Harmonized Diagnostic Assessment of Dementia (DAD) for Longitudinal Aging Study of India (LASI)-Genomic study

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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. Our preliminary analysis of the whole genome sequences from LASI-DAD shows that our study has the most comprehensive survey of genetic variation in South Asia. Further, we have uncovered that like most non-Africans, South Asians have ~1-3% ancestry from archaic hominins––Neanderthals and Denisovans. Surveys of Eurasians have shown that this history has played a critical role in shaping the genetic and phenotypic variation in modern humans. For instance, archaic ancestry in Eurasians has impacted numerous traits ranging from skin pigmentation to high altitude adaptation, and response to SARS-CoV-2. However, most studies have focused on Europeans and East Asians, with very few genomes from other parts of the world. Further, no study has investigated the role of archaic ancestry in impacting the risk of Alzheimer’s disease or cognitive phenotypes. To fill this gap, we aim to investigate how archaic hominins (Neanderthal and Denisovan) ancestry impacts the risk of Alzheimer’s disease and cognitive phenotypes in modern humans using the large dataset of 2,700 samples from our LASI-DAD study. The LASI-DAD dataset contains 2,700 individuals from diverse ethnolinguistic groups in India, with extensive phenotype information for Alzheimer’s disease risk and cognitive phenotypes. The detailed genotype and phenotype information from the LASI-DAD dataset provides a unique opportunity to study the impact of Neanderthal, Denisovan and introgressed segments from other unknown hominins on the health of present-day individuals and uncover introgressed genes associated with Alzheimer's disease risk. Moreover, we are currently collecting more samples from additional regions and the study is a very timely project as we can collect more samples from specific groups to increase our power for genotype-phenotype analysis that show promising results. In this application, we propose the following specific aims: (1) to generate a map of archai introgression in modern humans; (2) to perform association analysis to study the association of Alzheimer’s disease risk and archaic ancestry; (3) to recruit samples from additional regions to maximize its potential for future population genomics study.