Biomarkers of neurodegeneration in the US and India: A cross-national evaluation of the biological underpinnings of ADRD

PROJECT SUMMARY Inconsistencies between observed effects on biological versus clinical endpoints of recent disease-modifying therapies for Alzheimer's Disease and Related Dementias (ADRD) highlight existing gaps in our understanding of biological processes of ADRD. Better characterization of the interplay between biology and the social

environment may help explain these discrepancies. To address this critical gap, the proposed research takes a novel approach to understanding ADRD mechanisms by leveraging cross-national comparisons between the US and India to evaluate biological underpinnings of ADRD, focusing on biomarkers of neurodegeneration,

vascular, nutritional, and inflammatory systems, and their interface with social and economic factors. With over 1.4 billion people India is the world's most populous country with a rapidly growing older population and has very different social, economic, and demographic patterns of risk for ADRD compared to the US. Given this

novel opportunity for cross-national comparisons of the interface between biological markers of disease and clinical outcomes, we will be able to identify common biological pathways observed in very different social and economic contexts. Our overarching goals are to leverage data collected via Harmonized Cognitive

Assessment Protocols (HCAPs) in the US and India to assess the interplay between country, social factors, and ADRD biology using recently collected and rigorously cross-nationally harmonized data on neurodegenerative biomarkers, cognitive outcomes, and other markers of vascular, nutritional, and inflammatory systems. Aim 1 uses neurodegenerative biomarkers to classify people into pathological subtypes,

then evaluates associations of other vascular, nutritional, inflammatory, and demographic factors with these subtypes. Aim 2 associates each plasma biomarker with cognitive outcomes, while Aim 3 tests for effect modification by socioeconomic factors. Aim 4 will evaluate the relative contribution of variance in plasma

biomarkers alongside other factors in predicting cognitive outcomes. Key innovations include cross-national cohort integration, translational potential to interventions, biomarker research equity, and a research framework centered on the biological and social determinants of ADRD. This proposed research is pivotal in leveraging

biology to understand social differences in cognition because cross-national comparisons between the US and India, particularly regarding relationships of biomarkers to cognition and effect modification by social and economic factors, will provide evidence as to the generalizability of findings on ADRD mechanisms in different

contexts. Our results will set the stage for high-quality cross-national research to identify intervention targets for ADRD, with the ultimate objective of preventing and/or delaying the onset of ADRD from a global perspective.