ObjectivePsychosis is a significant neuropsychiatric symptom in Alzheimer's Disease (AD) and Mild Cognitive Impairment (MCI). While female APOE4 homozygotes are at the highest risk of psychosis, mechanisms underlying this association remain unclear. We investigated whether epigenetic age acceleration (EAA) is associated with psychosis in individuals with AD and MCI, and whether this association varies by sex and APOE4 status.MethodsParticipants with clinical MCI or AD were drawn from the Alzheimer's Disease Neuroimaging Initiative database. EAA was calculated from DNA methylation data using the PhenoAge epigenetic clock, with the Horvath and Hannum clocks included for comparison. Psychosis status was defined as experiencing hallucinations or delusions at any time, based on the Neuropsychiatric Inventory Questionnaire. Logistic regression models were used to assess associations between EAA and psychosis, including three-way interactions with sex and APOE4 carrier status.ResultsAmong 418 total participants (54 with psychosis, 84 female APOE4 carriers), EAA was not associated with psychosis for any of the 3 clocks utilized. However, a significant three-way interaction between sex, APOE4 carrier status, and PhenoAge EAA in predicting psychosis was observed (P = 0.013). Elevated PhenoAge EAA was associated with higher odds of psychosis in female APOE4 carriers (OR = 1.76 per 5-year, P = .025), whereas no associations were observed for other subgroups or clocks.ConclusionsPhenoAge EAA may serve as a novel biomarker of psychosis among female APOE4 carriers. These findings highlight the potential of second-generation epigenetic clocks for early risk stratification and biological investigations into psychosis in AD and MCI.
Kwan et al. (Sat,) studied this question.