Posttraumatic stress disorder is associated with Alzheimer's disease-relevant molecular alterations in the basolateral amygdala of older Veterans

Posttraumatic stress disorder (PTSD) is associated with accelerated cognitive aging and increased risk for Alzheimer's disease (AD) and related dementias (ADRD), yet the biological substrates linking trauma-related psychiatric illness to altered brain aging trajectories remain poorly defined. The basolateral amygdala plays a central role in threat processing and emotional memory and exhibits persistent hyperactivity in PTSD, but its molecular and pathological state in aging individuals with PTSD has not been examined. Postmortem basolateral amygdala tissue from older adult donors (≥70 years) with lifetime PTSD (n = 5) and age-matched controls (n = 5) was obtained from the National PTSD Brain Bank. A multimodal analysis integrated immunohistochemical quantification of β-amyloid and phosphorylated tau pathology, targeted transcriptional profiling of AD-related genes, gene network analysis, and protein quantification of pathological, inflammatory, and synaptic markers. PTSD cases showed enrichment of combined tau-amyloid pathology within the basolateral amygdala and greater β-amyloid burden. Targeted transcriptomic profiling identified coordinated upregulation of genes involved in amyloid processing, lipid metabolism, proteostasis, and inflammatory signaling. Network analysis revealed an APP-centered molecular architecture with APOE, and MAPT as hubs. Protein analyses demonstrated increased amyloid-β and pTau231 abundance, markers of gliosis, and synaptic alterations characterized by elevated excitatory receptor expression and reduced inhibitory signaling. Collectively, these findings provide convergent human evidence that PTSD is associated with region-specific molecular alterations engaging pathways implicated in brain aging and neurodegenerative vulnerability. These data suggest that chronic trauma-related circuit dysregulation may intersect with aging-associated inflammatory and synaptic processes, promoting vulnerability to neurodegenerative change within emotionally salient brain circuits.