Multi-omic subtypes of Alzheimer’s dementia are differentially associated with psychological traits

Psychological traits reflecting neuroticism, depressive symptoms, loneliness, and purpose in life are risk factors of AD dementia; however, the underlying biologic mechanisms of these associations remain largely unknown. In this study we examined whether pseudotime, representing molecular distance from no cognitive impairment (NCI) to AD dementia, and three distinct multi-omic brain molecular subtypes of AD dementia representing 3 omic pathways from NCI to AD dementia are differentially associated with these risk factors. Participants included 822 decedents with multi-omic data from the dorsolateral prefrontal cortex from two cohort-based studies; Religious Orders Study (ROS) and Rush Memory and Aging Project (MAP), both ongoing longitudinal clinical pathological studies. We first ran four separate linear regressions with neuroticism, depressive symptoms, loneliness, purpose in life as the outcomes, and pseudotime as the predictor, adjusting for age, sex and education. We then ran four separate analyses of covariance (ANCOVAs) with Bonferroni-corrected post-hoc tests to test whether the three multi-omic AD subtypes are differentially associated with the four risk factors, adjusting for the same covariates. Pseudotime was positively associated ( p  < 0.05) with neuroticism and loneliness. AD subtypes were differentially associated with the traits: AD subtypes 1 and 3 were associated with neuroticism; AD subtype 2 with depressive symptoms; AD subtype 3 with loneliness, and AD subtype 2 with purpose in life. Our results show that psychological risk factors might be associated with AD dementia via shared multi-omic molecular pathways. Our data provide novel insights into the biology underlying well-established associations between psychological traits and AD dementia.