Evaluating Mechanisms Underlying Resistance in Alzheimer’s Disease

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PROJECT SUMMARY Alzheimer disease (AD) is the most prevalent neurodegenerative disorder, affecting over 50 million people worldwide. Age and genetic variation can place individuals at high risk for developing AD, yet a unique subset of people at higher risk resist pathology and do not develop disease. Recent reports implicate the glymphatic system and corpora amylacea (CA) in the clearance of brain waste products. Corpora Amylacea amass cellular debris such as proteins and extrude them into the CSF where they travel to the cervical lymph nodes and are phagocytosed. The proper functioning of CA may play a role in AD resistance, and might be influenced by age, degree of pathology, and genetic risk. Understanding the brain’s innate response to toxic protein aggregates is essential for a deeper understanding of the development of AD pathology and potentially identifying disease biomarkers. Here we investigate whether CA contribute to resistance to AD pathology by quantifying CA location and number in the hippocampus of post- mortem AD and control brains. To evaluate the mechanisms underlying resistance we aim the answer the following questions: 1) Is clearance of intracellular pTau by CA associated with resistance to AD pathology? 2) In individuals who develop AD-related tau pathology, do CA, genetics, and vascular pathology influence the density of tau accumulation and the distribution across the hippocampus? Answering these questions will identify and quantify novel contributions to resistance of AD in the presence of elevated risk. This fellowship project proposal offers the opportunity to train in computational neuroscience and genetic epidemiology.