Multi-region brain transcriptomes uncover two subtypes of aging individuals with differences in Alzheimer risk and the impact of APOEε4.

The heterogeneity of the aging population suggests the existence of molecularly distinct subgroups that differ in vulnerability to Alzheimer's disease (AD), yet this population structure remains poorly defined. We performed unsupervised clustering of multi-region brain transcriptomes to assess whether integrating data across regions involved in cognition could uncover such subgroups. Canonical correlation-based analysis in a discovery cohort of 459 participants with RNA-sequencing data from three regions (dorsolateral prefrontal cortex, posterior cingulate cortex, and anterior caudate), followed by replication in 690 additional participants with partial data, identified two meta-clusters (MC-1 and MC-2). These groups differed in cognitive trajectories, with MC-2 showing a three-year delay in dementia onset relative to MC-1. This may reflect, in part, a greater impact of tau pathology on neuronal chromatin architecture, white matter loss, and APOEε4-related cognitive decline in MC-1. These findings reveal a molecular population structure of the aging brain that modulates vulnerability and resilience to AD and may inform targeted therapies and trials.