Age-Related TDP-43 Neuropathology: Using Disease-Driving Mechanisms to Guide Classification

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. There is consensus that the amygdala is the first brain region affected in LATE-NC and therefore may represent 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 the spectrum of age-related diseases such as LATE-NC, with hospital/clinic-based cohorts of less common TDP-43 proteinopathies, such as FTLD-TDP and ALS. Therefore, we will combine results from a large community-based autopsy cohort (U. Kentucky) with an excellent hospital-based cohort (Houston Methodist Hospital) to analyze pathologic and genetic phenomena associated with disease-driving mechanisms. The study will incorporate well-characterized human brains (n>1400) of patients with LATE-NC, amyotrophic lateral sclerosis/ frontotemporal lobar degeneration spectrum (ALS/FTD), and AD neuropathologic changes (ADNC), with and without comorbid LATE-NC. We will characterize the comorbid proteinopathies and vascular pathology associated with the earliest foci of TDP-43 pathology, including co-localization of TDP-43 and other misfolded proteins, such as tau (Aim 1). 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 (e.g., APOE, GRN, TMEM106B, and ABCC9 polymorphisms). We will address this hypothesis by examining and contrasting 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/FTLD) (Aim 2). We also hypothesize that pathologically and genetically distinct forms of LATE-NC exist in human brains, including: (a) an ADNC-related subtype influenced by APOE, (b) an FTLD-related subtype affected by FTLD-related gene variants (GRN, TMEM106B) and (c) an arteriosclerosis-related subtype associated with small vessel disease and an ABCC9 gene variant. We will operationalize methods of detection and test how these three subtypes co-exist (synergize or negate each other), and how they manifest clinically. We will develop a practical classification scheme of LATE-NC incorporating clinical, pathologic, proteomic, and genomic data (Aim 3). Overall, the project will clarify mechanisms contributing to TDP-43 pathology in human aging and amygdalae, and provide an optimized framework to guide future mechanistic studies, therapeutic development, and biomarker development.