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Cell type-specific roles of APOE4 in Alzheimer disease

Nature Reviews Neuroscience volume 25, pages 91–110 (2024)Cite this article

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Abstract

The ɛ4 allele of the apolipoprotein E gene (APOE), which translates to the APOE4 isoform, is the strongest genetic risk factor for late-onset Alzheimer disease (AD). Within the CNS, APOE is produced by a variety of cell types under different conditions, posing a challenge for studying its roles in AD pathogenesis. However, through powerful advances in research tools and the use of novel cell culture and animal models, researchers have recently begun to study the roles of APOE4 in AD in a cell type-specific manner and at a deeper and more mechanistic level than ever before. In particular, cutting-edge omics studies have enabled APOE4 to be studied at the single-cell level and have allowed the identification of critical APOE4 effects in AD-vulnerable cellular subtypes. Through these studies, it has become evident that APOE4 produced in various types of CNS cell — including astrocytes, neurons, microglia, oligodendrocytes and vascular cells — has diverse roles in AD pathogenesis. Here, we review these scientific advances and propose a cell type-specific APOE4 cascade model of AD. In this model, neuronal APOE4 emerges as a crucial pathological initiator and driver of AD pathogenesis, instigating glial responses and, ultimately, neurodegeneration. In addition, we provide perspectives on future directions for APOE4 research and related therapeutic developments in the context of AD.

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Fig. 1: CNS APOE expression and links to Alzheimer disease.
Fig. 2: Expression of APOE4 in astrocytes and its roles in AD pathogenesis.
Fig. 3: Expression of APOE4 in neurons and its roles in AD pathogenesis.
Fig. 4: Expression of APOE4 in microglia and its roles in AD pathogenesis.
Fig. 5: Expression of APOE4 in oligodendrocytes and vascular cells and its roles in AD pathogenesis.
Fig. 6: Cell type-specific APOE4 cascade model of AD and related therapeutic strategies.

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Acknowledgements

This work was supported by grants R01AG071697, RF1AG076647, R01AG065540 and P01AG073082 from the National Institutes of Health to Y.H. The authors would like to thank R. W. Mahley, L. Mucke and A. Yang for their critical review of the manuscript. They also thank J. Carroll for assistance with figure preparation, S. Ordway for editorial assistance, and Huang laboratory members for providing feedback on the Review.

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  1. These authors contributed equally: Jessica Blumenfeld, Oscar Yip.

Authors and Affiliations

  1. Gladstone Institute of Neurological Disease, Gladstone Institutes, San Francisco, CA, USA

    Jessica Blumenfeld, Oscar Yip, Min Joo Kim & Yadong Huang

  2. Neuroscience Graduate Program, University of California, San Francisco, San Francisco, CA, USA

    Jessica Blumenfeld & Yadong Huang

  3. Biomedical Sciences Graduate Program, University of California, San Francisco, San Francisco, CA, USA

    Oscar Yip, Min Joo Kim & Yadong Huang

  4. Gladstone Center for Translational Advancement, Gladstone Institutes, San Francisco, CA, USA

    Yadong Huang

  5. Department of Neurology, University of California, San Francisco, San Francisco, CA, USA

    Yadong Huang

  6. Department of Pathology, University of California, San Francisco, San Francisco, CA, USA

    Yadong Huang

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Glossary

APOE fragments

Neurotoxic fragments of the APOE protein that are generated as a result of APOE expression in neurons, with more fragments being generated from APOE4, owing to its unique conformation, than from APOE3 via neuron-specific proteolysis.

Cytokines

Classes of small secreted proteins that serve to signal and activate immune functions, including triggering of glial responses in the CNS.

Dementia

A general term for loss of memory and loss of language, problem-solving and other thinking abilities that are severe enough to interfere with daily life. Diseases grouped under the general term dementia are caused by abnormal brain changes, with Alzheimer disease being the most common cause.

Disease-associated gene signatures

Specific patterns or sets of genes that are consistently found to be altered or expressed differently in a disease context compared with physiological contexts. These gene signatures are often identified through various transcriptomic analyses, such as microarray or RNA sequencing experiments.

Exosome

A small, membrane-bound vesicle that is released by cells into the extracellular environment. These vesicles have a crucial role in intercellular communication by facilitating the transfer of various molecules between cells.

Gene editing

A type of genetic engineering by which specific changes can be made to DNA, including inserting, deleting or altering DNA sequences.

Gliosis

The proliferation or hypertrophy of microglia and/or astrocytes in response to stressors, insults, injury or diseases.

Human induced pluripotent stem cells

(hiPSCs). A type of pluripotent stem cell derived from adult somatic cells that have been genetically reprogrammed to an embryonic stem cell-like state through the forced expression of genes and factors important for maintaining the defining properties of embryonic stem cells.

Lysosomes

Membrane-bound organelles that are part of the endo-lysosomal system within cells and have a crucial role in cellular digestion and waste removal. Lysosomes contain various enzymes that are capable of breaking down different types of macromolecules, including proteins, lipids, nucleic acids and carbohydrates.

Mild cognitive impairment

(MCI). An early stage of memory loss or other cognitive ability loss (such as language or visual–spatial perception) in individuals who maintain the ability to independently perform most activities of daily living. For neurodegenerative diseases, such as Alzheimer disease, MCI can be an early stage of the disease continuum.

Pericytes

Contractile cells located at intervals along the walls of capillaries, playing a part in blood vessel formation, maintenance of the blood–brain barrier, regulation of immune cell entry to the central nervous system and control of brain blood flow.

Single-nucleus RNA sequencing

(snRNA-seq). A molecular biology technique used to analyse the gene expression profiles of individual cell nuclei within a complex tissue or organ. Traditional RNA sequencing methods usually require intact cells, but snRNA-seq allows researchers to study gene expression in individual nuclei, providing insights into cellular diversity and heterogeneity within tissues.

Tauopathy

One of a group of clinically, biochemically and morphologically heterogeneous neurodegenerative diseases, including Alzheimer disease, characterized by the abnormal hyperphosphorylation of microtubule-associated protein, tau, that leads to the formation of neurofibrillary tangles in the brain.

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Blumenfeld, J., Yip, O., Kim, M.J. et al. Cell type-specific roles of APOE4 in Alzheimer disease. Nat. Rev. Neurosci. 25, 91–110 (2024). https://doi.org/10.1038/s41583-023-00776-9

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