Sex-specific risk factors and trajectories of blood biomarkers for Alzheimer's disease and related dementias

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PROJECT SUMMARY / ABSTRACT Late-life Alzheimer’s disease and related dementias (ADRD) are devastating multifactorial conditions and the major contributors to loss of independence in older age. There is a critical unmet need to identify which individuals are at the great risk of these conditions, thus permitting accurate prognosis and timely preventative interventions to reduce the burden. Yet, while a number of risk factors have been identified for these conditions, sex differences in these associations have rarely been considered. Furthermore, exciting recent advances in blood amyloid, tau and neurodegeneration (AT(N)) biomarkers for ADRD means that they could soon be used as powerful clinical diagnostic and prognostic tools in a personalized medicine approach. However, a number of critical knowledge gaps remain. Importantly, 1) these biomarkers have not been sufficiently examined in longitudinal studies of older community- based populations without diagnosed dementia; 2) it is unclear how participant characteristics such as comorbidities affect the clinical interpretation of these biomarkers; and 3) how their interpretation may differ between men and women. Together, these large knowledge gaps highlight a crucial need to develop the first sex-specific risk score for ADRD that incorporates blood AT(N) biomarkers and ADRD risk factors. Our overarching hypothesis is that AT(N) plasma biomarkers will be predictive of ADRD in initially healthy community-dwelling older individuals, beyond known risk factors (including age, education, living alone, diabetes, hypertension, smoking, alcohol consumption, physical activity), and that these associations will vary by sex. This project provides an unprecedented opportunity to address this important question within the context of a rigorous, large-scale study of initially healthy individuals aged 65-98 years from the US and Australia (12,716 whites, 412 blacks, 339 other minorities) with comprehensive annual in-person cognitive assessments, adjudicated clinical outcomes, detailed data on socio-economic status, lifestyle and health factors collected over a median 9+ years, and existing genetic data (APOE4, dementia polygenic risk scores). Leveraging unique blood samples available at two time-points (n=13,435 at baseline, and ~8000 at 7 to 10 years), AT(N) biomarkers will be measured longitudinally. This proposal is a unique, highly cost-efficient opportunity to address gaps in our ability to accurately determine who is at the greatest risk of ADRD, individually for women and men. We will address critical gaps in identifying which factors influence blood biomarker levels and must be considered when establishing their clinical reference ranges. The sex-specific risk score resulting from this project will provide a powerful new tool for practitioners to predict risk of cognitive decline and ADRD that considers common comorbidities, social, lifestyle, and genomic risk factors, together with the unique predictive strength of the plasma AT(N) biomarkers.