GSE203337
Genome-wide Mapping Implicates 5-Hydroxymethylcytosines in Diabetes and Alzheimer's Disease
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. Overall design: 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. ** Due to the patient privacy policy of Rush Medical Center, the raw data and the diagnosis of each subject are not included here. The raw data and diagnoses can be requested at www.radc.rush.edu and are available with a Data Use Agreement **