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BACKGROUND: Limbic-predominant age-related TDP-43 encephalopathy neuropathological change (LATE-NC) is the third most significant contributor to late-onset dementia after Alzheimer's disease neuropathologic change (ADNC; amyloid-β and tau) and cerebrovascular disease. However, the molecular alterations underlying LATE-NC remain poorly understood.

METHOD: We studied 959 participants (Age=89.4±6.7, Female: 65.9%) from Religious Orders Study and the Rush Memory and Aging Project (ROSMAP). Bulk RNA sequencing (RNA-seq) was performed on post-mortem brain tissues from the amygdala (n = 97) and dorsolateral prefrontal cortex (DLPFC; n = 937), with 75 overlapping participants. Linear regression models were used to evaluate associations between RNA expression and LATE-NC burden (TDP-43 immunohistochemistry; the average semi-quantitative counts of neuronal cytoplasmic inclusions across six brain regions), adjusting for age, sex, and quantitative ADNC burden (amyloid-β and tau across eight brain regions). Gene Ontology (GO) terminology overrepresentation was assessed for genes with positive or negative associations with LATE-NC.

RESULTS: RNA-seq analysis of the amygdala (n = 97) identified 257 genes positively correlated and 178 genes negatively correlated with LATE-NC at false discovery rate (FDR) <0.05 (Figure 1A). Downregulated pathways (Figure 1B) included regulation of membrane potential, synaptic transmission, and vesicle-mediated transport, while upregulated pathways (Figure 1C) involved microtubule-based movement and cilium assembly. By contrast, despite a much larger sample size, we did not observe any associated genes in the DLPFC (all FDR>0.05)-a region involved only in advanced LATE-NC. Targeted analysis of the amygdala LATE-NC-associated genes in the DLPFC (nominal p <0.05, with a consistent direction of association) revealed 8 positively associated and 28 negatively associated genes (Figure 2A-C). The LATE-NC-associated genes downregulated in both amygdala and DLPFC captured synaptic function and vesicle transport pathways, reflecting shared neuronal/synaptic disruption across brain regions in LATE-NC.

CONCLUSIONS: Our findings highlight distinct molecular signatures of LATE-NC in the amygdala, including upregulation of microtubule-related pathways and downregulation of neuronal/synaptic genes. Interestingly, this LATE-NC signature was much weaker in the neocortex, underscoring the critical importance of brain-region-specific multi-omic studies in neurodegeneration. Our results provide one of the first large-scale molecular atlas of LATE-NC from the limbic region, providing foundations for disease models, biomarker discovery, and therapeutic approaches.