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

PROJECT SUMMARY/ ABSTRACT
Alzheimer’s Disease (AD) is a chronic and disabling condition, the 6th leading cause of death in the US, and a
major cause of personal, societal, and global burden. Yet, our understanding of pathobiologic mechanisms
underlying dementia and cognitive impairment in aging remains incomplete, and this gap in knowledge hinders
scientific advancement and improved clinical care and prevention. Vascular conditions such as diabetes
mellitus (DM) are common, especially among minority racial groups, and recognized as increasing dementia
risk. Because these factors are modifiable by treatment and lifestyle approaches, research linking vascular
factors to Alzheimer’s Disease/ Alzheimer’s Disease-Related Dementias (AD/ADRD) is more important than
ever. Emerging data suggests that the epigenome likely plays a role in this link, and novel methods to study
the epigenome are now available. 5-hydroxymethylcytosine (5hmC) is an epigenetic modification of cytosine
for which we can now measure genome-wide changes in circulating cell-free DNA (cfDNA) in blood and
genomic DNA (gDNA) in tissues. Our group has developed a highly sensitive and selective analytic approach
to capture and sequence 5hmC-containing DNA fragments in order to map genome-wide distributions, and
have successfully used this approach to develop 5hmC scores which distinguish between patients with and
without different conditions, including in recent studies of AD and DM. In response to the pressing need to
better understand the pathobiologic underpinnings of AD/ADRD, we propose a collaborative project with the
overall goal of elucidating epigenetic mechanisms linking vascular risk factors to AD/ADRD clinical and
pathological phenotypes, in older Whites and Blacks. The proposed study will leverage available resources
from two community-based cohort studies, including research participants from which to collect blood
specimens, as well as extensive longitudinal clinical data and postmortem neuropathologic data, and
biospecimens (e.g., frozen brain tissue samples). Among White and Black persons, we will collect new
genome-wide 5hmC data to generate serum-specific (Aims 1 and 4) and brain-specific 5hmC scores (Aims 2
and 4), using discovery and validation experiments in different sets of persons, that distinguishes between
persons with and without dementia. We will then link the blood and brain 5hmC data to AD/ADRD clinical and
pathologic phenotypes, including incident dementia and cognitive decline (Aims 1 and 4), cerebrovascular and
AD pathology (Aim 2). We will further examine if relations are differential by vascular risk factors (DM, blood
pressure [BP], and body mass index [BMI]) and by other factors (e.g., sex; Aims1-4), and if generalizable to
Black persons (Aim 4). Because vascular risk factors are common and modifiable, this study which will
elucidate 5hmC mechanisms in AD/ADRD and vascular diseases among White and Black older persons, will
fill a major gap in scientific knowledge about dementia and provide important data to inform future research
and to ultimately improve clinical dementia care and prevention.

Grant Number: 5R01AG074549-03
NIH Institute/Center: NIH
Principal Investigator: Zoe Arvanitakis