PROJECT SUMMARY Alzheimer’s disease (AD) is a neurodegenerative disorder that is marked by progressive damage and loss of neurons in the central nervous system. Current diagnosis of Alzheimer's disease relies largely on documenting mental decline, at which point Alzheimer's has already caused severe brain damage. There is an urgent need for novel methods to detect Alzheimer's before these devastating symptoms begin. Identifying pending cognitive impairment at an early stage can help design interventions that may reduce the risk of cognitive decline. Human Endogenous Retroviruses (ERVs) have integrated into mammalian genome over millions of years and comprise up to 5–8% of the human genome, as compared to 1-2% of protein coding sequences. Compared to the numerous studies describing proteins and their functions, very few studies have been performed on the impact of human ERVs on health and disease. Understanding how each ERV modulates both itself and its related genomic elements – functional proteins, disease-associated antigens, or genomic regulators – is crucial in determining the impact that ERVs can have on human health and diseases. ERVs have been reported to be transcriptionally active in the brains of AD patients. In addition, ERV activation is also associated with cognitive impairment in mice. In the parent grant, NIH/NCI R01CA226570 “Aggressive prostate cancer of African Americans is correlated with regulation of immunoregulatory genes in stroma”, we proposed that an epigenetic control of the antiviral immune response pathways via ERVs in prostate tumor microenvironment may contribute to differences in prostate cancer progression among patients of different racial groups. ERVs are highly repetitive and present in multiple copies throughout genome making it difficult to study them using existing computational tools. Most studies use PCR that can detect a few ERVs. We have developed a computational tool to study ERVs at the genome level, allowing detection of ERV changes at the global level. Applying this novel computational method, we have been able to correlate clinical outcomes with ERVs expression in prostate and cervical cancer. Here, we propose to extend these studies to AD and hypothesize that changes in ERV activation contribute to the inflammation and pathophysiology in AD. We will examine our hypothesis in two aims. First, we will investigate the global changes in ERV expression in peripheral blood mononuclear cells (PBMCs) from AD and mild cognitive impairment (MCI) patients, as well as healthy individuals (age matched). Second, we will determine the global changes in ERV expression in hippocampus tissue from all three cohorts (age matched). Identification of ERV changes may not only provide novel molecular target for strategies aimed at attenuating retroviral element sensing to treat dementia and neuropsychiatric disorders, but may also serve as potential early biomarkers for AD.