Hippocampal sclerosis of aging (HS-Aging) is a major pathologic substrate of dementia but there currently are no validated strategies in the clinical setting to diagnose or treat the disease. HS-Aging affects ~15% of elderly persons and is associated with substantial cognitive impairment. Our group has studied this area extensively, leading to the following major hypothesis: thyroid hormone (TH) dysregulation contributes to HS-Aging pathogenesis. This novel pathogenetic mechanism may provide the basis to diagnose HS- Aging during life using CSF analyses, and to develop a therapeutic strategy. However, critical knowledge gaps remain in terms of characterizing the specific association between TH dysfunction and brain pathology, and the potential to target the mechanism for therapeutic purposes. We propose a research program to fill these knowledge gaps while testing key hypotheses via the following Specific Aims: Hypothesis 1: Clinical TH status is associated with presence and severity of HS-Aging pathology. Specific Aim 1: Test the hypothesis in a convenience sample (n=205, including cognitively intact and diverse non-HS-Aging dementia controls) from the University of Kentucky AD Center biobank. We will apply rigorous, quantitative digital pathologic methods to assess TDP-43 pathology, AD plaques/tangles, and α- synucleinopathy for correlation with clinical TH status: self-reported TH disease and TH medications are well- documented. As expected in aged persons, more than 25% of the subjects exhibited clinical TH dysfunction. Hypothesis 2: CSF TH levels are associated with HS-Aging pathology and may provide a novel biomarker. Specific Aim 2: Evaluate TH (triiodothyronine, or T3) in CSF as a clinical biomarker of HS-Aging. We will assess human CSF TH levels with direct correlation with various subtypes of pathology. We also will test TH in clinical CSF from lumbar punctures, correlated with established AD-related biomarkers (Aβ and tau) and HS-Aging SNPs, with the goal of developing a new method to diagnose HS-Aging in living persons. We have obtained CSF from autopsied individuals (n=104) and clinical CSF samples (n=195) to accomplish this Aim. Hypothesis 3: Specific HS-Aging risk-associated gene variants induce altered brain TH levels with extensive impact on brain gene expression, and orally available drugs can alter this pathogenetic mechanism. Specific Aim 3: Define gene expression changes relevant to TH and HS-Aging. We will analyze human genomics databases to define how gene changes linked to HS-Aging risk contribute to variability in ABCC9 and SLCO1C1 (a major brain TH transporter) expression. We will test human cells (cultured human hESC astrocytes and lymphoblastoid cells transformed with DNA from people with known genotypes and pathology) to determine the potential for manipulating the levels of ABCC9, of TH transporter SLCO1C1, and of other TH- regulated genes. Finally, in mice, we will test how TH-responsive gene expression, neuropathol...