PROJECT SUMMARY The overall aim of this study is to identify social and biological pathways of racial/ethnic disparities for incident Mild Cognitive Impairment (MCI)/ Alzheimer's Disease and Related Disorders (ADRD) and cognitive decline that emerge in middle age. We have recruited over 1,500 middle-aged offspring of participants in the Washington Heights/Inwood Columbia Aging Project (WHICAP), and characterized them at baseline using measures of neuropsychological and psychosocial function, lifecourse measures of social and environmental determinants of health, stored blood samples, and brain structure with MRI. The Offspring study is unique among other cohorts, with large numbers of Latinx and African American participants in middle age who are not a convenience sample and are representative of their age and cultural groups, and whose parents are well-characterized with directly observed clinical and biological data. Our prior work in the Offspring cohort found 1) lower memory and executive function among middle aged people whose parents have MCI/AD, particularly among non-Latinx Whites compared with non-Latinx Blacks and Latinx, 2) among Whites, parental cognition had a stronger impact on offspring hippocampal volume, and among Blacks, parental cognition had a stronger impact on offspring WMH, 3) the negative impact of age on cognitive function and cortical thickness is disproportionately large among Black and Latinx participants compared with Whites, 4) early life social factors such as parental SES promote cognitive resilience to parental AD history, and 5) racial discrimination has a disproportionate negative impact on cognitive test performance among Black and Spanish-speaking Latinx offspring relative to White offspring. Over the next 5 years, we propose to recruit additional offspring for a total sample of 2,500, obtain baseline MRI scans on an additional 1,000 participants, obtain plasma biomarkers for AD risk and neurodegeneration on baseline blood samples, and obtain two repeat assessments of cognitive, psychosocial, and medical function. Our overarching hypothesis is that vascular and inflammatory pathways of transmission of parental AD risk play a greater role among Black and Latinx older adults compared with Whites, and that socioeconomic status, educational quality, and experience of discrimination will moderate the relationship between parental AD status and biomarkers of AD on Offspring cognition. Specifically, the project will 1) examine the impact of biological markers of vascular and inflammatory health, AD pathophysiology, neurodegeneration, biological aging, and genetic risk on cognitive decline and incident impairment across race/ethnicity and sex/gender and 2) determine the lifecourse educational, economic, and social moderators of parental AD risk and AD biomarkers on cognitive decline and incident impairment across race/ethnicity and sex/gender.

PROJECT NARRATIVE The prevalence of Alzheimer’s disease and related disorders (ADRD) and the associated societal and economic burden is expected to rise as baby boomers enter old age. This problem is particularly salient in African Americans and Latinx who are at higher risk for ADRD than similarly aged non-Latinx Whites. The proposed study will identify biological and social factors that increase and modify risk of ADRD and account for racial/ethnic disparities among middle-aged adults, when ADRD-related pathology begins to manifest in the brain and when intervention may delay or prevent onset.