Abstract

The heterogeneity of the older population suggests the existence of subsets of individuals which share certain brain molecular features and respond differently to risk factors for Alzheimers disease, but this population structure remains poorly defined. Here, we performed an unsupervised clustering of individuals with multi-region brain transcriptomes to assess whether a broader approach, simultaneously considering data from multiple regions involved in cognition would uncover such subsets. We implemented a canonical correlation-based analysis in a Discovery cohort of 459 participants from two longitudinal studies of cognitive aging that have RNA sequence profiles in three brain regions. 690 additional participants that have data in only one or two of these regions were used in the Replication effort. These clustering analyses identified two meta-clusters, MC-1 and MC-2. The two sets of participants differ primarily in their trajectories of cognitive decline, with MC-2 having a delay of 3 years to the median age of incident dementia. This is due, in part, to a greater impact of tau pathology on neuronal chromatin architecture and to broader brain changes including greater loss of white matter integrity in MC-1. Further evidence of biological differences includes a significantly larger impact of APOE{varepsilon}4 risk on cognitive decline in MC-1. These findings suggest that our proposed population structure captures an aspect of the more distributed molecular state of the aging brain that either enhances the effect of risk factors in MC-1 or of protective effects in MC-2. These observations may inform the design of therapeutic development efforts and of trials as both become increasingly more targeted molecularly. One Sentence Summary: There are two types of aging brains, with one being more vulnerable to APOE{varepsilon}4 and subsequent neuronal dysfunction and cognitive loss.