M48 comparative whole genome dna methylation profiling in costa rican nonagenarians with and without dementia: significant difference between chronological and epigenetic age and further evidence for a role of PM20D1

Abstract

Background: Alzheimer's disease (AD) is a complex disorder that results from a combination of genetic and non-genetic risk factors. There are genetic variants that may be protective against the development of dementia at advanced ages. Most epigenetic and non-epigenetics studies of successful cognitive aging have focused on individuals between 65 and 85 years old, there isn't much representation of nonagenarians or centenarians. There is abundant evidence about methylation patterns alterations in individuals with dementia compared with non-affected ones, but not much information about epigenetic markers of normal cognitive aging. Methods: In this study, we compared whole blood DNA methylation profiles of nonagenarians of Costa Rica, 21 cognitively healthy (mean age 93, SD=2.8) and 11 with dementia (mean age 95, SD=3.4), using the Infinium MethylationEPIC BeadChip. We calculated the epigenetic age based on Horvath's epigenetic clock. We used two different approaches; DMRcate and Bumphunter, to identify differentially methylated regions (DMRs). Results: On average, the epigenetic age was 73 years in both groups, which represents a difference between the epigenetic age and the chronological age of 23 years in the case of cognitive healthy people and of 22 in the case of people with dementia. The analysis revealed 11 DMRs between both groups, within which five genes, and two pseudogenes are located. Discussion: Epigenetic age results are consistent with other publications on nonagenarians and also on an aged Costa Rican population. However, in these studies the difference between epigenetic and chronological age is not as important as in our sample. The DMRs genes are involved in cell cycle regulation, embryogenesis, synthesis of ceramides, and migration of interneurons to the cerebral cortex. One of the five genes that we found differentially methylated is PM20D1. Consistently with other studies, we found that the gene is hypermethylated in AD. Association studies have found that this gene is associated with AD, also it is a QTL of both expression and methylation. PM20D1 potentially protect against AD and that loss of this expression is a risk factor for AD.