Work

Association of APOE Genotype With Heterogeneity of Cognitive Decline Rate in Alzheimer Disease

Year: 2021

Type: article

Abstract: Objective To test the hypothesis that the APOE genotype is a significant driver of heterogeneity in Alzheimer disease (AD) clinical progression, which could have important implications for clinical trial design and interpretation. Methods We applied novel reverse-time longitudinal models to analyze the trajectories of Clinical Dementia Rating Sum of Boxes (CDR-SOB) and Mini-Mental State Examination (MMSE) scores—2 common outcome measures in AD clinical trials—in 1,102 autopsy-proven AD cases (moderate/frequent neuritic plaques and Braak tangle stage III or greater) from the National Alzheimer's Coordinating Center Neuropathology database resembling participants with mild to moderate AD in therapeutic clinical trials. Results APOE ε4 carriers exhibited ≈1.5 times faster CDR-SOB increase than APOE ε3/ε3 carriers (2.12 points per year vs 1.44 points per year) and ≈1.3 times faster increase than APOE ε2 carriers (1.65 points per year), whereas APOE ε2 vs APOE ε3/ε3 difference was not statistically significant. APOE ε4 carriers had ≈1.1 times faster MMSE decline than APOE ε3/ε3 carriers (−3.45 vs −3.03 points per year) and ≈1.4 times faster decline than APOE ε2 carriers (−2.43 points per year), whereas APOE ε2 carriers had ≈1.2 times slower decline than APOE ε3/ε3 carriers (−2.43 vs −3.03 points per year). These findings remained largely unchanged after controlling for the effect of AD neuropathologic changes on the rate of cognitive decline and for the presence and severity of comorbid pathologies. Conclusion Compared to the APOE ε3 / ε3 reference genotype, the APOE ε2 and ε4 alleles have opposite (slowing and accelerating, respectively) effects on the rate of cognitive decline, which are clinically relevant and largely independent of the differential APOE allele effects on AD and comorbid pathologies. Thus, APOE genotype contributes to the heterogeneity in rate of clinical progression in AD.

Source: Neurology

DOI: 10.1212/wnl.0000000000011883

Authors: Jing Qian, Rebecca A. Betensky, Bradley T. Hyman, Alberto Serrano-Pozo

Institutions: Harvard University, University of Massachusetts Amherst, Massachusetts General Hospital, New York University

Language: English

Topic: Dementia and Cognitive Impairment Research

Subfield: Psychiatry and Mental health

Field: Medicine

Domain: Health Sciences

SDG: Good health and well-being

Open Access status: hybrid

Funders: Alzheimer's Association, National Institutes of Health, National Institute on Aging, National Institute of Neurological Disorders and Stroke