A recent postmortem multi-omics study suggests that long-standing psychological traits such as neuroticism, loneliness, and purpose in life may be associated with specific molecular routes through Alzheimer’s dementia, according to a June 22 report. The research indicates that these traits could help explain the biological diversity observed among patients beyond what standard pathology reveals.
The study, published in Translational Psychiatry, involved 822 deceased older adults from the Religious Orders Study and the Rush Memory and Aging Project. All participants were free of known dementia at enrollment and underwent regular clinical evaluations during their lives. After death, researchers collected brain tissue from the dorsolateral prefrontal cortex for multi-omics analysis—including DNA methylation, RNA sequencing, protein expression profiling, and metabolomic assessments.
Researchers applied a machine-learning framework called Multimodal Contrastive Trajectories Inference to generate a molecular pseudotime representing progression from no cognitive impairment to Alzheimer’s dementia. This approach identified three distinct molecular subtypes of Alzheimer’s disease: AD1 (with abundant metabolomic changes), AD2 (enriched for transcriptomic changes), and AD3 (characterized by epigenomic changes). The strongest distinguishing markers between subtypes were metabolites rather than genes or proteins.
Pathologic Alzheimer’s disease was present in more than 70% of participants across all subtypes. Postmortem MRI showed greater brain atrophy in all Alzheimer's groups compared with cognitively healthy individuals; however, differences between subtypes did not reach statistical significance. Genetic analyses revealed that polygenic risk scores correlated with overall disease progression but did not differentiate among the three molecular subtypes.
When examining psychological characteristics assessed near baseline—neuroticism, depressive symptoms, loneliness, and purpose in life—the study found higher neuroticism and loneliness scores associated with increased proximity to Alzheimer's dementia on the molecular scale. Neuroticism was linked to all Alzheimer's types; a greater sense of purpose was related to lower likelihood of certain subtypes (AD1 and AD2). These associations remained significant even after accounting for traditional neuropathology in some cases but were limited after correcting for multiple comparisons.
The authors noted limitations including reliance on self-reported measures for psychological traits, smaller sample sizes for some analyses such as loneliness and purpose in life assessments available only within one cohort group, lack of certain biomarkers like PET scans or plasma data collected during life, as well as omics data restricted to one brain region. The findings suggest stable psychological characteristics may relate uniquely to underlying biological mechanisms driving heterogeneity in Alzheimer’s dementia.
