PROJECT SUMMARY: Although Alzheimer's disease (AD) is typically defined by the accumulation of beta- amyloid and hyperphosphorylated tau proteins, synaptic loss and neuronal degeneration, the disease is not restricted to the gray matter. Neuroimaging and neuropathological studies have documented a significant loss of white matter in AD, which begins early in the disease course and is correlated with cognitive decline. In addition to contributions of hypoperfusion-related ischemic injury and neurodegeneration-associated axonal loss, emerging evidence indicates a decline and dysfunction of oligodendrocyte populations as additional factors in this multifactorial white matter disease process. Oligodendrocytes are the most abundant glial cell type in the brain, but are the least studied cell population in the context of neurodegeneration despite their vital role for myelin maintenance and neuronal support. With the increasing recognition of the role of myelin in AD, it becomes important to understand the genetic and molecular factors that link oligodendrocytes to the AD process. Our knowledge about genetic variants contributing to overall AD risk and influencing AD-associated endophenotypes is accelerating. Our proposal is designed to bring these two lines of investigation together and begin to explore genetic modifiers of oligodendrocyte and myelin abnormalities in AD and underlying molecular mechanisms using a quantitative trait approach of neuropathologically defined myelin endophenotypes. The central hypothesis of our proposal is that loss of myelin integrity and oligodendrocyte dysfunction in AD are associated with genetic variants and molecular changes. We will test this hypothesis by first performing genome-wide association studies (GWAS) of white and gray matter neuropathological endophenotypes in human postmortem brain tissue samples and will then conduct bulk and spatially defined gene expression studies to explore underlying molecular mechanisms. Our experiments are divided into two specific aims: Aim 1) To determine genetic modifiers of myelin and oligodendrocyte pathologies in AD. Aim 2) To determine associations between white matter gene expression changes and white matter pathologies in AD. The above aims benefit from the tight integration and leveraging of a diverse group of investigators with expertise in the neuropathology of AD and digitally quantified pathology endophenotypes (PI Kofler), AD- associated oligodendrocyte pathology (Co-I Herrup), GWAS data analysis (Co-Is Kamboh and Fan), biostatistical analysis of transcriptomics datasets (Co-I Ding) and digital image analysis and machine learning (Co-I Pearce). Upon completion of our proposed studies, we will have identified novel candidate genes as mediators of myelin pathology in AD, increased our understanding about the biology underlying their linkage to AD and revealed novel targets for therapeutic interventions. As our study design includes separate analyses of gray and whit...