Previous post-mortem assessments ofTREM2expression and its association with brain pathologies have been limited by sample size. This study sought to correlate region-specificTREM2mRNA 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).TREM2gene expression of the dorsolateral prefrontal cortex, posterior cingulate cortex, and caudate nucleus was assessed with respect to core pathology of Alzheimer’s disease (amyloid-β, and tau), cerebrovascular pathology (cerebral infarcts, arteriolosclerosis, atherosclerosis, and cerebral amyloid angiopathy), microglial activation (proportion of activated microglia), and cognitive performance. We found that corticalTREM2levels were positively related to AD diagnosis, cognitive decline, and amyloid-β neuropathology but were not related to the proportion of activated microglia. In contrast, caudateTREM2levels 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 caudateTREM2levels 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 inTREM2transcript abundance in AD and suggest that its pathological associations are brain-region-dependent.Supplementary InformationThe online version contains supplementary material available at 10.1007/s00401-023-02564-2.