Jennifer Manly - US grants

DESCRIPTION (provided by applicant): Neuropsychological tests have poor specificity among minority populations and thus misdiagnosis of dementia is more likely among cognitively normal African Americans as compared to non-Hispanic Whites. During the prior funding period, this study directly addressed the problem of misdiagnosis of cognitive impairment and dementia among African American elders by measuring cultural and educational factors that differ within and between racial groups, and then using these data to understand of the role of race and culture on cognitive test performance. Our work identified aspects of cultural and educational experience that could be explicitly measured and related these variables to test performance both cross-sectionally and longitudinally. We found that after accounting for literacy level (an estimate of quality of education), differences in the test performance of education matched African American and White elders largely disappeared. Regardless of race, literacy level was the strongest predictor of performance on measures of verbal and nonverbal ability and the best predictor of future memory decline. Despite this wide-ranging effect of literacy on cognition, several researchers have suggested that the primary influence of literacy is on the functioning of a specific buffer or short-term storage system, the phonological loop. However, this theory has been put forth without adequately assessing visuospatial short-term memory or well-characterized tasks of working memory. To date, this project has generated major insights into the role of cultural and educational experience on cognitive test performance and the risk of cognitive decline over time. The current proposal will use these insights to guide new studies of the relationship between culture, literacy, and cognition. The three aims of the study are to: 1) use resource characteristics and a broad measure of literacy skill to determine if a measure of reading recognition is a true reflection of quality of education; 2) determine whether school resource variables are the best predictors of cognitive decline and development of dementia regardless of race; and 3) test the hypotheses that literacy affects storage of visuospatial material and the functioning of the central executive or working memory, by administering specific and well characterized tasks of storage and manipulation of verbal and visuospatial information.

The proposed Clinical Assessment Core represents an evolution of methods from our past nine years of studies and will continue to carry out essential aspects of participant follow-up, assessment, and diagnosis for the projects. In our follow-up of the WHICAP II cohort, we will maintain uniformity and coherence in our approach to case identification. Guided by a tracking form generated by the Epidemiology, Database Management and Statistics Core, participants are contacted, interviewed and examined in a standardized fashion every 12-18 months. All subjects are administered measures assessing personal self-maintenance activities, perceived difficulty with memory, and mobility. Comprehensive neuropsychological testing includes measures of memory, language, executive functioning, visuospatial skill, and orientation. Neuropsychological data are available to the projects through raw and demographically corrected individual tests scores, and Neuropsychological Factor Scores representing memory, executive function, and language abilities. All participants receive a medical/psychiatric evaluation and an assessment of functional capacity that is independent of neuropsychological test performance. Participants with history of stroke or Parkinson's disease or those with functional or neuropsychoiogical signs of dementia will receive an evaluation by a board-certified neurologist. Information for all participants is reviewed at a diagnostic consensus conference of neuropsychologists, research physicians, and neurologists, and diagnoses are derived based on standardized diagnostic criteria. Emphasis has been placed on the consistency of these criteria over the entire study period. The clinical core will coordinate with the Brain Imaging Core to schedule eligible participants for MRI scans. The Clinical Assessment Core also coordinates with the Pathology Molecular Core to approach all participants about brain donation, obtain provisional consent, and obtain autopsies at the time of death.

DESCRIPTION (provided by applicant): A number of studies have found that African Americans have significantly higher prevalence and incidence of non-familial Alzheimer's Disease (AD) than Caucasians. However, because the cognitive tests used in part to diagnose AD have low specificity among African Americans, it is unclear whether misdiagnosis contributed to these findings. If rates of AD are in fact elevated, these studies suggest that different genetic or environmental factors may influence AD risk among African Americans. While the APOE D4 allele, the major genetic risk factor for AD, is more frequent among African Americans, the relative risk is somewhat lower than in other populations. It is possible that the association of APOE with AD is modified by the presence and severity of cardiovascular and cerebrovascular disease. The current proposal will address these issues by conducting a genetic association study of AD among African Americans with a carefully refined phenotype, including cognitive test performance, cardiovascular health, and brain imaging data. We propose a collaborative study to be conducted at four sites which specialize in assessment of AD and serve large populations of African Americans: Columbia University in New York City, Duke University and North Carolina A&T State University in North Carolina, and Vanderbilt University in Tennessee. We will 1) refine the phenotype of AD among African Americans by incorporating our past work on the role of cultural and educational experience on cognitive test performance in order to provide accurate diagnoses of AD, collect biomarkers related to subclinical cardiovascular disease, and obtain MRI brain images to quantify volume of white matter hyperintensities, infarct burden, and total brain;2) we will test the association of select candidate genes in matched African American AD cases and controls, and examine the effect of cardiovascular and cerebrovascular disease as potential modifiers of risk;and 3) we will examine genotype- phenotype relations among candidate genes and several quantitative traits, including performance on measures of learning and memory, age at onset of AD, and cardiovascular and cerebrovascular disease burden.

DESCRIPTION (provided by applicant): The objective of this scientific meeting application is to create an interdisciplinary research team that will lay the theoretical and methodological groundwork for novel investigation of the neuroscience of cognitive aging among African Americans. The central goal of this team's work will be to provide the foundation needed to close critical gaps in knowledge and to enhance the quality, innovation, and productivity of cognitive aging research among African Americans. This interdisciplinary team of neuropsychologists, cognitive psychologists, neuroscientists, epidemiologists, gerontologists, statisticians, sociologists, and geneticists, will produce a blueprint for research on cognitive aging among African Americans that will facilitate new discoveries about the impact of socio-cultural experiences throughout the life span on brain health. By incorporating measures of these diverse experiences of African Americans, from childhood to older age, into research on the neuroscience of aging, complex interactions between cognition, cardiovascular health, genetics, brain structure, and brain function can be elucidated. An integrated understanding of these interactions is critical for developing interventions to maintain cognitive health among this understudied population. This objective will be achieved by holding a series of in-person meetings and video conferences that bring together researchers with expertise in diverse research sub-disciplines to promote scientific exchange and develop a comprehensive agenda on African American cognitive aging. At these meetings, the interdisciplinary group will: 1) determine the most innovative models, methodology and analytic approaches to address critical gaps in research knowledge on cognitive aging among African Americans, and will develop a blueprint for research with specific recommendations for future work; 2) determine how existing data or new follow-up data from large, ethnically diverse cohorts of children, young and middle-aged adults, and older persons can be used to address critical research questions in cognitive aging among African Americans; and 3) disseminate recommendations about how to increase numbers of African Americans enrolled in current or planned studies of cognitive aging, by leveraging resources already created by RCMARs and other NIH-funded studies that have been successful with minority recruitment, and integration of community-based participatory research (CBPR). PUBLIC HEALTH RELEVANCE: Prior studies show that African Americans have higher prevalence and incidence of cognitive impairment and dementia as compared with non-Hispanic Whites. However, our understanding of the reasons for this disparity, risk factors for cognitive impairment, and early markers of future decline among African Americans has lagged behind our understanding of these factors among Whites. The proposed scientific meeting will address this gap in knowledge using an interdisciplinary approach, and is timely given the rapid population growth of older African Americans.

The overall aim of this study is to identify underlying biological and sociocultural mechanisms of racial/ethnic disparities in cognitive function among a middle-aged cohort of 3,000 offspring whose parents do and do not have Alzheimer's Disease (AD). Studies of non-Hispanic Whites have shown that children of people with AD are at increased risk of developing the disease, and that factors such as parental age at onset and APOE allele status may modify risk associated with a family history of AD. Rates of AD are two to three times higher among Hispanic and African American than among non-Hispanic White elders and the prevalence of many cardiovascular and demographic risk factors for AD is higher among ethnic minorities than among non- Hispanic Whites. However, potential mediators and modifiers of family risk have not been well examined among racial and ethnic minorities, nor has much prior work been conducted among families where data from detailed clinical and biomarker examinations on parents were available from in-person examinations. Since pathology begins to manifest in the brain in the fifth and sixth decades of life, we propose that mechanisms for racial/ethnic disparities can be more clearly revealed in middle age and thus help to clarify the determinants and pathways of ethnic disparities in cognitive impairment with aging and potential critical periods for intervention. Our overarching hypothesis is that the primary mode of transmission of parental AD risk among racial/ethnic minorities is via vascular and social pathways, while the primary transmission of parental AD risk among Whites is via genetic pathways that affect amyloid deposition in the brain. Specifically, the project will 1) determine which biological mediators of parental risk of AD on offspring cognition differ most across race/ethnicity, 2) determine which educational, economic, and social moderators of parental risk of AD on offspring cognition differ most across race/ethnicity, and 3) use directly measured parental risk factor data to refine our understanding of mechanisms of racial/ethnic disparities in AD.

The American Institutes for Research (AIR) will provide staff for the School Quality and Racial Disparities in Alzheimer?s Disease in Project Talent study and will assist Dr. Jennifer Manly (PI, Columbia University) in activities to create shared data resources and to support all aspects of this research project. Socioeconomic adversity in early life is a risk factor for poor brain health?impaired cognitive function and cerebrovascular disease?in later life, but some individuals are resilient, achieving better-than-expected outcomes despite facing early life adversity. The mechanisms of resilience, as well as the causal pathways between early life adversity and later life brain health, are unclear, but educational experiences are very likely critical. This project will focus on mortality, cognitive function, and cardiovascular health conditions that increase risk for cerebrovascular disease, all outcomes that have been linked to early life socioeconomic adversity, and will evaluate the role of educational experiences in potentially promoting resilience to early life adversity. A central research question in our evaluation of school quality and long term impacts on brain health is whether there are racial/ethnic differences in the benefits of attending higher quality schools or the mechanisms though which education influences later health. The study will include ~9000 participants, currently aged 69-74, to assess cognitive abilities, health, and other aspects of resilience. Other innovations of this study include: a contemporary battery of cognitive abilities measures harmonized with several of the original 1960 measures, allowing direct measurement of change across 1960 to 2017 on multiple cognitive abilities; use of adaptive testing to reduce participant burden; and assessment via mailed tablet computers to facilitate measurement of memory and visuospatial abilities. This study has many advantages, including its sample size, prospective design, high quality measurement of multiple cognitive abilities in adolescence and older adulthood, assessment of educational quality and experiences, cognitive complexity of occupational and leisure activities, all in the context of its unique design that provides an unprecedented opportunity to address causal hypotheses.

ADMINISTRATIVE CORE SUMMARY The focus of the Columbia University Center for Interdisciplinary Research on Alzheimer?s Disease Disparities (CIRAD) is biological, behavioral, sociocultural, and environmental mechanisms of ADRD disparities, including risk and resilience factors, biomarkers, and caregiving. The CIRAD will assemble a multidisciplinary team of investigators at the four schools of the Columbia University Medical Center including the Physicians and Surgeons, Nursing, Public Health and Dental Medicine, the Taub Institute for Research on Alzheimer?s Disease and Aging, the Columbia University Alzheimer?s Disease Research Center (CU-ADRC), the Gertrude H. Sergievsky Center, and the New York State Psychiatric Institute. Additionally, the CIRAD will have partnerships with the Mount Sinai School of Medicine ADRC, Weill Cornell Medical Center (WCMC), The Einstein Aging Study at Albert Einstein College of Medicine, Hebrew Home for the Aged at Riverdale (HHAR), the State University of New York ? Downstate Medical Center and the City University of New York. The CIRAD Administrative Core will: (a) provide scientific leadership, oversight and evaluation to all center components, including supporting an executive committee, a pilot study review panel, an external advisory board; and engagement with community partners (b) ensure that all center activities comply with federal regulations and policies; (c) coordinate and support the integration of CIRAD Cores and leveraged NIA and other resources in order to meet the training, research, and community engagement goals of the center; and (d) evaluate the activities of the center. The Administrative Core will coordinate and integrate all Center functions; provide rigorous and regular fiscal oversight of the research projects and cores; guide and facilitate interactions between the RCMAR Scientists projects and the Cores, the Research and Education Core Faculty, the and the community. The Administrative Core will facilitate the engagement with the NIA and the RCMAR program.

Project summary The Department of Neurology at Columbia University Medical Center serves as a rich site for multidisciplinary neurological research, with particular focus on the aging nervous system and Alzheimer?s disease and Related Dementias (AD and ADRD). This proposal seeks to continue funding for positions for 20 preclinical students participating in the Brief Research in Aging and Interdisciplinary Neurosciences (BRAIN) program each summer. For the BRAIN program, we have developed a comprehensive approach to develop a formal research program for predoctoral students early in developing careers in biomedical, behavioral and clinical research. The work is collaboratively approached through brief but intensive mentored summer research training experiences for these students. The research training provides opportunities in basic, behavioral and clinical research through ongoing research in the fields of basic neuroscience, neuropathology, neurogenetics, neuropsychology, epidemiology, and clinical trials, with a focus on Alzheimer?s disease and Related Dementias, aging-related motor neuron disease, stroke, and epilepsy, as well as neurologic clinical trials treating patients with these disorders. Methods for inclusion of biological and cognitive markers of neurological disease progression, such as cerebral amyloid and tau, structural brain imaging, as well as assessment of memory, executive function, and other cognitive domains are embedded within the training curriculum. In addition, a comprehensive structured research education curriculum is delivered over the course of the intense research experience, with topics including good clinical practice, basic research methodologies, introductions to abstract authorship and poster presentations, and introduction of statistical concepts and approach to analyses, as well as epidemiologic and pathophysiologic reviews of the most common neurologic disorders such as Alzheimer?s disease. Our institution has the strongest track record of developing academic neurologists of anywhere worldwide, and this short-term, intense program builds upon this wealth of resources through hands-on introductions to neurological research, comprehensive review of principles of research, and thus assures the best opportunity for these students to develop research careers in the field of disorders of the aging nervous system including Alzheimer?s disease.

OVERALL SUMMARY The focus of the Columbia University Center for Interdisciplinary Research on Alzheimer?s Disease Disparities (CIRAD) is biological, behavioral, sociocultural, and environmental mechanisms of ADRD disparities, including risk and resilience factors, biomarkers, and caregiving. The CIRAD will assemble a multidisciplinary team of investigators at the four schools of the Columbia University Medical Center including the Physicians and Surgeons, Nursing, Public Health and Dental Medicine, the Taub Institute for Research on Alzheimer?s Disease and Aging, the Columbia University Alzheimer?s Disease Research Center (CU-ADRC), the Gertrude H. Sergievsky Center, and the New York State Psychiatric Institute. Additionally, the CIRAD will have partnerships with the Mount Sinai School of Medicine ADRC, Weill Cornell Medical Center (WCMC), The Einstein Aging Study at Albert Einstein College of Medicine, Hebrew Home for the Aged at Riverdale (HHAR), the State University of New York ? Downstate Medical Center and the City University of New York. The team includes experts in research in social determinants of health (SDOH), caregiving and dementia, mental health, physical health, stress, prevention, behavioral research, observational studies, clinical trials, bioinformatics and community- based participatory research. CIRAD will partner with community based organizations and members of the New York City community. The CIRAD team has access to tremendous resources for training in ADRD disparities research and career development activities that will be provided to the RCMAR Scientists before, during, and after their pilot studies are funded. The goal of CIRAD is to provide mentoring and career development, support for pilot studies, training in health disparities, and interdisciplinary collaboration to investigators from under-represented backgrounds who are pursuing ADRD research, and to support and accelerate research on the biological, behavioral, sociocultural, and environmental mechanisms of ADRD disparities so that they can be narrowed or eliminated.

The American Institutes for Research (AIR) will provide staff for the School Quality and Racial Disparities in Alzheimer?s Disease in Project Talent study and will assist Dr. Jennifer Manly (PI, Columbia University) in activities to create shared data resources and to support all aspects of this research project. Socioeconomic adversity in early life is a risk factor for poor brain health?impaired cognitive function and cerebrovascular disease?in later life, but some individuals are resilient, achieving better-than-expected outcomes despite facing early life adversity. The mechanisms of resilience, as well as the causal pathways between early life adversity and later life brain health, are unclear, but educational experiences are very likely critical. This project will focus on mortality, cognitive function, and cardiovascular health conditions that increase risk for cerebrovascular disease, all outcomes that have been linked to early life socioeconomic adversity, and will evaluate the role of educational experiences in potentially promoting resilience to early life adversity. A central research question in our evaluation of school quality and long term impacts on brain health is whether there are racial/ethnic differences in the benefits of attending higher quality schools or the mechanisms though which education influences later health. The study will include ~9000 participants, currently aged 69-74, to assess cognitive abilities, health, and other aspects of resilience. Other innovations of this study include: a contemporary battery of cognitive abilities measures harmonized with several of the original 1960 measures, allowing direct measurement of change across 1960 to 2017 on multiple cognitive abilities; use of adaptive testing to reduce participant burden; and assessment via mailed tablet computers to facilitate measurement of memory and visuospatial abilities. This study has many advantages, including its sample size, prospective design, high quality measurement of multiple cognitive abilities in adolescence and older adulthood, assessment of educational quality and experiences, cognitive complexity of occupational and leisure activities, all in the context of its unique design that provides an unprecedented opportunity to address causal hypotheses.

PROJECT SUMMARY Alzheimer?s disease (AD) is one of the most devastating international public health epidemics. There are currently no effective disease-modifying or preventative strategies. Current pathogenic models of AD emphasize a precipitating role of beta amyloid (A?) pathology, which stimulates tau deposition, neurodegeneration, and cognitive dysfunction. But recent work suggests that tau deposition frequently occurs prior to A?, could begin in midlife, and could be potentiated by other factors, including cerebrovascular disease. Tau pathology may play a role in AD racial/ethnic disparities, as the incidence and prevalence of AD is greater among African Americans and Hispanics, who have greater exposure to vascular risk factors and cerebrovascular disease. Thus, there are likely multiple pathways beginning in midlife that promote tau deposition and cognitive decline associated with AD, which may vary across racial/ethnic groups. The purpose of this study is to examine the extent to which tau deposition is related to cognitive function, to determine whether tau deposition varies across racial/ethnic groups, and to determine the extent to which cerebrovascular disease is associated with tau pathology in midlife. We will obtain tau positron emission tomography (PET) imaging among 150 middle-aged adults who are receiving high-resolution magnetic resonance imaging, A? PET, and comprehensive clinical evaluation as part of their participation in a study titled ?Offspring study of mechanisms for racial disparities in Alzheimer?s disease? (RF1 AG054070, MPI: J.J. Manly/A.M. Brickman). The aims of the proposed project are: 1. To determine whether tau pathology is associated with cognitive functioning in midlife. We hypothesize that increased tau deposition in the medial temporal lobes will be associated with poorer episodic memory functioning and odor identification deficits. 2. To determine whether tau pathology differs across racial and ethnic groups in midlife. We hypothesize that Hispanics and African Americans will have greater amounts of tau pathology relative to non-Hispanic Whites. 3. To determine whether markers of cerebrovascular disease are associated with tau pathology in midlife and whether race/ethnicity moderates this association. We hypothesize that magnetic resonance imaging-derived markers of cerebrovascular disease, including white matter hyperintensities, infarcts, and microbleeds, will be associated with increased tau. We also expect that the relationship between markers of cerebrovascular disease and tau pathology will vary across racial/ethnic groups. Successful completion of this study will potentially point to novel intervention targets for the prevention of AD in addition to identifying sources of racial/ethnic disparities in the disease.

PROJECT SUMMARY/ABSTRACT    Mild cognitive impairment (MCI), dementia and stroke are substantially higher among blacks aged 45+, and among residents of the southeastern region of the US. The REasons for Geographic And Racial Differences in Stroke (REGARDS) Study is national, longitudinal cohort study of ~ 30,000 blacks and whites designed to advance the understanding of the epidemiology of cognitive decline and stroke, and the contributors to racial and geographic disparities in these outcomes. The current application has three aims: 1. Identify social, cardiovascular, and environmental mechanisms of racial and geographic disparities in incident vascular contributions to cognitive impairment and dementia (VCID). With assessment in mid-life and over a decade of longitudinal cognitive data, REGARDS is uniquely positioned to identify vascular, social, and behavioral mechanisms underlying disparities in VCID, and modifiable pathways on which interventions may narrow disparities in VCID. After completion of a nested calibration/confirmation study to develop an algorithm for the classification of MCI and dementia, we will characterize racial and geographic disparities in VCID and determine if interventions on mediators would diminish or eliminate disparities. 2. Answer as-yet-unanswered questions in stroke and cerebrovascular disease epidemiology. By continuing the successful approaches for stroke surveillance among 17000 active cohort members, the study will assess the association of risk factor changes and novel biomarkers quantified with the completion of the second in-person exam with stroke risk and disparities in stroke risk. In addition, with the aging of the cohort, this aim will provide greatly needed information on stroke epidemiology in the elderly. 3. Utilize incident risk factor data and biospecimens to identify pathways for development of incident hypertension and diabetes, with the goal of understanding the impact on incident VCID and stroke. We have documented that ?30% of the racial disparity in stroke risk is attributable to racial disparities in prevalence of hypertension and diabetes, and the study will investigate the biomarker pathways contributing to the higher incidence of hypertension and diabetes in blacks. Each proposed aim addresses a topic of profound public health impact, and REGARDS progress to date uniquely positions the study to address these aims using proven approaches in an efficient manner.

ABSTRACT. The analysis of cerebrospinal fluid (CSF) and molecular PET biomarkers of A? 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 (A?40, A?42, 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 A?40 and A?42), 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 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.