8/18/1999
Victor A. McKusick - updated : 4/16/1999
Orest Hurko - updated : 3/23/1999
Ada Hamosh - updated : 3/19/1999
Victor A. McKusick - updated : 1/5/1999
Orest Hurko - updated : 12/3/1998
Victor A. McKusick - updated : 11/5/1998
Victor A. McKusick - updated : 7/27/1998
Victor A. McKusick - updated : 5/11/1998
Victor A. McKusick - updated : 10/9/1997
Victor A. McKusick - updated : 6/12/1997
Victor A. McKusick - updated : 4/8/1997
Stylianos E. Antonarakis - updated : 3/20/1997
Iosif W. Lurie - updated : 1/8/1997
Orest Hurko - edited : 12/19/1996
Orest Hurko - updated : 12/16/1996
Lori M. Kelman - updated : 11/15/1996
Cynthia K. Ewing - updated : 9/6/1996
Orest Hurko - updated : 5/14/1996
Orest Hurko - updated : 5/8/1996
Orest Hurko - updated : 4/3/1996
Orest Hurko - updated : 3/6/1996
Orest Hurko - updated : 2/22/1996
Orest Hurko - updated : 2/7/1996
Orest Hurko - updated : 1/25/1996
Orest Hurko - updated : 11/13/1995

Creation Date:

Victor A. McKusick : 1/26/1990

Edit History:

carol : 09/27/2024

alopez : 09/26/2024
alopez : 09/25/2024
carol : 06/08/2023
alopez : 06/27/2022
carol : 04/28/2022
mgross : 11/03/2020
alopez : 11/25/2019
alopez : 11/22/2019
carol : 01/10/2018
alopez : 12/27/2017
carol : 10/18/2017
carol : 10/05/2017
carol : 02/21/2017
carol : 02/15/2017
carol : 02/14/2017
carol : 11/10/2016
carol : 08/05/2016
alopez : 08/04/2015
alopez : 8/4/2015
mgross : 7/24/2015
mcolton : 7/8/2015
mgross : 12/10/2014
mcolton : 12/4/2014
mcolton : 12/4/2014
carol : 11/18/2014
mgross : 7/28/2014
alopez : 11/13/2013
alopez : 10/7/2013
alopez : 10/7/2013
carol : 9/30/2013
joanna : 9/23/2013
alopez : 9/12/2013
alopez : 3/11/2013
terry : 10/10/2012
carol : 8/17/2012
carol : 8/10/2012
terry : 8/10/2012
terry : 7/13/2012
terry : 7/5/2012
alopez : 6/7/2012
alopez : 6/7/2012
alopez : 6/7/2012
terry : 6/6/2012
terry : 6/5/2012
terry : 5/24/2012
alopez : 5/15/2012
terry : 5/15/2012
carol : 3/6/2012
carol : 3/6/2012
carol : 3/6/2012
wwang : 8/9/2011
wwang : 4/22/2011
ckniffin : 4/18/2011
alopez : 1/24/2011
wwang : 7/7/2010
ckniffin : 6/25/2010
terry : 5/12/2010
wwang : 1/20/2010
ckniffin : 1/19/2010
ckniffin : 1/6/2010
ckniffin : 1/6/2010
mgross : 9/4/2009
terry : 8/27/2009
mgross : 8/17/2009
mgross : 8/17/2009
terry : 8/6/2009
wwang : 8/5/2009
wwang : 7/31/2009
ckniffin : 7/21/2009
wwang : 7/17/2009
ckniffin : 6/17/2009
terry : 6/3/2009
carol : 3/17/2009
carol : 2/13/2009
carol : 2/12/2009
terry : 1/8/2009
terry : 1/8/2009
carol : 8/13/2008
terry : 8/6/2008
terry : 7/3/2008
wwang : 7/1/2008
ckniffin : 6/19/2008
carol : 6/5/2008
carol : 4/2/2008
carol : 4/1/2008
wwang : 2/25/2008
ckniffin : 2/7/2008
alopez : 2/6/2008
terry : 12/20/2007
alopez : 11/12/2007
carol : 10/29/2007
wwang : 9/25/2007
ckniffin : 9/20/2007
wwang : 6/27/2007
ckniffin : 6/15/2007
wwang : 5/30/2007
terry : 5/22/2007
alopez : 1/29/2007
wwang : 1/26/2007
ckniffin : 1/4/2007
wwang : 11/8/2006
carol : 10/6/2006
terry : 10/6/2006
wwang : 9/12/2006
terry : 9/8/2006
terry : 8/24/2006
alopez : 7/18/2006
terry : 7/12/2006
alopez : 6/12/2006
terry : 6/6/2006
wwang : 6/2/2006
wwang : 5/10/2006
ckniffin : 4/24/2006
wwang : 4/24/2006
ckniffin : 4/18/2006
alopez : 2/16/2006
terry : 2/15/2006
wwang : 2/1/2006
ckniffin : 1/4/2006
alopez : 12/12/2005
wwang : 11/30/2005
wwang : 11/15/2005
wwang : 11/15/2005
ckniffin : 11/7/2005
alopez : 11/4/2005
terry : 11/2/2005
terry : 10/12/2005
wwang : 9/19/2005
ckniffin : 9/1/2005
carol : 8/29/2005
wwang : 7/27/2005
ckniffin : 7/12/2005
ckniffin : 7/12/2005
tkritzer : 6/6/2005
terry : 6/2/2005
terry : 3/11/2005
terry : 3/11/2005
tkritzer : 3/9/2005
ckniffin : 3/4/2005
alopez : 12/14/2004
terry : 12/10/2004
tkritzer : 11/11/2004
tkritzer : 11/4/2004
terry : 11/3/2004
tkritzer : 10/4/2004
ckniffin : 9/17/2004
tkritzer : 9/13/2004
mgross : 8/31/2004
terry : 8/16/2004
tkritzer : 7/28/2004
terry : 7/26/2004
carol : 7/7/2004
tkritzer : 7/6/2004
ckniffin : 6/21/2004
carol : 6/17/2004
terry : 3/30/2004
carol : 3/17/2004
tkritzer : 2/4/2004
ckniffin : 1/29/2004
tkritzer : 12/9/2003
terry : 12/8/2003
carol : 11/5/2003
tkritzer : 10/7/2003
tkritzer : 10/7/2003
tkritzer : 9/11/2003
ckniffin : 9/5/2003
carol : 8/19/2003
cwells : 7/2/2003
carol : 6/23/2003
ckniffin : 6/20/2003
carol : 6/11/2003
mgross : 6/2/2003
ckniffin : 5/28/2003
terry : 5/23/2003
cwells : 5/21/2003
carol : 5/20/2003
ckniffin : 5/15/2003
ckniffin : 5/15/2003
cwells : 5/2/2003
cwells : 5/2/2003
terry : 4/28/2003
tkritzer : 4/8/2003
tkritzer : 4/7/2003
ckniffin : 3/13/2003
ckniffin : 3/4/2003
carol : 2/25/2003
ckniffin : 2/11/2003
cwells : 1/14/2003
ckniffin : 1/8/2003
terry : 1/6/2003
carol : 9/9/2002
ckniffin : 9/6/2002
carol : 6/18/2002
ckniffin : 6/13/2002
terry : 6/12/2002
carol : 6/12/2002
ckniffin : 6/12/2002
ckniffin : 6/5/2002
carol : 5/28/2002
ckniffin : 5/28/2002
cwells : 5/17/2002
cwells : 5/7/2002
carol : 4/19/2002
terry : 4/18/2002
mgross : 4/3/2002
mgross : 4/3/2002
mcapotos : 10/26/2001
mgross : 8/10/2001
alopez : 8/8/2001
mcapotos : 7/5/2001
mcapotos : 6/27/2001
terry : 6/21/2001
cwells : 6/21/2001
cwells : 6/21/2001
cwells : 5/16/2001
mcapotos : 5/4/2001
mcapotos : 5/3/2001
mcapotos : 4/27/2001
terry : 4/26/2001
carol : 4/6/2001
mgross : 4/5/2001
mcapotos : 11/14/2000
mcapotos : 11/9/2000
mcapotos : 11/6/2000
mcapotos : 10/30/2000
terry : 10/20/2000
alopez : 10/3/2000
terry : 9/15/2000
terry : 9/13/2000
mcapotos : 5/11/2000
mcapotos : 5/10/2000
terry : 5/1/2000
terry : 4/18/2000
alopez : 3/30/2000
terry : 3/27/2000
mcapotos : 3/22/2000
mcapotos : 3/7/2000
mcapotos : 3/7/2000
mcapotos : 3/7/2000
alopez : 2/3/2000
terry : 2/1/2000
carol : 12/3/1999
terry : 12/2/1999
alopez : 8/18/1999
terry : 7/7/1999
carol : 6/28/1999
carol : 4/19/1999
terry : 4/16/1999
carol : 3/23/1999
alopez : 3/19/1999
carol : 1/6/1999
terry : 1/5/1999
carol : 12/3/1998
carol : 11/15/1998
dkim : 11/13/1998
terry : 11/5/1998
alopez : 7/31/1998
alopez : 7/30/1998
alopez : 7/30/1998
terry : 7/27/1998
carol : 5/28/1998
terry : 5/11/1998
terry : 10/9/1997
terry : 9/15/1997
alopez : 7/10/1997
jenny : 7/9/1997
joanna : 6/23/1997
carol : 6/23/1997
mark : 6/18/1997
terry : 6/12/1997
mark : 5/8/1997
mark : 5/8/1997
terry : 4/10/1997
jenny : 4/8/1997
terry : 4/4/1997
jenny : 3/31/1997
jenny : 3/25/1997
jenny : 3/21/1997
jenny : 3/20/1997
jenny : 3/20/1997
jenny : 3/18/1997
mark : 3/10/1997
terry : 3/6/1997
terry : 3/6/1997
jenny : 3/4/1997
jenny : 2/24/1997
jenny : 1/21/1997
jenny : 1/8/1997
mark : 12/19/1996
mark : 12/19/1996
mark : 12/16/1996
mark : 12/16/1996
terry : 12/9/1996
jamie : 11/15/1996
jamie : 11/6/1996
jamie : 11/1/1996
terry : 10/22/1996
mark : 7/22/1996
mark : 6/21/1996
mark : 6/20/1996
mark : 6/20/1996
terry : 5/17/1996
terry : 5/14/1996
mark : 5/10/1996
terry : 5/10/1996
mark : 5/8/1996
mark : 5/8/1996
terry : 5/2/1996
mark : 4/25/1996
terry : 4/19/1996
mark : 4/12/1996
terry : 4/5/1996
mark : 4/3/1996
terry : 3/23/1996
mark : 3/6/1996
mark : 3/6/1996
terry : 2/23/1996
mark : 2/22/1996
terry : 2/9/1996
mark : 2/7/1996
mark : 2/2/1996
terry : 1/27/1996
mark : 1/25/1996
mark : 1/25/1996
terry : 1/19/1996
mark : 10/12/1995
jason : 6/14/1994
warfield : 4/7/1994
pfoster : 4/1/1994
mimadm : 2/21/1994

* 107741

APOLIPOPROTEIN E; APOE

HGNC Approved Gene Symbol: APOE

SNOMEDCT: 37821003, 412642004, 446923008;

Cytogenetic location: 19q13.32 Genomic coordinates (GRCh38) : 19:44,905,796-44,909,393 (from NCBI)

Gene-Phenotype Relationships

Location	Phenotype	Phenotype MIM number	Inheritance	Phenotype mapping key
19q13.32	{?Alzheimer disease, protection against, due to APOE3-Christchurch}	607822	Autosomal dominant	3
	{?Macular degeneration, age-related}	603075	Autosomal dominant	3
	{Coronary artery disease, severe, susceptibility to}	617347		3
	Alzheimer disease 2	104310	Autosomal dominant	3
	Hyperlipoproteinemia, type III	617347		3
	Lipoprotein glomerulopathy	611771		3
	Sea-blue histiocyte disease	269600	Autosomal recessive	3

TEXT

Description

Apolipoprotein E is the recognition site for receptors involved in the clearance of remnants of very low density lipoproteins and chylomicrons (summary by Blum, 2016).

Cloning and Expression

Rall et al. (1982) published the full amino acid sequence of apoE. Mature apoE is a 299-amino acid polypeptide.

Mapping

Gene Function

The E2 isoform shows defective binding of remnants to hepatic lipoprotein receptors (Schneider et al., 1981; Rall et al., 1982) and delayed clearance from plasma (Gregg et al., 1981).

Evolution

Population Genetics

Molecular Genetics

Data on gene frequencies of apoE allelic variants were tabulated by Roychoudhury and Nei (1988).

In a comprehensive review of apoE variants, de Knijff et al. (1994) found that 30 variants had been characterized, including the most common variant, apoE3.

Hyperlipoproteinemia Type III

Role in Cardiovascular Disease

Sea-Blue Histiocyte Disease

Nguyen et al. (2000) reported 2 kindreds in which the sea-blue histiocyte syndrome (269600) was associated with an apoE variant (del149Leu; 107741.0031) in the absence of severe dyslipidemia.

Lipoprotein Glomerulopathy

In 3 Japanese patients with lipoprotein glomerulopathy (LPG; 611771), Oikawa et al. (1997) identified heterozygosity for a mutation in the APOE gene (R145P; 107741.0032).

Alzheimer Disease 2

Myers et al. (1996) examined the association of apolipoprotein E4 with Alzheimer disease and other dementias in 1,030 elderly individuals in the Framingham Study cohort. They found an increased risk for Alzheimer disease as well as other dementias in patients who were homozygous or heterozygous for E4. However, they pointed out that most apoE4 carriers do not develop dementia, and about one-half of Alzheimer disease is not associated with apoE4.

In a study of 140 elderly Nigerian patients with dementia, of which 123 were diagnosed with AD, Gureje et al. (2006) found no association between the APOE4 allele and dementia or AD.

Role in Alzheimer Disease 3

Role in Cognitive Decline with Aging

Possible Role in Multiple Sclerosis

Role in Recovery From Traumatic Brain Injury

Possible Role in Other Neurologic Disorders

In a metaanalysis of 1,500 cases of schizophrenia versus 2,702 controls, Allen et al. (2008) found that the odds ratio for the APOE4 versus the APOE3 genotype was 1.16 (95% CI, 1.00-1.34; p = 0.043).

Possible Role in Ocular Disorders

Possible Role in Other Disorders

Animal Model

History

ALLELIC VARIANTS 34 Selected Examples):

.0001 HYPERLIPOPROTEINEMIA, TYPE III, DUE TO APOE2, AUTOSOMAL RECESSIVE

APOE, ARG158CYS
SNP: rs7412, gnomAD: rs7412, ClinVar: RCV000019428, RCV000019439, RCV000019452, RCV000211178, RCV000346955, RCV000825286, RCV000845582, RCV001262472, RCV001529800

The common E2 isoform carrying arg158-to-cys (R158C) was found in 98 of 100 E2 alleles by Emi et al. (1988).

.0002 HYPERLIPOPROTEINEMIA, TYPE III, AND ATHEROSCLEROSIS ASSOCIATED WITH APOE5

APOE, GLU3LYS
SNP: rs121918392, gnomAD: rs121918392, ClinVar: RCV000019429

Using isoelectric focusing with immunoblotting in the study of blood specimens from 1,269 Japanese subjects, Matsunaga et al. (1995) found that the epsilon-5 allele had a frequency of 0.001.

.0003 HYPERLIPOPROTEINEMIA, TYPE III, DUE TO APOE2-CHRISTCHURCH

APOE, APOE2 AND ARG136SER
SNP: rs121918393, gnomAD: rs121918393, ClinVar: RCV000019430, RCV000856604

.0004 HYPERLIPOPROTEINEMIA, TYPE III, ASSOCIATED WITH APOE2

APOE, ARG145CYS
SNP: rs769455, gnomAD: rs769455, ClinVar: RCV000019432, RCV000019443, RCV000884152, RCV001777143, RCV002326680, RCV003924846

.0005 HYPERLIPOPROTEINEMIA, TYPE III, ASSOCIATED WITH APOE DEFICIENCY

APOE, IVS3AS, A-G, -1
SNP: rs397514253, ClinVar: RCV000019433

.0006 HYPERLIPOPROTEINEMIA, TYPE III, ASSOCIATED WITH APOE3-LEIDEN

APOE, 21-BP DUP, CODONS 121-127
SNP: rs397514254, ClinVar: RCV000019434

.0007 HYPERLIPOPROTEINEMIA, TYPE III, AND ATHEROSCLEROSIS ASSOCIATED WITH APOE7

APOE-SUITA

APOE, GLU244LYS AND GLU245LYS
SNP: rs140808909, rs190853081, gnomAD: rs140808909, rs190853081, ClinVar: RCV000019435

Using isoelectric focusing with immunoblotting in the study of blood specimens from 1,269 Japanese subjects, Matsunaga et al. (1995) found that the epsilon-7 allele (E7) had a frequency of 0.007.

This variant has also been designated APOE-SUITA. Yamamura et al. (1984) had identified the apoE-Suita isoform in 4 unrelated patients with hyperlipidemia and/or atherosclerosis.

.0008 HYPERLIPOPROTEINEMIA, TYPE III, AUTOSOMAL DOMINANT, ASSOCIATED WITH APOE3

APOE, APOE3, CYS112ARG AND ARG142CYS
SNP: rs387906567, rs429358, gnomAD: rs387906567, rs429358, ClinVar: RCV000019438, RCV000019448, RCV000019455, RCV000019456, RCV000019458, RCV000292119, RCV000826089, RCV000845581, RCV000991302, RCV001175124, RCV001195807, RCV001262791, RCV003227801

.0009 HYPERLIPOPROTEINEMIA DUE TO APOE1

APOE, GLY127ASP AND ARG158CYS
SNP: rs267606664, gnomAD: rs267606664, ClinVar: RCV000019428, RCV000019439, RCV000019452, RCV000211178, RCV000346955, RCV000825286, RCV000845582, RCV001262472, RCV001262660, RCV001529800, RCV001579351, RCV002476210

.0010 HYPERLIPOPROTEINEMIA, TYPE III, DUE TO APOE1-HARRISBURG

APOE, LYS146GLU
SNP: rs121918394, gnomAD: rs121918394, ClinVar: RCV000019440

.0011 HYPERLIPOPROTEINEMIA, TYPE III, DUE TO APOE2

APOE, APOE2, LYS146GLN
SNP: rs121918394, gnomAD: rs121918394, ClinVar: RCV001804151

.0012 APOE2-DUNEDIN

HYPERLIPOPROTEINEMIA, TYPE IV/V, DUE TO APOE2-DUNEDIN

APOE, APOE2, ARG228CYS
SNP: rs121918395, gnomAD: rs121918395, ClinVar: RCV000019442, RCV004556717

.0013 HYPERLIPOPROTEINEMIA, TYPE III, DUE TO APOE4-PHILADELPHIA

APOE, GLU13LYS AND ARG145CYS
SNP: rs201672011, gnomAD: rs201672011, ClinVar: RCV000019432, RCV000019443, RCV000019453, RCV000884152, RCV001777143, RCV002225641, RCV002326680, RCV003924846

.0014 HYPERLIPOPROTEINEMIA, TYPE III, ASSOCIATED WITH APOE DEFICIENCY

HYPERLIPOPROTEINEMIA, TYPE III, ASSOCIATED WITH APOE3(WASHINGTON)

APOE, TRP210TER
SNP: rs121918396, gnomAD: rs121918396, ClinVar: RCV000019445, RCV000856605

.0015 APOE3 ISOFORM

APOE, CYS112 AND ARG158
SNP: rs429358, gnomAD: rs429358, ClinVar: RCV000019447, RCV000856604

.0016 ALZHEIMER DISEASE 2 DUE TO APOE4 ISOFORM

APOE, CYS112ARG
SNP: rs429358, gnomAD: rs429358, ClinVar: RCV000019438, RCV000019448, RCV000019455, RCV000019456, RCV000019458, RCV000292119, RCV000826089, RCV000845581, RCV000991302, RCV001175124, RCV001195807, RCV001262791

.0017 HYPERLIPOPROTEINEMIA, TYPE III, ASSOCIATED WITH APOE DEFICIENCY, AUTOSOMAL RECESSIVE

APOE, 1-BP DEL, 2919G
SNP: rs2122132718, ClinVar: RCV000019444

.0018 HYPERLIPOPROTEINEMIA, TYPE III, DUE TO APOE3(-)-KOCHI

APOE, ARG145HIS
SNP: rs121918397, gnomAD: rs121918397, ClinVar: RCV000019449, RCV002250463

.0019 HYPERLIPOPROTEINEMIA, TYPE III, DUE TO APOE2-FUKUOKA

APOE, ARG224GLN
SNP: rs267606663, gnomAD: rs267606663, ClinVar: RCV000019428, RCV000019439, RCV000019452, RCV000211178, RCV000346955, RCV000825286, RCV000845582, RCV001262472, RCV001529800

.0020 APOE5 VARIANT

APOE, GLU13LYS
ClinVar: RCV000019429, RCV000019443, RCV000019453, RCV002225641

.0021 HYPERLIPOPROTEINEMIA, TYPE III, ASSOCIATED WITH APOE2

APOE, APOE2, VAL236GLU
SNP: rs199768005, gnomAD: rs199768005, ClinVar: RCV000019428, RCV000019439, RCV000019452, RCV000211178, RCV000346955, RCV000825286, RCV000845582, RCV001262472, RCV001529800, RCV001579858, RCV001701092, RCV004559221

.0022 HYPERLIPOPROTEINEMIA, TYPE III, ASSOCIATED WITH APOE3

APOE, CYS112ARG AND ARG251GLY
SNP: rs267606661, gnomAD: rs267606661, ClinVar: RCV000019438, RCV000019448, RCV000019455, RCV000019456, RCV000019458, RCV000292119, RCV000826089, RCV000845581, RCV000991302, RCV001175124, RCV001195807, RCV001262791, RCV001565388, RCV002483522, RCV003227792, RCV003352927, RCV004730981

.0023 APOE4(-)-FREIBURG

APOE, LEU28PRO AND CYS112ARG
SNP: rs769452, gnomAD: rs769452, ClinVar: RCV000019438, RCV000019448, RCV000019455, RCV000019456, RCV000019458, RCV000292119, RCV000429606, RCV000826089, RCV000845581, RCV000991302, RCV001175124, RCV001195807, RCV001195944, RCV001262791, RCV002379036

.0024 APOE3(-)-FREIBURG

APOE, THR42ALA
SNP: rs28931576, gnomAD: rs28931576, ClinVar: RCV000019457

.0025 APOE5 VARIANT

APOE, PRO84ARG AND CYS112ARG
SNP: rs11083750, gnomAD: rs11083750, ClinVar: RCV000019438, RCV000019448, RCV000019455, RCV000019456, RCV000019458, RCV000292119, RCV000826089, RCV000845581, RCV000991302, RCV001175124, RCV001195807, RCV001262791

.0026 APOE3 VARIANT

APOE, ALA99THR AND ALA152PRO
SNP: rs267606662, rs28931577, ClinVar: RCV000019459

.0027 APOE2 VARIANT

APOE, ARG134GLN
SNP: rs28931578, gnomAD: rs28931578, ClinVar: RCV000019460

.0028 APOE4 VARIANT

APOE, ARG274HIS
SNP: rs121918398, gnomAD: rs121918398, ClinVar: RCV000019461

.0029 APOE4(+)

APOE, SER296ARG
SNP: rs28931579, gnomAD: rs28931579, ClinVar: RCV000019462

.0030 CORONARY ARTERY DISEASE, SEVERE, SUSCEPTIBILITY TO

APOE, -219G-T ({dbSNP rs405509})
SNP: rs405509, gnomAD: rs405509, ClinVar: RCV001804152

.0031 SEA-BLUE HISTIOCYTE DISEASE

APOE, 3-BP DEL, 499CTC
SNP: rs515726148, ClinVar: RCV000202536, RCV002336246, RCV003221804, RCV004755773

.0032 LIPOPROTEIN GLOMERULOPATHY

APOE, ARG145PRO
SNP: rs121918397, gnomAD: rs121918397, ClinVar: RCV000019466

.0033 LIPOPROTEIN GLOMERULOPATHY

APOE, ARG25CYS
SNP: rs121918399, gnomAD: rs121918399, ClinVar: RCV000019468, RCV002496418

Rovin et al. (2007) identified APOE Kyoto in 2 American males of European descent with LPG.

.0034 ALZHEIMER DISEASE 3, PROTECTION AGAINST, DUE TO APOE3-CHRISTCHURCH (1 family)

APOE, APOE3, ARG136SER
ClinVar: RCV000019430, RCV000856604

REFERENCES

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Contributors:

Ada Hamosh - updated : 09/25/2024
Ada Hamosh - updated : 11/03/2020
Ada Hamosh - updated : 11/22/2019
Ada Hamosh - updated : 12/27/2017
Carol A. Bocchini - updated : 02/14/2017
Patricia A. Hartz - updated : 12/4/2014
Ada Hamosh - updated : 11/13/2013
Ada Hamosh - updated : 10/7/2013
Ada Hamosh - updated : 8/10/2012
Ada Hamosh - updated : 6/5/2012
Ada Hamosh - updated : 5/15/2012
Cassandra L. Kniffin - updated : 4/18/2011
Cassandra L. Kniffin - updated : 6/25/2010
Cassandra L. Kniffin - updated : 1/6/2010
Paul J. Converse - updated : 8/27/2009
Paul J. Converse - updated : 8/6/2009
Cassandra L. Kniffin - updated : 7/21/2009
Cassandra L. Kniffin - updated : 6/17/2009
Marla J. F. O'Neill - updated : 2/12/2009
Ada Hamosh - updated : 8/6/2008
Cassandra L. Kniffin - updated : 6/19/2008
Jane Kelly - updated : 6/5/2008
Ada Hamosh - updated : 4/1/2008
Cassandra L. Kniffin - updated : 2/7/2008
Victor A. McKusick - updated : 12/20/2007
Victor A. McKusick - updated : 11/12/2007
Jane Kelly - updated : 10/29/2007
Cassandra L. Kniffin - updated : 9/20/2007
Cassandra L. Kniffin - updated : 6/15/2007
George E. Tiller - updated : 5/22/2007
Cassandra L. Kniffin - updated : 1/4/2007
Jane Kelly - updated : 10/6/2006
Marla J. F. O'Neill - updated : 9/8/2006
Victor A. McKusick - updated : 7/12/2006
Victor A. McKusick - updated : 6/6/2006
Cassandra L. Kniffin - updated : 4/24/2006
Cassandra L. Kniffin - updated : 4/18/2006
Cassandra L. Kniffin - updated : 1/4/2006
Marla J. F. O'Neill - updated : 11/30/2005
Marla J. F. O'Neill - updated : 11/15/2005
Cassandra L. Kniffin - updated : 11/7/2005
Ada Hamosh - updated : 11/2/2005
Cassandra L. Kniffin - updated : 9/1/2005
Cassandra L. Kniffin - updated : 7/12/2005
Ada Hamosh - updated : 6/2/2005
Cassandra L. Kniffin - updated : 3/4/2005
Ada Hamosh - updated : 12/10/2004
Marla J. F. O'Neill - updated : 11/3/2004
Cassandra L. Kniffin - updated : 9/17/2004
Marla J. F. O'Neill - updated : 9/13/2004
Patricia A. Hartz - updated : 8/16/2004
Jane Kelly - updated : 7/26/2004
Natalie E. Krasikov - updated : 7/7/2004
Cassandra L. Kniffin - updated : 6/21/2004
Natalie E. Krasikov - updated : 3/30/2004
Cassandra L. Kniffin - updated : 1/29/2004
Victor A. McKusick - updated : 12/8/2003
Victor A. McKusick - updated : 10/7/2003
Cassandra L. Kniffin - updated : 9/5/2003
Jane Kelly - updated : 8/19/2003
Michael B. Petersen - updated : 7/2/2003
Cassandra L. Kniffin - updated : 6/20/2003
Victor A. McKusick - updated : 5/23/2003
Cassandra L. Kniffin - updated : 5/15/2003
Patricia A. Hartz - updated : 4/28/2003
Cassandra L. Kniffin - updated : 3/4/2003
Cassandra L. Kniffin - updated : 2/11/2003
Cassandra L. Kniffin - updated : 1/8/2003
Cassandra L. Kniffin - updated : 9/6/2002
Cassandra L. Kniffin - updated : 6/13/2002
Victor A. McKusick - updated : 6/12/2002
Cassandra L. Kniffin - updated : 6/12/2002
Cassandra L. Kniffin - updated : 5/28/2002
George E. Tiller - updated : 5/7/2002
Sonja A. Rasmussen - updated : 4/18/2002
Jane Kelly - updated : 4/3/2002
Victor A. McKusick - updated : 8/10/2001
John A. Phillips, III - updated : 8/8/2001
Victor A. McKusick - updated : 6/21/2001
Paul J. Converse - updated : 5/16/2001
Ada Hamosh - updated : 4/26/2001
George E. Tiller - updated : 11/14/2000
Victor A. McKusick - updated : 10/20/2000
Victor A. McKusick - updated : 9/15/2000
Ada Hamosh - updated : 9/13/2000
Victor A. McKusick - updated : 5/1/2000
Victor A. McKusick - updated : 4/18/2000
Ada Hamosh - updated : 3/27/2000
Ada Hamosh - updated : 2/1/2000
Orest Hurko - updated : 12/2/1999
Michael J. Wright - updated : 8/18/1999
Victor A. McKusick - updated : 4/16/1999
Orest Hurko - updated : 3/23/1999
Ada Hamosh - updated : 3/19/1999
Victor A. McKusick - updated : 1/5/1999
Orest Hurko - updated : 12/3/1998
Victor A. McKusick - updated : 11/5/1998
Victor A. McKusick - updated : 7/27/1998
Victor A. McKusick - updated : 5/11/1998
Victor A. McKusick - updated : 10/9/1997
Victor A. McKusick - updated : 6/12/1997
Victor A. McKusick - updated : 4/8/1997
Stylianos E. Antonarakis - updated : 3/20/1997
Iosif W. Lurie - updated : 1/8/1997
Orest Hurko - edited : 12/19/1996
Orest Hurko - updated : 12/16/1996
Lori M. Kelman - updated : 11/15/1996
Cynthia K. Ewing - updated : 9/6/1996
Orest Hurko - updated : 5/14/1996
Orest Hurko - updated : 5/8/1996
Orest Hurko - updated : 4/3/1996
Orest Hurko - updated : 3/6/1996
Orest Hurko - updated : 2/22/1996
Orest Hurko - updated : 2/7/1996
Orest Hurko - updated : 1/25/1996
Orest Hurko - updated : 11/13/1995

Creation Date:

Victor A. McKusick : 1/26/1990

Edit History:

carol : 09/27/2024
alopez : 09/26/2024
alopez : 09/25/2024
carol : 06/08/2023
alopez : 06/27/2022
carol : 04/28/2022
mgross : 11/03/2020
alopez : 11/25/2019
alopez : 11/22/2019
carol : 01/10/2018
alopez : 12/27/2017
carol : 10/18/2017
carol : 10/05/2017
carol : 02/21/2017
carol : 02/15/2017
carol : 02/14/2017
carol : 11/10/2016
carol : 08/05/2016
alopez : 08/04/2015
alopez : 8/4/2015
mgross : 7/24/2015
mcolton : 7/8/2015
mgross : 12/10/2014
mcolton : 12/4/2014
mcolton : 12/4/2014
carol : 11/18/2014
mgross : 7/28/2014
alopez : 11/13/2013
alopez : 10/7/2013
alopez : 10/7/2013
carol : 9/30/2013
joanna : 9/23/2013
alopez : 9/12/2013
alopez : 3/11/2013
terry : 10/10/2012
carol : 8/17/2012
carol : 8/10/2012
terry : 8/10/2012
terry : 7/13/2012
terry : 7/5/2012
alopez : 6/7/2012
alopez : 6/7/2012
alopez : 6/7/2012
terry : 6/6/2012
terry : 6/5/2012
terry : 5/24/2012
alopez : 5/15/2012
terry : 5/15/2012
carol : 3/6/2012
carol : 3/6/2012
carol : 3/6/2012
wwang : 8/9/2011
wwang : 4/22/2011
ckniffin : 4/18/2011
alopez : 1/24/2011
wwang : 7/7/2010
ckniffin : 6/25/2010
terry : 5/12/2010
wwang : 1/20/2010
ckniffin : 1/19/2010
ckniffin : 1/6/2010
ckniffin : 1/6/2010
mgross : 9/4/2009
terry : 8/27/2009
mgross : 8/17/2009
mgross : 8/17/2009
terry : 8/6/2009
wwang : 8/5/2009
wwang : 7/31/2009
ckniffin : 7/21/2009
wwang : 7/17/2009
ckniffin : 6/17/2009
terry : 6/3/2009
carol : 3/17/2009
carol : 2/13/2009
carol : 2/12/2009
terry : 1/8/2009
terry : 1/8/2009
carol : 8/13/2008
terry : 8/6/2008
terry : 7/3/2008
wwang : 7/1/2008
ckniffin : 6/19/2008
carol : 6/5/2008
carol : 4/2/2008
carol : 4/1/2008
wwang : 2/25/2008
ckniffin : 2/7/2008
alopez : 2/6/2008
terry : 12/20/2007
alopez : 11/12/2007
carol : 10/29/2007
wwang : 9/25/2007
ckniffin : 9/20/2007
wwang : 6/27/2007
ckniffin : 6/15/2007
wwang : 5/30/2007
terry : 5/22/2007
alopez : 1/29/2007
wwang : 1/26/2007
ckniffin : 1/4/2007
wwang : 11/8/2006
carol : 10/6/2006
terry : 10/6/2006
wwang : 9/12/2006
terry : 9/8/2006
terry : 8/24/2006
alopez : 7/18/2006
terry : 7/12/2006
alopez : 6/12/2006
terry : 6/6/2006
wwang : 6/2/2006
wwang : 5/10/2006
ckniffin : 4/24/2006
wwang : 4/24/2006
ckniffin : 4/18/2006
alopez : 2/16/2006
terry : 2/15/2006
wwang : 2/1/2006
ckniffin : 1/4/2006
alopez : 12/12/2005
wwang : 11/30/2005
wwang : 11/15/2005
wwang : 11/15/2005
ckniffin : 11/7/2005
alopez : 11/4/2005
terry : 11/2/2005
terry : 10/12/2005
wwang : 9/19/2005
ckniffin : 9/1/2005
carol : 8/29/2005
wwang : 7/27/2005
ckniffin : 7/12/2005
ckniffin : 7/12/2005
tkritzer : 6/6/2005
terry : 6/2/2005
terry : 3/11/2005
terry : 3/11/2005
tkritzer : 3/9/2005
ckniffin : 3/4/2005
alopez : 12/14/2004
terry : 12/10/2004
tkritzer : 11/11/2004
tkritzer : 11/4/2004
terry : 11/3/2004
tkritzer : 10/4/2004
ckniffin : 9/17/2004
tkritzer : 9/13/2004
mgross : 8/31/2004
terry : 8/16/2004
tkritzer : 7/28/2004
terry : 7/26/2004
carol : 7/7/2004
tkritzer : 7/6/2004
ckniffin : 6/21/2004
carol : 6/17/2004
terry : 3/30/2004
carol : 3/17/2004
tkritzer : 2/4/2004
ckniffin : 1/29/2004
tkritzer : 12/9/2003
terry : 12/8/2003
carol : 11/5/2003
tkritzer : 10/7/2003
tkritzer : 10/7/2003
tkritzer : 9/11/2003
ckniffin : 9/5/2003
carol : 8/19/2003
cwells : 7/2/2003
carol : 6/23/2003
ckniffin : 6/20/2003
carol : 6/11/2003
mgross : 6/2/2003
ckniffin : 5/28/2003
terry : 5/23/2003
cwells : 5/21/2003
carol : 5/20/2003
ckniffin : 5/15/2003
ckniffin : 5/15/2003
cwells : 5/2/2003
cwells : 5/2/2003
terry : 4/28/2003
tkritzer : 4/8/2003
tkritzer : 4/7/2003
ckniffin : 3/13/2003
ckniffin : 3/4/2003
carol : 2/25/2003
ckniffin : 2/11/2003
cwells : 1/14/2003
ckniffin : 1/8/2003
terry : 1/6/2003
carol : 9/9/2002
ckniffin : 9/6/2002
carol : 6/18/2002
ckniffin : 6/13/2002
terry : 6/12/2002
carol : 6/12/2002
ckniffin : 6/12/2002
ckniffin : 6/5/2002
carol : 5/28/2002
ckniffin : 5/28/2002
cwells : 5/17/2002
cwells : 5/7/2002
carol : 4/19/2002
terry : 4/18/2002
mgross : 4/3/2002
mgross : 4/3/2002
mcapotos : 10/26/2001
mgross : 8/10/2001
alopez : 8/8/2001
mcapotos : 7/5/2001
mcapotos : 6/27/2001
terry : 6/21/2001
cwells : 6/21/2001
cwells : 6/21/2001
cwells : 5/16/2001
mcapotos : 5/4/2001
mcapotos : 5/3/2001
mcapotos : 4/27/2001
terry : 4/26/2001
carol : 4/6/2001
mgross : 4/5/2001
mcapotos : 11/14/2000
mcapotos : 11/9/2000
mcapotos : 11/6/2000
mcapotos : 10/30/2000
terry : 10/20/2000
alopez : 10/3/2000
terry : 9/15/2000
terry : 9/13/2000
mcapotos : 5/11/2000
mcapotos : 5/10/2000
terry : 5/1/2000
terry : 4/18/2000
alopez : 3/30/2000
terry : 3/27/2000
mcapotos : 3/22/2000
mcapotos : 3/7/2000
mcapotos : 3/7/2000
mcapotos : 3/7/2000
alopez : 2/3/2000
terry : 2/1/2000
carol : 12/3/1999
terry : 12/2/1999
alopez : 8/18/1999
terry : 7/7/1999
carol : 6/28/1999
carol : 4/19/1999
terry : 4/16/1999
carol : 3/23/1999
alopez : 3/19/1999
carol : 1/6/1999
terry : 1/5/1999
carol : 12/3/1998
carol : 11/15/1998
dkim : 11/13/1998
terry : 11/5/1998
alopez : 7/31/1998
alopez : 7/30/1998
alopez : 7/30/1998
terry : 7/27/1998
carol : 5/28/1998
terry : 5/11/1998
terry : 10/9/1997
terry : 9/15/1997
alopez : 7/10/1997
jenny : 7/9/1997
joanna : 6/23/1997
carol : 6/23/1997
mark : 6/18/1997
terry : 6/12/1997
mark : 5/8/1997
mark : 5/8/1997
terry : 4/10/1997
jenny : 4/8/1997
terry : 4/4/1997
jenny : 3/31/1997
jenny : 3/25/1997
jenny : 3/21/1997
jenny : 3/20/1997
jenny : 3/20/1997
jenny : 3/18/1997
mark : 3/10/1997
terry : 3/6/1997
terry : 3/6/1997
jenny : 3/4/1997
jenny : 2/24/1997
jenny : 1/21/1997
jenny : 1/8/1997
mark : 12/19/1996
mark : 12/19/1996
mark : 12/16/1996
mark : 12/16/1996
terry : 12/9/1996
jamie : 11/15/1996
jamie : 11/6/1996
jamie : 11/1/1996
terry : 10/22/1996
mark : 7/22/1996
mark : 6/21/1996
mark : 6/20/1996
mark : 6/20/1996
terry : 5/17/1996
terry : 5/14/1996
mark : 5/10/1996
terry : 5/10/1996
mark : 5/8/1996
mark : 5/8/1996
terry : 5/2/1996
mark : 4/25/1996
terry : 4/19/1996
mark : 4/12/1996
terry : 4/5/1996
mark : 4/3/1996
terry : 3/23/1996
mark : 3/6/1996
mark : 3/6/1996
terry : 2/23/1996
mark : 2/22/1996
terry : 2/9/1996
mark : 2/7/1996
mark : 2/2/1996
terry : 1/27/1996
mark : 1/25/1996
mark : 1/25/1996
terry : 1/19/1996
mark : 10/12/1995
jason : 6/14/1994
warfield : 4/7/1994
pfoster : 4/1/1994
mimadm : 2/21/1994

NOTE: OMIM is intended for use primarily by physicians and other professionals concerned with genetic disorders, by genetics researchers, and by advanced students in science and medicine. While the OMIM database is open to the public, users seeking information about a personal medical or genetic condition are urged to consult with a qualified physician for diagnosis and for answers to personal questions.
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Printed: Nov. 2, 2024

▼ External Links

APOLIPOPROTEIN E; APOE

TEXT

▼ Description

▼ Cloning and Expression

▼ Mapping

▼ Gene Function

▼ Evolution

▼ Population Genetics

▼ Molecular Genetics

▼ Animal Model

▼ History

▼ ALLELIC VARIANTS ( 34 Selected Examples):

.0001 HYPERLIPOPROTEINEMIA, TYPE III, DUE TO APOE2, AUTOSOMAL RECESSIVE

.0002 HYPERLIPOPROTEINEMIA, TYPE III, AND ATHEROSCLEROSIS ASSOCIATED WITH APOE5

.0003 HYPERLIPOPROTEINEMIA, TYPE III, DUE TO APOE2-CHRISTCHURCH

.0004 HYPERLIPOPROTEINEMIA, TYPE III, ASSOCIATED WITH APOE2

.0005 HYPERLIPOPROTEINEMIA, TYPE III, ASSOCIATED WITH APOE DEFICIENCY

.0006 HYPERLIPOPROTEINEMIA, TYPE III, ASSOCIATED WITH APOE3-LEIDEN

.0007 HYPERLIPOPROTEINEMIA, TYPE III, AND ATHEROSCLEROSIS ASSOCIATED WITH APOE7

.0008 HYPERLIPOPROTEINEMIA, TYPE III, AUTOSOMAL DOMINANT, ASSOCIATED WITH APOE3

.0009 HYPERLIPOPROTEINEMIA DUE TO APOE1

.0010 HYPERLIPOPROTEINEMIA, TYPE III, DUE TO APOE1-HARRISBURG

.0011 HYPERLIPOPROTEINEMIA, TYPE III, DUE TO APOE2

.0012 APOE2-DUNEDIN

.0013 HYPERLIPOPROTEINEMIA, TYPE III, DUE TO APOE4-PHILADELPHIA

.0014 HYPERLIPOPROTEINEMIA, TYPE III, ASSOCIATED WITH APOE DEFICIENCY

.0015 APOE3 ISOFORM

.0016 ALZHEIMER DISEASE 2 DUE TO APOE4 ISOFORM

.0017 HYPERLIPOPROTEINEMIA, TYPE III, ASSOCIATED WITH APOE DEFICIENCY, AUTOSOMAL RECESSIVE

.0018 HYPERLIPOPROTEINEMIA, TYPE III, DUE TO APOE3(-)-KOCHI

.0019 HYPERLIPOPROTEINEMIA, TYPE III, DUE TO APOE2-FUKUOKA

.0020 APOE5 VARIANT

.0021 HYPERLIPOPROTEINEMIA, TYPE III, ASSOCIATED WITH APOE2

.0022 HYPERLIPOPROTEINEMIA, TYPE III, ASSOCIATED WITH APOE3

.0023 APOE4(-)-FREIBURG

.0024 APOE3(-)-FREIBURG

.0025 APOE5 VARIANT

.0026 APOE3 VARIANT

.0027 APOE2 VARIANT

.0028 APOE4 VARIANT

.0029 APOE4(+)

.0030 CORONARY ARTERY DISEASE, SEVERE, SUSCEPTIBILITY TO

.0031 SEA-BLUE HISTIOCYTE DISEASE

.0032 LIPOPROTEIN GLOMERULOPATHY

.0033 LIPOPROTEIN GLOMERULOPATHY

.0034 ALZHEIMER DISEASE 3, PROTECTION AGAINST, DUE TO APOE3-CHRISTCHURCH (1 family)

▼ See Also:

▼ REFERENCES

* 107741

APOLIPOPROTEIN E; APOE

Gene-Phenotype Relationships

TEXT

Description

Cloning and Expression

Mapping

Gene Function

Evolution

Population Genetics

Molecular Genetics

Animal Model

History

ALLELIC VARIANTS 34 Selected Examples):

.0001 HYPERLIPOPROTEINEMIA, TYPE III, DUE TO APOE2, AUTOSOMAL RECESSIVE

.0002 HYPERLIPOPROTEINEMIA, TYPE III, AND ATHEROSCLEROSIS ASSOCIATED WITH APOE5

.0003 HYPERLIPOPROTEINEMIA, TYPE III, DUE TO APOE2-CHRISTCHURCH

.0004 HYPERLIPOPROTEINEMIA, TYPE III, ASSOCIATED WITH APOE2

.0005 HYPERLIPOPROTEINEMIA, TYPE III, ASSOCIATED WITH APOE DEFICIENCY

.0006 HYPERLIPOPROTEINEMIA, TYPE III, ASSOCIATED WITH APOE3-LEIDEN

.0007 HYPERLIPOPROTEINEMIA, TYPE III, AND ATHEROSCLEROSIS ASSOCIATED WITH APOE7

.0008 HYPERLIPOPROTEINEMIA, TYPE III, AUTOSOMAL DOMINANT, ASSOCIATED WITH APOE3

.0009 HYPERLIPOPROTEINEMIA DUE TO APOE1

.0010 HYPERLIPOPROTEINEMIA, TYPE III, DUE TO APOE1-HARRISBURG

.0011 HYPERLIPOPROTEINEMIA, TYPE III, DUE TO APOE2

.0012 APOE2-DUNEDIN

.0013 HYPERLIPOPROTEINEMIA, TYPE III, DUE TO APOE4-PHILADELPHIA

.0014 HYPERLIPOPROTEINEMIA, TYPE III, ASSOCIATED WITH APOE DEFICIENCY

.0015 APOE3 ISOFORM

.0016 ALZHEIMER DISEASE 2 DUE TO APOE4 ISOFORM

.0017 HYPERLIPOPROTEINEMIA, TYPE III, ASSOCIATED WITH APOE DEFICIENCY, AUTOSOMAL RECESSIVE

▼

External Links