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Genome-wide Mapping Implicates 5-Hydroxymethylcytosines in Diabetes and Alzheimer’s Disease

ABSTRACT: Background: Diabetes mellitus (DM) is a recognized risk factor for dementias, including AD, increasing its odds by two-fold. Because DM is potentially modifiable risk factor, a greater understanding of the mechanisms linking DM to the clinical expression of AD may provide insights into much needed dementia therapeutics. Epigenetics offers a novel approach, and previously under-investigated 5-hydroxymethylcytosines (5hmC) is now emerging as a promising measure to investigate in diabetes related conditions. Methods: Using 5hmC-Seal, a highly sensitive chemical labeling technique developed by our team, we performed genome-wide profiling of 5hmC in circulating cell-free DNA (cfDNA) and prefrontal cortex tissue from 80 individuals across four groups: AD, DM, DM and AD (AD+DM), and non-AD/non-DM controls. We used differential analysis and machine-learning to explore whether 5hmC and biological pathways might be implicated in DM-associated AD under a balanced design. Results: We uncovered distinct 5hmC genome-wide signatures and biological pathways associated with AD or AD+DM compared to non-AD/non-DM controls or DM alone. We further demonstrated potential diagnostic value of 5hmC profiling in circulating cfDNA through feature selection based on machine learning. Conclusions: Genome-wide 5hmC profiling uncovered genomic features and biological pathways linking DM to DM-associated AD. Our findings also demonstrate the potential of utilizing 5hmC in circulating cfDNA as diagnostic biomarkers or disease monitoring tools, with the ultimate goal of preventing or ameliorating DM-associated AD dementia and improving clinical outcomes.

ORGANISM(S): Homo sapiens

PROVIDER: GSE203337 | GEO | 2023/05/16

REPOSITORIES: GEO

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