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. 2012 Aug 30;367(9):795-804.
doi: 10.1056/NEJMoa1202753. Epub 2012 Jul 11.

Clinical and biomarker changes in dominantly inherited Alzheimer's disease

Randall J Bateman  1 , Chengjie Xiong, Tammie L S Benzinger, Anne M Fagan, Alison Goate, Nick C Fox, Daniel S Marcus, Nigel J Cairns, Xianyun Xie, Tyler M Blazey, David M Holtzman, Anna Santacruz, Virginia Buckles, Angela Oliver, Krista Moulder, Paul S Aisen, Bernardino Ghetti, William E Klunk, Eric McDade, Ralph N Martins, Colin L Masters, Richard Mayeux, John M Ringman, Martin N Rossor, Peter R Schofield, Reisa A Sperling, Stephen Salloway, John C Morris; Dominantly Inherited Alzheimer Network
Affiliations

Clinical and biomarker changes in dominantly inherited Alzheimer's disease

Randall J Bateman et al. N Engl J Med. .

Erratum in

  • N Engl J Med. 2012 Aug 23;367(8):780

Abstract

Background: The order and magnitude of pathologic processes in Alzheimer's disease are not well understood, partly because the disease develops over many years. Autosomal dominant Alzheimer's disease has a predictable age at onset and provides an opportunity to determine the sequence and magnitude of pathologic changes that culminate in symptomatic disease.

Methods: In this prospective, longitudinal study, we analyzed data from 128 participants who underwent baseline clinical and cognitive assessments, brain imaging, and cerebrospinal fluid (CSF) and blood tests. We used the participant's age at baseline assessment and the parent's age at the onset of symptoms of Alzheimer's disease to calculate the estimated years from expected symptom onset (age of the participant minus parent's age at symptom onset). We conducted cross-sectional analyses of baseline data in relation to estimated years from expected symptom onset in order to determine the relative order and magnitude of pathophysiological changes.

Results: Concentrations of amyloid-beta (Aβ)(42) in the CSF appeared to decline 25 years before expected symptom onset. Aβ deposition, as measured by positron-emission tomography with the use of Pittsburgh compound B, was detected 15 years before expected symptom onset. Increased concentrations of tau protein in the CSF and an increase in brain atrophy were detected 15 years before expected symptom onset. Cerebral hypometabolism and impaired episodic memory were observed 10 years before expected symptom onset. Global cognitive impairment, as measured by the Mini-Mental State Examination and the Clinical Dementia Rating scale, was detected 5 years before expected symptom onset, and patients met diagnostic criteria for dementia at an average of 3 years after expected symptom onset.

Conclusions: We found that autosomal dominant Alzheimer's disease was associated with a series of pathophysiological changes over decades in CSF biochemical markers of Alzheimer's disease, brain amyloid deposition, and brain metabolism as well as progressive cognitive impairment. Our results require confirmation with the use of longitudinal data and may not apply to patients with sporadic Alzheimer's disease. (Funded by the National Institute on Aging and others; DIAN ClinicalTrials.gov number, NCT00869817.).

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Figures

Figure 1
Figure 1. Cross-Sectional Analyses of Clinical, Cognitive, Structural, Metabolic, and Biochemical Changes in Autosomal Dominant Alzheimer’s Disease Mutation Carriers versus Noncarriers, According to Estimated Years from Expected Symptom Onset
The clinical and cognitive measures of the Clinical Dementia Rating–Sum of Boxes (scores range from 0 [cognitive normality] to 18 [maximal cognitive impairment]) (Panel A), the Mini–Mental State Examination (scores range from 0 [severe impairment] to 30 [no impairment]) (Panel B), and the Logical Memory subtest of the Wechsler Memory Scale–Revised (scores range from 0 [no recall] to 25 [complete recall]) (Panel C) showed impaired ratings beginning approximately 5 to 10 years before expected symptom onset. MRI measures of hippocampal volume (Panel D) showed increased brain atrophy approximately 15 years before expected symptom onset. Decreases in cerebral glucose metabolism, as measured by positron-emission tomography (PET) with the use of fluorodeoxyglucose (Panel E), occurred approximately 10 years before expected symptom onset, and deposition of amyloid-beta (Aβ) in the precuneus, as measured by PET with the use of Pittsburgh compound B (Panel F), began approximately 15 to 20 years before expected symptom onset. In the cerebrospinal fluid (CSF), levels of tau protein (Panel G) increased beginning 10 to 15 years before expected symptom onset, and levels of Aβ42 (Panel H) decreased at least 15 years before expected symptom onset. Plasma Aβ42 levels were elevated throughout the range of estimated years from expected symptom onset (Panel I). Dashed lines represent 95% confidence intervals of the fitted curves. SUVR denotes standardized uptake value ratio.
Figure 2
Figure 2. Comparison of Clinical, Cognitive, Structural, Metabolic, and Biochemical Changes as a Function of Estimated Years from Expected Symptom Onset
The normalized differences between mutation carriers and noncarriers are shown versus estimated years from expected symptom onset and plotted with a fitted curve. The order of differences suggests decreasing Aβ42 in the CSF (CSF Aβ42), followed by fibrillar Aβ deposition, then increased tau in the CSF (CSF tau), followed by hippocampal atrophy and hypometabolism, with cognitive and clinical changes (as measured by the Clinical Dementia Rating–Sum of Boxes [CDR-SOB]) occurring later. Mild dementia (CDR 1) occurred an average of 3.3 years before expected symptom onset. 95% confidence interval bands are shown in Figure S2 in the Supplementary Appendix.
Figure 3
Figure 3. Aβ Deposition in Autosomal Dominant Alzheimer’s Disease Years before Expected Clinical Symptoms
Panel A compares the fibrillar Aβ deposition, as measured by PET with the use of Pittsburgh compound B (PIB), of the average of autosomal dominant Alzheimer’s disease mutation carriers and noncarriers 20 years before the estimated time of onset of symptoms. There was significant Aβ deposition in the caudate and cortex in mutation carriers more than 10 years before expected symptom onset, as compared with noncarriers (Panel B). Panel C shows additional Aβ deposition throughout the cortex and neostriatum at the estimated time of symptom onset. An increased SUVR indicates increased binding of PIB to fibrillar amyloid. The scale ranges from low SUVR values (bluer colors), indicating low amounts of amyloid, to high SUVR values (redder colors), indicating high amounts of amyloid.
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