ABSTRACT. The analysis of cerebrospinal fluid (CSF) and molecular PET biomarkers of Aβ and phospho-tau combined with MRI assessment of global and regional neurodegeneration led to the development of the “A/T/N” classification scheme for Alzheimer's disease (AD) that was intended to add precision to the diagnosis for clinical purposes, therapeutic trials and regulatory agencies. For observational epidemiological research the widespread use of these types of biomarkers is not possible because of the expense and limited access to cyclotrons necessary for molecular imaging and the difficulty in obtaining CSF in large studies. Further, it is clear that the relationship of biomarker values to clinical diagnoses can also differ by age, sex and race/ethnic group, and few studies have included diverse cohorts, representative of the population in the US. The advent of newly- established, blood-based biomarkers (Aβ40, Aβ42, p-tau217, neurofilament light chain or NFL) combined with brain MRI provides an opportunity to investigate the application of “A/T/N biomarker profile” in community-based, observational study, and create endophenotypes that can be used to identify genetic susceptibility. The Washington Heights, Inwood Columbia Aging Project (WHICAP) study is one of the few cohorts where the newly established blood-based biomarkers and well-established neuroimaging biomarkers for AD can be used to investigate a blood-based “A/T/N biomarker profile” across race/ethnic groups and by age and sex. Amyloid (plasma Aβ40 and Aβ42), Tau (plasma total tau and p-tau217), and Neurodegeneration (plasma neurofilament light [NfL], and MRI (brain volumes and cortical thickness) will be assessed in a longitudinal, multi-ethnic community-based elderly cohort (24% white non-Hispanic, 28% African American, 48% Caribbean Hispanic). The cohort has been genetically characterized, and has stored DNA, sera, and plasma. The effects of cerebrovascular disease “V” and psychosocial factors will also be investigated as potential modulators of the “A/T/N biomarker profile”. We will use publicly available genetic data in African American, Caribbean Hispanic and non-Hispanic white participants that included the WHICAP cohort to create ethnic-specific polygenic risk scores (ePRS). This will allow the identification of variants associated with the endophenotypes underlying the “A/T/N biomarker profile” and augment the ePRS association with the clinical diagnoses of AD. We will maintain longitudinal follow-up of the WHICAP cohort, adding participants only to account for attrition, collecting whole blood for plasma and sera, ascertaining psychosocial and biomedical risk and protective factors and obtaining structural MRI measures at least twice in participants over a four-year period. The overall goals of this project are to: 1) investigate variability in blood-based biomarkers and MRI measures in the “A/T/N biomarker profile” as it applies to clinical diagnoses in a multi-ethnic cohort; 2) investigate blood-based biomarkers as endophenotypes in genetic analyses for earlier detection and diagnosis of AD; 3) investigate how cerebrovascular disease and psychosocial factors modulate the use of blood-based and MRI biomarkers.

PROJECT NARRATIVE (RELEVANCE) The availability of new blood-based biomarkers provides an opportunity to investigate the application of “A/T/N biomarker profile” in community-based, observational study, and provide endophenotypes that can be used to identify genetic research. The Washington Heights, Inwood Columbia Aging Project study is one of the few cohorts where these newly-established blood-based biomarkers (Aβ40, Aβ42, total tau, phosporylated-tau217, neurofilament light chain or NFL) and well-established neuroimaging biomarkers for AD can be used to investigate the application of “A/T/N biomarker profile” across race/ethnic groups and by age and sex.