Blood methylomic signatures of presymptomatic dementia in elderly subjects with type 2 diabetes mellitus

Abstract

Due to an aging population, the incidence of dementia is steadily rising. The ability to identify early markers in blood, which appear before the onset of clinical symptoms is of considerable interest to allow early intervention, particularly in “high risk” groups such as those with Type 2 Diabetes (T2D). Here we present a longitudinal study of genome-wide DNA methylation in whole blood from 18 elderly individuals with T2D who developed pre-symptomatic dementia within an 18 month period following baseline assessment and 18 age, sex and education matched controls who maintained normal cognitive function. We identified a significant overlap in methylomic differences between groups at baseline and follow-up, with ten CpG sites, several in the vicinity of loci previously implicated in neurodegenerative processes, being consistently differentially methylated above our nominal significance threshold prior to symptoms at baseline and at 18 month follow up, after a diagnosis of pre-symptomatic dementia. Finally we report a significant overlap between DNA methylation differences identified in converters, only after they develop symptoms of dementia, with differences at the same loci in blood samples from patients with clinically-diagnosed Alzheimer’s disease compared to unaffected controls.

The role of environmental stress and DNA methylation in the longitudinal course of bipolar disorder

“…Taking power into consideration, and as an attempt to address the inherent multiple testing problem associated with EWAS, we limited our EWAS to only the most variable CpG sites according to MAD scores. While the fact that not a single site-specific association in DNAm survived correction for multiple testing could reflect the limited statistical power of our small sample, it may also be related to an overly conservative multiple testing correction considering the lack of variability in methylation at many CpGs and spatial correlation of methylation with nearby sites (Walker et al 2016;Lunnon et al 2015). A recent study estimated there are approximately 530,000 independent tests in a whole blood EPIC array DNAm study.…”

Lower DNA methylation levels in CpG island shores of CR1, CLU, and PICALM in the blood of Japanese Alzheimer’s disease patients

“…Genome-wide surveys that aimed at detecting AD-related methylation changes in blood have been conducted using Illumina HM450K and 850K (MethylationEPIC) arrays; however, AD-associated hypomethylation was not detected in CR1, CLU, or PICALM [8,46,47]. This discrepancy may be explained by the modest mean differences detected in CR1, CLU, and PICALM, which were all less than 10%, because depending on the probes, these arrays are not sufficiently sensitive to detect small differences, especially when sample numbers are limited [12,13].…”

Peripheral DNA Methylation, Cognitive Decline and Brain Aging: Pilot Findings from The Whitehall II Imaging Study

“…At present, there is limited data available on the potential utility of peripheral DNAm as a marker for cognitive decline before the onset of dementia. One study of patients with Type 2 diabetes mellitus who later developed presymptomatic dementia highlighted leukocyte DNAm changes that were comparable to changes identified in blood in AD patients and could thus potentially represent early markers of dementia [9]. Recently DNAm epigenetic clocks have been developed, which provide a measure of epigenetic age, based on DNAm levels at 353 CpG sites [10] and 71 CpG sites [11], respectively.…”