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

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.