Non-Hispanic Black (NHB) patients have a two-fold higher risk of developing Alzheimer’s disease than non-Hispanic White (NHW) patients for unknown reasons; now, a fascinating epigenetics study reveals the involvement of DNA methylation at imprinting control regions (ICRs).
Researchers headed by Randy L. Jirtle and Cathrine Hoyo (North Carolina State University) explored ethnic variation in disease prevalence through an analysis of potentially aberrant DNA methylation patterns at ICRs after whole-genome bisulfite sequencing of samples from the brains of affected patients and matched controls. Why? One hypothesis for the increased prevalence of Alzheimer’s disease in NHB patients involves disparities that result in elevated exposures to environmental and life course stressors, prompting enduring functional alterations to the epigenome, with ICRs that regulate the expression of imprinted genes critical to embryo development displaying particular sensitivity. Can this epigenetic analysis show how ethnic disparities can affect disease prevalence and support improved management?
Let’s hear more from Cevik and colleagues on the epigenetic analysis of geographic variations in disease prevalence:
- Cross-referencing differentially methylated regions (DMRs) with candidate ICRs in the human imprintome revealed 120 regions of interest, with the majority of ICRs plausible Alzheimer’s disease pathological targets
- 81 display differential methylation in NHB patients and 27 ICRs display differential methylation in NHW Alzheimer’s disease patients (a three times difference)
- Network analysis reveals the white adipose tissue browning pathway as a common enriched pathway associated with Alzheimer’s disease in both NHB and NHW patients, with obesity an already known risk factor for dementia
- Network analysis also implies the importance of netrin signaling in NHB Alzheimer’s disease patients, which may impact amyloid beta production and neuroinflammation/neurodegeneration
- Common ICRs between patients included two proximal to an inflammasome gene (NLRP1) and a known imprinted gene (MEST/MESTIT1)
- Decreased MEST expression by promoter hypermethylation facilitates disease progression via Wnt signaling
- NLRP1 (an inflammasome component) associates with neurodegenerative diseases
- An examination of lncRNAs/miRNAs associated with the 120 ICRs revealed nine lncRNAs associated with differentially methylated Alzheimer’s disease-associated ICRs in NHB patients and one in NHW patients (all with links to brain development) and two miRNAs in NHB patients, with one (miR1260b) linked to Alzheimer’s disease
Overall, the authors provide evidence that ethnic disparities in Alzheimer’s disease prevalence may involve potentially heritable alterations of DNA methylation levels at ICRs during early development; therefore, the methylation status of these select regions may represent an early detection tool for disease risk, which may help slow progression.
“We know that targeted prevention over long periods can alter risk,” co-corresponding author Hoyo notes. “So if you can alert people early on about their risk and apply targeted interventions, you could prevent disease onset.” “Epigenetics is the science of hope,” co-corresponding author Jirtle adds. “You can’t necessarily reverse genetic mutations, but when you know disease risks result from changes in the epigenome you can potentially negate them.”
For more on the epigenetics of Alzheimer’s disease risk, see Clinical Epigenetics, April 2024.