Summary Genetic factors play an important role in Alzheimer's disease (AD), and there is evidence that genes may play a bigger role in cognition as we age. Studies comparing the correlation in traits between identical and fraternal twins suggest 30-60 percent of the variance in episodic memory is related to the genetic makeup of individuals, with the remainder attributed to environmental influences not shared by family members. However, we still know very little about such complicated interplay between genes and lifestyle in onset, progress, and cognitive aging, calling for furthering genetic epidemiologic research to fight AD. Further, the vast majority of work examining the genetics of cognition has been performed in populations of European ancestry. With greater than 1.35 billion people, India is the second largest country in the world with over 4.1 million people estimated to have dementia. However, Indian/South Asian populations are rarely represented in genomic studies of dementia. To fill this gap, we propose to sequence 2,400 individuals from 12 regions of India to better define the mutational spectrum underlying dementia risk in the Longitudinal Aging Study of India (LASI). LASI is a representative, both nationally and at state-level, survey of the Indian population at age 45 or older (N=61,000). The Harmonized Diagnostic Assessment of Dementia for LASI (LASI-DAD) is an in-depth study of late-life cognition and dementia, drawing a sub-sample of 3,000 LASI respondents aged 60 or older and administering the Harmonized Cognitive Assessment Protocol (HCAP) that was designed to harmonize well with ongoing longitudinal studies of aging around the world, including the Health and Retirement Study (HRS) in the United States, and prior studies in India. This rich set of cognitive phenotypes along with brain imaging and a variety of other health and social environment phenotypes collected in this sub-sample will give us a unique opportunity to identify the mutational spectrum underlying risk of dementia and AD in a representative sample of India. In this application, we propose the following specific aims: (1) to perform whole genome sequencing (WGS) and population genetic analyses of 2,400 participants from 12 regions of India surveyed in the LASI- DAD; (2) to evaluate the association between known AD and dementia gene/genetic variants and cognitive function in sequenced LASI-DAD participants; and (3) to disseminate the WGS data as a reference panel for Southeast Asian mutations and develop, pilot, and evaluate a Southeast Asian genotyping chip to ensure proper assay of Southeast Asian mutations.

Public Health Relevance Statement Despite advances in genome-wide SNP and whole genome sequence (WGS) studies which have greatly accelerated our molecular understanding of AD, motivated new drug development, and improved our ability to identify high-risk individuals, families, and populations, these advances are likely to have limited value worldwide because they have arisen from genomic studies conducted primarily in cohorts of European ancestry. Indian or Southeast Asian populations are rarely represented in genomic studies of dementia. We aim to fill this gap by sequencing 2,400 individuals from 12 regions of India to better define the mutational spectrum underlying dementia risk in India and by disseminating the WGS data as a reference panel for Southeast Asian mutations.