Project 2: Biomarker Analysis, Non-Genetic Risk Factors, and Their Genetic Interactions

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Project 2 Summary for Overall The overarching goal of Project 2 is to enhance clinical trial readiness for ASAC. Successful identification of effective treatment and prevention for AD will require inclusion of all populations in clinical trials, with all individuals having accurate diagnosis of disease. Molecular measures of AD pathology have gained increasing traction to support clinical diagnosis of AD. Peripheral biomarkers, specifically plasma proteins that reflect AD neuropathology, have shown increasing utility and represent an accessible opportunity to diagnose and treat AD sooner. While no plasma biomarker has yet been approved for diagnostic use, blood biomarkers of AD neuropathology (Aβ42/40, Tau-181), axonal injury (neurofilament light [NfL]), and astrogliosis (glial fibrillary acidic protein [GFAP]) have shown promising utility in AD diagnosis given their strong associations with cognitive decline, gray matter loss, and AD conversion. However, most biomarker development has been performed in homogenous, European ancestry populations. There is an urgent need for the field to test whether AD biomarker thresholds generalize across diverse populations, including Asians. Meanwhile, it has been reported that 40- 50% of all dementia cases can be prevented by modifiable risk factors. Again, such findings are mainly based on studies focused mainly on European Americans and may not be generalized to ASAC. Prior studies have shown that effect sizes, and the relative contributions, of non-genetic risk factors on AD often differ between racial/ethnic groups. In addition, ASAC, being an ethnic minority living in North America, has unique risk profiles for AD compared to Asians living in Asia. Numerous non-genetic factors may contribute to such differences, including education, immigration history and acculturation level, leisure and physical activities, diet, and psychosocial stress. Better characterizing the risk profiles has critical implications for the design of future interventional trials for individuals with diverse ancestry, particularly for understudied groups like ASAC. To accurately identify those at highest risk for AD and to design an effective preventive trial, we require a better understanding of the impact of non-genetic factors on AD risk. Overall, Project 2 will address these gaps in knowledge by leveraging the unique resources of the multi-center ACAD to determine ASAC-specific diagnostic cut-offs for promising AD plasma biomarkers (Aβ42/40, Tau-181, NfL, and GFAP), and to investigate non-genetic factors in conferring AD risk and in moderating the association between genetic factors and AD in ASAC. Project 2 will test the overarching hypothesis that there are ASAC-specific AD biomarker thresholds and unique non- genetic factors that interact with genetic risk for AD. Together, through biomarkers and non-genetic factors (and integration with genetic factors in Project 1), Project 2 will generate a significant, sustained impact on the field by enhancing our ability to accurately profile AD risk in the ASAC community, which will be extremely valuable information when designing new interventions to prevent AD development and progression in all populations.