PROJECT SUMMARY/ABSTRACT Alzheimer?s disease (AD) can affect patients in different ways. It typically presents with progressive memory loss that leads to dementia. However, AD can have atypical presentations when other areas of cognition are affected more prominently, such as language, visuospatial or executive functioning. Patients with AD may also have symptoms that are indicative of dementia with Lewy bodies (DLB), such as parkinsonism, visual hallucinations, cognitive fluctuations or dream enactment behavior. In these cases, it is difficult to predict the pathology. At autopsy, AD is diagnosed by findings of senile plaques made of amyloid and neurofibrillary tangles made of tau. Lewy bodies (LB), made of ?-synuclein, are found in DLB, but are also commonly found in AD. Mixed pathology has been linked to poorer outcomes. We do not know what causes the clinical variability nor how mixed pathology affects the clinical syndrome. These knowledge gaps make it difficult to predict disease course, which has implications when treating patients and developing new treatments for AD. Protein tau, which spreads and accumulates abnormally throughout the brain in AD, may be a key factor. The hypothesis is that tau spreads like proteins in prion disease, where an abnormal tau ?strain? that is prone to buildup spreads from cell to cell to convert native tau to the abnormal strain. This then ?seeds? further buildup and spread of abnormal tau. There are many tau strain types, each with distinct properties including how they accumulate and how fast they spread. Our working hypotheses are that different tau strains account for the variability in AD presentations and that certain tau strains interact with ?-synuclein to affect the clinical syndrome. We will test these hypotheses by studying autopsy specimens from the UT Southwestern Alzheimer?s Disease Center. Dr. Diamond?s lab will identify tau strains and measuring tau seeding in sections from selected cases using their novel biosensor cell line panel. Aim 1 will compare tau strains in cases with typical and atypical presentations. Tau strain identifications here will determine if strains are associated with a particular clinical presentation. Aim 2 will study tau and ?-synuclein interactions by selecting cases that have AD, LB, or mixed pathology. Cases will be defined by clinical syndrome (AD or DLB) and whether this matched pathology (e.g. clinical AD with AD-only pathology), had mixed pathology, or had a mismatch (e.g. clinical AD high LB pathology). Tau seeding and strain types will be compared to the tau and ?-synuclein pathology in different brain regions and between groupings based on pathology and clinical diagnoses. We suspect that certain tau strains have increased seeding with ?-synuclein and are associated with a DLB syndrome. The advancements in understanding disease mechanisms of AD resulting from this project will improve our abilities to predict disease course and refine research efforts in developing and new disease- modifying therapies.