Spatial transcriptomic patterns underlying regional vulnerability to amyloid-β and tau pathologies and their relationships to cognitive dysfunction in Alzheimer's disease

Amyloid-{beta} (A{beta}) and tau proteins accumulate within distinct neuronal systems in Alzheimers disease (AD). Although it is not clear why certain brain regions are more vulnerable to A{beta} and tau pathologies than others, gene expression may play a role. We studied the association between brain-wide gene expression profiles and regional vulnerability to A{beta} (gene-to-A{beta} associations) and tau (gene-to-tau associations) pathologies leveraging two large independent cohorts (n = 715) of participants along the AD continuum. We identified several AD susceptibility genes and gene modules in a gene co-expression network with expression profiles related to regional vulnerability to A{beta} and tau pathologies in AD. In particular, we found that the positive APOE-to-tau association was only seen in the AD cohort, whereas patients with AD and frontotemporal dementia shared similar positive MAPT-to-tau association. Some AD candidate genes showed sex-dependent negative gene-to-A{beta} and gene-to-tau associations. In addition, we identified distinct biochemical pathways associated with the gene-to-A{beta} and the gene-to-tau associations. Finally, we proposed a novel analytic framework, linking the identified gene-to-pathology associations to cognitive dysfunction in AD at the individual level, suggesting potential clinical implication of the gene-to-pathology associations. Taken together, our study identified distinct gene expression profiles and biochemical pathways that may explain the discordance between regional A{beta} and tau pathologies, and filled the gap between gene-to-pathology associations and cognitive dysfunction in individual AD patients that may ultimately help identify novel personalized pathogenetic biomarkers and therapeutic targets. One Sentence SummaryWe identified replicable cognition-related associations between regional gene expression profiles and selectively regional vulnerability to amyloid-{beta} and tau pathologies in AD.