ALZHEIMER'S RESEARCH PROJECT: Methylation changes, gene-environment interactions and the occurrence of Alzheimer's Disease: the AGES-RS Study

National Institute On Aging

Investigators

Abstract

A recent advancement towards understanding the pathobiology of AD is the identification the role of the epigenome, an intermediary between genetic and environmental interactions that can contribute to the risk of complex disease. The epigenome modulates cell- and tissue-specific gene expression, and is also affected by nongenetic risk factors, smoking being a well-established modulator of the epigenome. Ultimately, the epigenome can change gene and protein expression, and vulnerability to disease. This project will create a new and novel resource of DNA methylation data based on a deeply phenotyped longitudinal cohort, AGES-RS, of older men and women born 1914 to 1934. The sample to be included in this study will also have available whole genome sequencing data and a complete ascertainment of dementia cases. This project started July, 2020. For each of 4000 AGES participants a bio-specimen was drawn from AGES1 and AGES2 which was collected 5 years after AGES1. All samples have been processed and normalized and data were sent to NIA via the Icelandic Heart Association. Hardware and software preparations to accommodate this large dataset are being prepared. Analyses have started with a first questions focusing on metrics of accelerated aging using scores based on epigenetic tags (epigenetic clocks), whether there are changes in the epigenetic clocks over 5 years, and if so are there risk factors for these changes. This project creates a new and novel resource of DNA methylation data based on a deeply phenotyped longitudinal cohort, AGES-RS, of older men and women. To date, we have interesting findings that a longitudinal increase in a methylation-based Biologic Aging score is strongly associated with smoking, and with an increase in brain aging. In contrast a decrease in the score is associated with a healthy heart risk factor profile recommended by the American Heart Association. Also investigated is the change in methylation signals as a person transitions or doesn't to a dementia diagnosis.