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’s 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 CDR-SOB and MMSE scores —two common outcome measures in AD clinical trials— in 1,102 autopsy-proven AD subjects (moderate/frequent neuritic plaques and Braak tangle stage ≥III) from the National Alzheimer’s Coordinating Center (NACC) Neuropathology database resembling mild-to-moderate AD participants in therapeutic clinical trials.

RESULTS: APOEε4 carriers exhibited ≈1.5 times faster CDR-SOB increase than APOEε3/ε3 carriers (2.12 points/year versus 1.44 points/year), and ≈1.3 times faster increase than APOEε2 carriers (1.65 points/year), whereas APOEε2 versus APOEε3/ε3 difference was not statistically significant. APOEε4 carriers had ≈1.1 times faster MMSE decline than APOEε3/ε3 subjects (-3.34 points/year versus -3.03 points/year) and ≈1.4 times faster decline than APOEε2 carriers (-2.43 points/year), whereas APOEε2 carriers had ≈1.2 times slower decline than APOEε3/ε3 subjects (-2.43 points/year versus -3.03 points/year). These findings remained largely unchanged after controlling for the effect of AD neuropathological changes on the rate of cognitive decline and for the presence and severity of comorbid pathologies.

CONCLUSIONS: compared to the APOEε3/ε3 reference genotype, the APOEε2 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.