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


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.


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.


APOE 4 carriers exhibited 1.5 times faster CDR-SOB increase than APOE 3/3 carriers (2.12 points per year vs 1.44 points per year) and 1.3 times faster increase than APOE 2 carriers (1.65 points per year), whereas APOE 2 vs APOE 3/3 difference was not statistically significant. APOE 4 carriers had 1.1 times faster MMSE decline than APOE 3/3 carriers (–3.45 vs –3.03 points per year) and 1.4 times faster decline than APOE 2 carriers (–2.43 points per year), whereas APOE 2 carriers had 1.2 times slower decline than APOE 3/3 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.


Compared to the APOE 3/3 reference genotype, the APOE 2 and 4 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.

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