The role of human blood and brain 5-hydroxymethylcytosine in linking vascular risk factors to ADRD in older White and Black persons

Dementia is the 5th leading cause of death in the US and a growing public health challenge. We and others have shown that diabetes mellitus (DM), currently affecting >30 million people, doubles dementia risk. Because DM is a potentially modifiable risk factor for Alzheimer’s Disease (AD) and Related Dementias (ADRDs), mechanisms linking DM to dementia need further elucidation, and practical tools are needed to identify who will develop dementia, among those with DM. The overall goal of the proposed study is to characterize epigenetic signatures in blood and brain of older persons, to identify potential genome-wide 5hmC blood biomarkers for dementia by DM status and to elucidate brain-specific mechanisms of disease. To achieve these goals, we will leverage the Rush Memory and Aging Project (MAP; 5R01AG017917-17), with biospecimen collection in clinically- and pathologically-characterized older community-dwelling women and men, to address the following: Aim 1: Collect blood data to discover and validate genome-wide 5hmC biomarker signatures from serum cfDNA that predict who will develop dementia and cognitive decline, considering age, sex, and DM status. Aim 2: Among deceased and autopsied persons in whom existing 5hmC brain data are available, discover and validate genome-wide brain 5hmC signatures (from dorsolateral prefrontal cortex) that distinguish between persons with and without dementia, considering age, sex, and DM status. Aim 3: Conduct analyses as in Aims 1 and 2, but with other vascular risk factors, including blood pressure and body mass index, to examine the specificity of the associations of blood and brain 5hmC panels with DM. Impact: We will create a blood-based panel that identifies persons with DM at-risk for dementia and elucidate epigenetic mechanisms of dementia in DM. We have access to unique resources including biospecimens from well-characterized persons, and a team of accomplished collaborators with complementary specializations. For poorly-treated conditions like dementia, early detection of at-risk persons from among those with common and potentially modifiable diseases such as DM, offers a powerful opportunity for advancing aging research, and for targeted clinical interventions to improve individual and societal outcomes.