PROJECT SUMMARY Alzheimer’s disease (AD) is the most common form of dementia, and disease mechanisms important in AD beyond amyloid and tau are not well defined. Myelin integrity is an understudied field in AD research and it is currently not well understood why myelin injury that occurs in all aging adults is exacerbated to a pathologic amount in those with AD. Decreased myelin quantity has been demonstrated in amyloid-positive preclinical AD patients, which may be a separate process from gray matter degeneration seen in preclinical and prodromal disease. Recent literature suggests that oligodendrocyte progenitor cells (OPC), which differentiate into oligodendrocytes and promote myelin sheath maintenance and repair, are dysfunctional in AD. Microglia are also known to contribute to myelin maintenance and repair specifically through the recently characterized glia- to-glia signaling pathway downstream of microglia-derived transglutaminase-2 cross-linking enzyme (TG2), which promotes OPC proliferation and thus myelination via g-coupled protein receptors. Although the literature implicates impaired myelin repair in AD this pathway has not been investigated in relation to current AD biomarkers. Of note, the acetylcholinesterase inhibitor donepezil promotes oligodendrocyte differentiation and repair of the myelin sheath and provides significant therapeutic effect in animal models of demyelination. The overarching objective of this proposal is to explore underlying mechanisms of myelin repair as drivers of white matter degeneration, repair, and disease progression in AD. In Aim 1, I will analyze gene variants of five candidate myelin repair genes, OLIG1, OLIG2, SOX10, SOX17, and MBP, which have been chosen due to extensive literature support of their role in myelin repair and relative lack of assessment in AD to date. In Aim 2 I will analyze mRNA expression levels to understand functionality of these variants. Finally, in Aim 3 I will investigate gene variants and mRNA expression of a candidate pathway that may be responsible for inhibited myelin repair. This project will test two hypotheses: 1) genetic variations (SNPs) and mRNA expression of selected myelin repair genes will be associated with both abnormal imaging and clinical biomarkers of AD; and, 2) genetic variations (SNPS) and abnormal mRNA expression of the upstream microglia-derived TG2-ADGRG1 signaling pathway, important in myelin repair, will be associated with abnormal imaging and clinical biomarkers of AD. The project will use neuroimaging and genetic data in patients across the AD continuum, utilizing data from the AD Neuroimaging Initiative (ADNI) and Indiana Memory and Aging Study (IMAS) cohort followed by the NIA-designated Indiana ADRC. It will also allow me to shadow relevant clinicians as well as facilitate training in imaging, genetics, and relevant neurobiology necessary to submission of a novel and translational doctoral thesis.