Abstract
Posttraumatic stress disorder (PTSD) has been associated with accelerated cognitive aging and increased risk for Alzheimer's disease (AD) and related dementias (ADRD), yet the neural substrates linking trauma-related psychiatric illness to late-life neurodegenerative vulnerability remain poorly defined. The 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 systematically examined. Postmortem 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 was performed integrating 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 amygdala and significantly greater β-amyloid burden. Targeted transcriptomic profiling identified coordinated upregulation of AD-related genes involved in amyloid processing, lipid metabolism, proteostasis, and inflammatory signaling. Network analysis revealed an APP-centered molecular architecture with APOE, MAPT, and CLU functioning as highly connected secondary hubs. Protein analyses demonstrated increased amyloid-β and pTau231 abundance, selective markers of gliosis, and synaptic alterations characterized by elevated excitatory receptor expression and reduced inhibitory GABABR1a. Older adults with PTSD exhibit convergent evidence of AD-relevant molecular and pathological remodeling in the amygdala. These findings suggest that chronic trauma-related circuit dysregulation may intersect with aging-associated inflammatory and synaptic processes, creating a biological environment permissive for neurodegenerative vulnerability in emotionally salient brain circuits.