TREM2 gene expression associations with Alzheimer's disease neuropathology are region-specific: implications for cortical versus subcortical microglia

Previous post-mortem assessments of TREM2 expression and its association with brain pathologies have been limited by sample size. This study sought to correlate region-specific TREM2 mRNA expression with diverse neuropathological measures at autopsy using a large sample size (N = 945) of bulk RNA sequencing data from the Religious Orders Study and Rush Memory and Aging Project (ROS/MAP). TREM2 gene expression of the dorsolateral prefrontal cortex, posterior cingulate cortex, and caudate nucleus was assessed with respect to core pathology of Alzheimer's disease (amyloid-beta, and tau), cerebrovascular pathology (cerebral infarcts, arteriolosclerosis, atherosclerosis, and cerebral amyloid angiopathy), microglial activation (proportion of activated microglia), and cognitive performance. We found that cortical TREM2 levels were positively related to AD diagnosis, cognitive decline, and amyloid-beta neuropathology but were not related to the proportion of activated microglia. In contrast, caudate TREM2 levels were not related to AD pathology, cognition, or diagnosis, but were positively related to the proportion of activated microglia in the same region. Diagnosis-stratified results revealed caudate TREM2 levels were inversely related to AD neuropathology and positively related to microglial activation and longitudinal cognitive performance in AD cases. These results highlight the notable changes in TREM2 transcript abundance in AD and suggest that its pathological associations are brain-region-dependent.

Automated summary

This study investigated the correlation between region-specific TREM2 mRNA expression and neuropathology measures in a large sample size. The results showed that TREM2 expression was related to Alzheimer's disease pathology, cerebrovascular pathology, microglial activation, and cognitive decline, but the associations varied across different brain regions. These findings suggest that TREM2's pathological associations are dependent on the brain region.