Limbic-predominant age-related TDP-43 encephalopathy neuropathologic change (LATE-NC) is a common pathology of aging, associated with an amnestic syndrome mimicking Alzheimer’s disease (AD). The co- morbid pathologic and genetic risk factors of LATE-NC remain incompletely understood. The goals of this proposal are to clarify the mechanisms underlying LATE-NC, to determine how these mechanisms interact and affect subregions of human amygdalae, and to generate a practical classification scheme of LATE-NC that is necessary to guide future studies. The amygdala is the first brain region affected in LATE-NC and therefore represents the best anatomic region to understand LATE-NC in its earliest phase(s). A major challenge has been to reconcile mechanisms underlying TDP-43 proteinopathy in community-based autopsy cohorts of older adults (which show a spectrum of complex age-related diseases such as LATE-NC, and mixed pathologies), with results in hospital/clinic-based cohorts that tend to include autopsy patients with less common but “pure” TDP-43 proteinopathies, such as FTLD-TDP and ALS. Therefore, we will combine results from a high quality community-based autopsy cohort (U. Kentucky) with an excellent hospital-based cohort (Houston Methodist Hospital) to analyze common disease-driving mechanisms. The study will incorporate well-characterized human brains (N>1400 total) of patients with ALS-FTD spectrum disorders, and AD neuropathologic changes (ADNC), with and without comorbid LATE-NC. We will characterize the comorbid proteinopathies and vascular pathologies associated with the earliest foci of TDP-43 pathology, including co-localization of TDP-43 and other misfolded proteins, such as Tau. We hypothesize that the initiation of LATE-NC in human amygdalae results from a selective cellular vulnerability that varies in association with specific genetic risk factors. We will examine and contrast the proteomic profiles of susceptible and resistant subregions of human amygdalae, both within individuals and across disease states (e.g., LATE-NC versus ADNC, LATE-NC versus ALS-FTD spectrum, including FTLD-TDP cases. We also hypothesize that pathologically and genetically distinct forms of age-related TDP-43 proteinopathy exist in human brains, including: (a) an ADNC-related subtype influenced by APOE, (b) a FTLD-related subtype affected by GRN and TMEM106B, and (c) an arteriosclerosis-related subtype associated with ABCC9 gene variant. We will test methods of disease delineation - areas of overlap and points of difference - and evaluate how these hypothesized mechanism-classified subtypes synergize or negate each other when they are comorbid, and how the disease subtypes manifest clinically. The multimodal data may indicate a practical classification scheme. The two-institution study design enables us to evaluate inter-rater reliability and to emphasize replicability. Overall, the project will clarify mechanisms contributing to age-related TDP-43 pathology, ...