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

Automated summary

The study found that compared to the APOE epsilon 3/epsilon 3 reference genotype, the APOE epsilon 2 and epsilon 4 alleles have opposite effects on the rate of cognitive decline. These effects are clinically relevant and largely independent of the differential APOE allele effects on AD and comorbid pathologies, indicating that APOE genotype contributes to the heterogeneity in the rate of clinical progression in AD.