Harmonized Diagnostic Assessment of Dementia for the Longitudinal Aging Study in India (LASI-DAD): Epigenomic Assays

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Summary Epigenetic modifications of DNA, such as DNA methylation, have been strongly associated with chronological age and can be used to estimate age acceleration in individuals. Epigenetic factors may also mediate or modify the effects of AD-related genetic variants. Given the dynamic nature of epigenome and many influencing factors (both environmental and genetic), longitudinal studies that measure methylation at multiple timepoints are being increasingly recognized as the most suitable approach to analyze the epigenetics of complex diseases. However, longitudinal studies to estimate change in epigenetics are very limited anywhere in the world and are virtually non-existent in population-based representative samples. Furthermore, little work has been done on epigenetics and AD and cognitive function in lower income, non-Western countries. To fill this gap, we aim to measure longitudinal epigenomic variation in the Harmonized Diagnostic Assessment of Dementia for the Longitudinal Aging Study in India (LASI-DAD) in DNA samples that are already extracted (Wave 1) and venous blood samples currently being collected (Wave 2). This work will enable essential studies of the epigenetic predictors of aging, cognitive impairment, and Alzheimer’s disease and related dementias (ADRD) in South Asians from India, as well as the study of epigenetic mediators and modifiers of genetic risk for cognitive impairment and dementia. Moreover, since epigenomic variation often reflects environmental variation with risk factors that have been associated with AD (e.g., environmental pollutants, socioeconomic and social stressors, health behaviors, and dietary habits), it is critical to evaluate potential biological mechanisms by which these social, environmental, and individual risk factors may influence disease in South Asian and other non-Western populations, including how they change over time. In this application, we propose the following specific aims: (1) to simultaneously conduct epigenomic assays for longitudinal study by first extracting DNA from the Wave 1 VBS (1a), sorting and pairing wave 1 and wave 2 samples and preparing plates for methylation assays (1b), and conducting epigenomic assays for paired samples (DNAs extracted for the same individuals at two different timepoints, 5-years apart) using the Infinium Methylation EPIC 2 BeadChip; (2) to conduct a cross-laboratory calibration study for future cross-country comparisons, particularly with the Health and Retirement Study (HRS) and its international network of studies.