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

Zammit, A. R.; Yu, L.; Poole, V. N.; Arfanakis, K.; Schneider, J. A.; Petyuk, V. A.; De Jager, P.; Kaddurah-Daouk, R.; Iturria-Medina, Y.; Bennett, D. A.

doi:10.1101/2025.02.21.639584

bioRxiv · 10.1101/2025.02.21.639584

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

Zammit, A. R.·Yu, L.·Poole, V. N.·Arfanakis, K.·Schneider, J. A.·Petyuk, V. A.·De Jager, P.·Kaddurah-Daouk, R.·Iturria-Medina, Y.·Bennett, D. A.

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Abstract

ImportancePsychological 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. ObjectiveTo examine whether one or more multi-omic brain molecular subtypes of AD is associated with neuroticism, depressive symptoms, loneliness, and/or purpose in life. DesignTwo cohort-based studies; Religious Orders Study (ROS) and Rush Memory and Aging Project (MAP), both ongoing longitudinal clinical pathological studies that began enrollment in 1994 and 1997. SettingOlder priests, nuns, and brothers from across the U.S. (ROS) and older adults from across the greater Chicago metropolitan area (MAP). Participants822 decedents with multi-omic data from the dorsolateral prefrontal cortex. Exposure(s)Pseudotime, representing molecular distance from no cognitive impairment (NCI) to AD dementia, and three multi-omic brain molecular subtypes of AD dementia representing 3 omic pathways from no cognitive impairment (NCI) to AD dementia that differ by their omic constituents. Main outcome(s) and measure(s)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 traits, adjusting for the same covariates. ResultPseudotime 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. Conclusions and RelevanceThree multi-omic brain molecular subtypes of AD dementia differentially share omic features with four psychological risk factors of AD dementia. Our data provide novel insights into the biology underlying well-established associations between psychological traits and AD dementia. Key pointsO_ST_ABSQuestionC_ST_ABSAre three distinct multi-omic brain molecular subtypes of Alzheimers disease (AD) dementia associated with four well-established psychological AD risk factors (neuroticism, depressive symptoms, loneliness and purpose in life)? FindingsWe found differential associations: AD subtypes 1 and 3 were associated with neuroticism, AD subtype 2 was associated with depressive symptoms, AD subtype 3 was associated with loneliness; and AD subtype 2 was associated with purpose in life. MeaningPsychological risk factors might be associated with AD dementia via shared multi-omic molecular pathways.

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Zammit, A. R., Yu, L., Poole, V. N., Arfanakis, K., Schneider, J. A., Petyuk, V. A., De Jager, P., Kaddurah-Daouk, R., Iturria-Medina, Y., Bennett, D. A.. 2025-02-26. Multi-omic subtypes of Alzheimer's dementia are differentially associated with psychological traits. https://doi.org/10.1101/2025.02.21.639584

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