ABSTRACT. Comorbid pathologies are extremely common in the aging population. In recent years, inclusions containing the hyperphosphorylated form of transactive response DNA-binding protein 43 (TDP-43) have been found in a vast proportion of elderly with common amnestic dementia and pathologically confirmed Alzheimer’s disease (AD; characterized by amyloid plaques and tau-containing tangles). These cooccurring diseases, referred here to as “AD/TDP”, impact cognition, functioning, and brain integrity, and target older adults—a population that continues to rise globally. Despite this, the clinical and biologic features of AD/TDP remain undefined. The major goal of this study is to identify the clinical, cellular, and pathologic signatures of AD/TDP using brain specimens from participants who were characterized by rigorous neuropsychological tests during life and neuropathologically after death. This project is carefully designed to focus on affected neurons in the corticolimbic system that play a critical role in memory, cognition, and mood/behavior. It is anchored to neuronal groups in anatomic regions that typically show early susceptibility to 1) AD but not TDP-43 (Ch4 cells of the nucleus basalis); 2) TDP-43 but not AD (e.g., dentate gyrus); 3) both (e.g., amygdala); and 4) neither (e.g., visual cortex). It is based on longitudinal data acquired over decades, along with unbiased stereological quantification in corticolimbic regions from AD/TDP, AD, cognitively-healthy controls, and persons found to show TDP-43 of the FTLD-type. Clinicopathologic information on AD/TDP will help characterize its syndromic phenotype, clarify the link between clinical syndrome and neuropathology, and can address critical questions about the determinants of selective vulnerability and disease spread in dementia. Through longitudinal psychometric analysis, Aim 1 will identify the shared versus distinct clinical, neuropsychological, and psychiatric features of AD/TDP , with a focus on initial symptom onset and patterns of decline. Aim 2 will determine the cellular features and distribution of TDP-43 and AD-related pathology in amnestic dementia. The design confined to neuronal groups that show early susceptibility to either AD, TDP-43, both, or neither, will allow us to glean novel insights into the substrates of neurodegeneration. Stereological and digital analysis of pathology in white & grey matter microglia, cell number/size, dendritic trees & spines, and synapses will be performed in hemispheric regions. Aim 3 will investigate the well-known trans-synaptic circuitry of the memory-related hippocampus as a putative anatomic mechanism for spread and memory dysfunction in AD/TDP. Relationships between antemortem (Aim 1) and postmortem findings (Aims 2 & 3) will establish clinicopathologic concordance between the unique phenotype and anatomic vulnerability profile of AD/TDP. The study will leverage the resources of the Northwestern ADRC and will be carried out by a tea...