Association of <i>APOE</i> Genotype With Heterogeneity of Cognitive Decline Rate in Alzheimer Disease
Jing Qian, Rebecca A. Betensky, Bradley T. Hyman, Alberto Serrano‐Pozo
Abstract
OBJECTIVE: 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: 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: genotype contributes to the heterogeneity in rate of clinical progression in AD.