APOE4 moderates the association of sleep disturbance with cerebral amyloid burden but not with clinical conversion in cognitively normal older adults

Background Sleep disturbance has been linked to Alzheimer's disease (AD), but whether its relationships with cerebral amyloid-β (Aβ) pathology and clinical progression are modified by APOE ε4 ( APOE4 ) carrier status in cognitively normal elderly remains unclear. Objective To examine APOE4 moderation of the associations of sleep disturbance with Aβ pathology and clinical conversion in cognitively normal elderly. Methods In 301 cognitively normal elderly from the Alzheimer's Disease Neuroimaging Initiative, baseline sleep disturbance was assessed using the Neuropsychiatric Inventory. Linear regression with Sleep × APOE4 interaction examined baseline 18 F-florbetapir PET Aβ burden and accumulation rate, complemented by a linear mixed-effects model using all available PET data. Cox proportional hazards models evaluated clinical conversion to mild cognitive impairment or AD dementia, adjusted for age, sex, education, and APOE4 . Results Over a mean follow-up of 4.7 years, 39 participants (13.0%) converted. APOE4 moderated the association between sleep disturbance and baseline Aβ burden (p = 0.029); the interaction for accumulation rate was only nominal (p = 0.048) and did not persist in the mixed-effects model. Sleep disturbance was associated with conversion in the overall cohort (HR = 4.58, 95% CI 1.97–10.65, p < 0.001), with no moderation by APOE4 (interaction p = 0.961). Conclusions In APOE4 carriers, sleep disturbance was associated with higher amyloid burden, whereas its association with clinical conversion was independent of APOE4 . Sleep represents a clinically relevant, potentially modifiable factor in preclinical AD, and APOE4 status may inform sleep-targeted prevention.