Hippocampal sclerosis of aging (HS-A) and Limbic predominant age related TDP-43 encephalopathy neuropathologic change (LATE-NC) are important degenerative pathologies that are closely related but distinct. Around 20% of older age dementia is attributable to these two conditions. HS-A is diagnosed when there is disproportionate atrophy in a brain structure called hippocampus and LATE-NC is characterized by abnormality of an essential protein, TDP-43. Clinically, both pathologic changes mimic Alzheimer’s disease pathology and present with memory problems. Despite their importance, none of the pathologies can be diagnosed during life and can only be found by examining the brain after patients die. Moreover, both HS-A and LATE-NC frequently co-occur with Alzheimer’s disease pathology. This makes their diagnosis even more challenging. This is especially important in an era that specific treatments for these protein abnormalities are being developed. Therefore, there is significant unmet need for discovering ways to diagnose them during life. In the current cycle of the grant, we showed that our quantitative method is more informative than standard pathologic measures in identifying relationships between HS-A and clinical impairment and presence of other pathologies. We also found that clinical features of HS-A and LATE-NC are remarkably similar to Alzheimer’s disease. We found that MRI detects atrophy of hippocampus in HS-A, and this is an early finding making MRI a suitable tool for HS-A diagnosis. We have also found indications that autoimmunity plays a role in HS-A. The objective of this proposal is to advance our HS-A discoveries and to start new investigations on pathological assessment and diagnosis of LATE-NC in an ethnically diverse group of participants. Inclusion of ethnically diverse participants will allow for studying the prevalence and impact of these important pathologies in a representative sample of our population. The study will use the resources of four ongoing studies of older individuals across two Alzheimer’s disease research centers at University of California (UC), Irvine and UC Davis, The 90+ Study, and LifeAfter90 Study. In aim 1, we will replicate our HS-A results in a new and ethnically diverse group of participants that will validate our methods. We will also test the hypothesis that quantitative assessment of LATE-NC will identify novel associations with cognitive impairment and other brain pathologies. In aim 2, we will test the hypothesis that brain MRI and glucose PET scan, can identify features that are specific to HS-A and LATE-NC. In aim 3, we hypothesize that blood markers of autoimmunity and inflammation are related to HS-A and LATE-NC respectively and measuring TDP-43 and progranulin in blood, can serve as markers of LATE-NC. Successful completion of this proposal, we lead to major advancement in the diagnosis of two important dementia related pathologies that cannot be diagnosed during life. This will not only ...