Adam M. Brickman, Ph.D. - US grants

[unreadable] DESCRIPTION (provided by applicant): Several converging lines of research have demonstrated brain volume and neuropsychological functioning reduction associated with age, particularly in anterior white matter and executive functioning, respectively. However, increased variability in both neuropsychological functioning and brain morphometry is also associated with increased age, which suggests the presence of a moderating factor in the relationship between age-related morphometric change and neuropsychological functioning. Cognitive reserve is a relatively new theoretical construct that refers to an individual's ability to withstand varying degrees of brain pathology; it could be protective against the effects of age both in terms of morphometric change and neuropsychological functioning decline. The proposed study is the first to examine whether cognitive reserve moderates the interaction among age, neuromorphometry, and neuropsychological functioning. Using high-resolution structural MRI and comprehensive neuropsychological evaluation of younger and older individuals with high and low cognitive reserve, this study aims to (1) examine selective age-associated changes in neuromorphometry and neuropsychological functioning, and (2) determine whether cognitive reserve moderates age-associated neuromorphometric and neuropsychological decline. Results from the study will provide important insights into the normal aging process and will yield valuable information towards understanding the underpinnings of age-associated pathologies. [unreadable] [unreadable]

[unreadable] DESCRIPTION (provided by applicant): This is an application for a Mentored Patient-Oriented Research Development Award (K23). The goal of the proposed project is to provide the Applicant with advanced skills needed to establish an independent program of research in cognitive aging using neuroimaging and epidemiological methodologies. The Applicant proposes a comprehensive training plan, combining didactic instruction with established researchers; formal coursework; participation in ongoing seminars at Columbia University; and applied training experiences with individual advisors. Specific training goals include advanced knowledge and skill acquisition in the neurobiological mechanisms of cognitive aging; potential mediators and moderators of cognitive aging, including cerebrovascular risk factors and cross-cultural issues; design, implementation, and statistical analysis of epidemiological studies; principles of magnetic resonance imaging (MRI) and advanced neuromorphometric analysis; and the responsible conduct of research. The training plan will be executed in coordination with a proposed study that utilizes data from the Washington Heights Inwood Columbia Aging Project (WHICAP), an ongoing NIA funded study (P01AG007232) of risk factors for dementia in a multiethnic population of older adults residing in northern Manhattan. Although the main goal of WHICAP is to elucidate risk factors of Alzheimer's disease, it does not explicitly characterize neuromorphology or cognition in individuals who do not develop dementia. The proposed study will address the determinants of neuromorphology and related cognitive profiles among approximately 700 older individuals in the WHICAP cohort with "normal" age-related cognitive function. The project will examine the association between chronological age and several measures of neuromorphology, including regional volumes, white matter hyperintensity burden, and a new multivariate approach for the characterization of age-associated patterns of gray and white matter. These measures will be related to baseline performance on neuropsychological tests and change in cognition following an 18-month period. A secondary goal will be to examine the mediating effect of cerebrovascular risk factors (i.e., hypertension, insulin resistance, obesity, and hypercholesterolemia) and ethnic group differences on neuromorphology. The proposed project aims will therefore elucidate neurobiological changes [unreadable] [unreadable] associated with aging and will serve as a bridge for the Applicant to establish an independent investigator career in conducting large- scale neuromorphometry studies on clinical populations. [unreadable] [unreadable] [unreadable]

DESCRIPTION (provided by applicant): As the elderly population increases, dementia due to Alzheimer's disease (AD) poses an escalating public health threat. Research suggests that there are multiple pathways that lead to the development and expression of AD. Small vessel cerebrovascular disease, visualized on magnetic resonance imaging (MRI) as white matter hyperintensities (WMH), is common in normal aging and is associated with normal age-related cognitive decline. Emerging evidence, however, suggests that cerebrovascular disease may also play a role in the pathogenesis of AD. Work from our laboratory shows that WMH are increased among those at risk for AD; are more severe among patients with AD; and predict the rate of cognitive decline among those with AD. These initial observations strongly indicate that it is essential to demonstrate that longitudinal progression of WMH is related to cognitive decline and incident AD in order to establish causality. The overall aim of this study is to examine how the progression of small vessel vascular disease contributes to cognitive decline and incident AD. This study interfaces with ongoing follow up of the Washington Heights Inwood Columbia Aging Project (WHICAP; P01 AG07232), a community-based epidemiological study of aging and dementia. Beginning in 2003, MRI scans were acquired on a subset of 717 non-demented elderly participants. The current study seeks to re-evaluate these participants with follow up MRI 6 years after their baseline scans. Advanced MRI analysis techniques will be applied to quantify the degree o f WMH change in major neuroanatomical regions. Cerebral microbleeds, a marker of amyloid angiopathy, will also be quantified to explore their association with WMH. The aims include: 1. To examine the longitudinal change in regional WMH with cognitive decline and incident AD. 2. To examine whether severity and WMH change accounts for ethnic group differences in incident AD. 3. To examine the association of WMH distribution and lobar microbleeds, a putative marker of cerebral amyloid angiopathy, among patients with AD and controls. Exploratory aims will examine interrelations among WMH, white matter microstructure, hippocampal volume, and cognition. Findings from this study will clarify the role of small vessel vascular disease in the pathogenesis of cognitive aging and AD, will determine if small vessel vascular disease is a source of ethnic group disparities in AD, and will begin to elucidate the mechanism linking vascular disease to AD. PUBLIC HEALTH RELEVANCE: The prevalence of Alzheimer's disease and associated societal and economic burden is rising as the size of the elderly population continues to increase. This project will identify and characterize vascular factors that may contribute to the development and expression of the disease. It will also identify important factors that may account for ethnic-group disparities in Alzheimer's disease.

DESCRIPTION (provided by applicant): Ongoing research in our center in Northern Manhattan has consistently shown that the prevalence and incidence of cognitive impairment and dementia are greater among older Caribbean Hispanics, predominantly from Dominican Republic, than among Caucasians. Despite the consistency of this observation, the causes for this health disparity remain elusive. Individuals from low and middle income countries, such as Dominican Republic, may be at increased risk because of the interacting influences of socioeconomic factors, unique genetic risk factors, and high representation of cerebrovascular disease. The proposed work, in response to PAR-11-031, Brain disorders in the developing world: Research across the lifespan, seeks ultimately to understand the sources of this disparity by building a collaboration with investigators in Santiago, Dominican Republic to integrate high resolution magnetic resonance imaging (MRI) into ongoing genetic studies of cognitive aging. Magnetic resonance imaging can be used to quantify small and large cerebrovascular disease (e.g., infarct, white matter hyperintensities, microbleeds) and to examine markers of neurodegeneration (e.g., hippocampus atrophy). The Estudio Familiar de Influencia Genetica de Alzheimer (EFIGA; NIH R37 AG015473 PI: R. Mayeux) [Family Study of the Genetic Influence of Alzheimer's Disease] is a large scale longitudinal genetic study of Alzheimer's disease (AD) comprising individuals with and without AD from families with and without strong histories of the disease; there are over 4,500 active older adult participants, over 2,700 of whom reside in in Santiago. Our proposed pilot study will collect MRI scans in Santiago on 70 active participants from EFIGA and integrate MRI data with clinical and genetic data collected as part of the parent project. We will explore the relationships of markers of cerebrovascular disease and neurodegeneration with demographic factors, cognitive function/diagnosis, and genetics. We will establish feasibility and pilot data for a prospective, large-scale MRI project of cognitive aging and genetics, carried out in Santiago. As part of the efforts proposed here, we will work towards establishing the local capacity to acquire standardized MRI data and carry out MRI analysis for research involving older adults. Finally, we aim to introduce formal and informal training opportunities on interdisciplinary cognitive aging research via clinical preceptorship, formal didactics, ongoing active collaboration, and a symposium. The proposed project will result in a strong collaboration poised to uncover sources of disparities of cognitive aging among Caribbean Hispanics. PUBLIC HEALTH RELEVANCE: Suboptimal cognitive aging is becoming a true pandemic, particularly in Latin America, where the prevalence of dementia is the highest globally. The proposed project will integrate magnetic resonance imaging into ongoing studies of cognitive aging in Santiago, Dominican Republic, with the ultimate goal of understanding what factors contribute to health disparities in cognitive impairment among Caribbean Hispanics. Integration of neuroimaging into studies of cognitive aging may improve cognitive outcomes in an aging population through the identification of novel and specific treatment targets for intervention and prevention.

DESCRIPTION (provided by applicant): Ongoing research in our center in Northern Manhattan has consistently shown that the prevalence and incidence of cognitive impairment and dementia are greater among older Caribbean Hispanics, predominantly from Dominican Republic, than among Caucasians. Despite the consistency of this observation, the causes for this health disparity remain elusive. Individuals from low and middle income countries, such as Dominican Republic, may be at increased risk because of the interacting influences of socioeconomic factors, unique genetic risk factors, and high representation of cerebrovascular disease. The proposed work, in response to PAR-11-031, Brain disorders in the developing world: Research across the lifespan, seeks ultimately to understand the sources of this disparity by building a collaboration with investigators in Santiago, Dominican Republic to integrate high resolution magnetic resonance imaging (MRI) into ongoing genetic studies of cognitive aging. Magnetic resonance imaging can be used to quantify small and large cerebrovascular disease (e.g., infarct, white matter hyperintensities, microbleeds) and to examine markers of neurodegeneration (e.g., hippocampus atrophy). The Estudio Familiar de Influencia Genetica de Alzheimer (EFIGA; NIH R37 AG015473 PI: R. Mayeux) [Family Study of the Genetic Influence of Alzheimer's Disease] is a large scale longitudinal genetic study of Alzheimer's disease (AD) comprising individuals with and without AD from families with and without strong histories of the disease; there are over 4,500 active older adult participants, over 2,700 of whom reside in in Santiago. Our proposed pilot study will collect MRI scans in Santiago on 70 active participants from EFIGA and integrate MRI data with clinical and genetic data collected as part of the parent project. We will explore the relationships of markers of cerebrovascular disease and neurodegeneration with demographic factors, cognitive function/diagnosis, and genetics. We will establish feasibility and pilot data for a prospective, large-scale MRI project of cognitive aging and genetics, carried out in Santiago. As part of the efforts proposed here, we will work towards establishing the local capacity to acquire standardized MRI data and carry out MRI analysis for research involving older adults. Finally, we aim to introduce formal and informal training opportunities on interdisciplinary cognitive aging research via clinical preceptorship, formal didactics, ongoing active collaboration, and a symposium. The proposed project will result in a strong collaboration poised to uncover sources of disparities of cognitive aging among Caribbean Hispanics.

The goal of this revision application is to add a metabolomics study to the project called ?Interdisciplinary research to understand the interplay of diabetes, cerebrovascular disease, and Alzheimer?s disease? (DiCAD; RF1AG051556; PI: Brickman, Luchsinger [contact], Moreno; 10/01/15-08/31/20), in Years 4 and 5 of the parent project, after collection of most biospecimens is completed in Year 3. The proposed new metabolomics procedures are not included in the parent grant. This project will enhance metabolomics discovery in the DiCAD project and the M2OVE-AD and AMP-AD consortia by implementing the targeted metabolomic discovery approaches in humans from the Alzheimer?s disease metabolomics consortium (ADCM) in human and mice studies in DiCAD. In this application we propose to (a) study whether we can reproduce metabolomics signatures found by the ADCM in the Alzheimer?s Disease Neuroimaging Initiative (ADNI), which is a cohort sampled on the basis of cognitive diagnoses, in the DiCAD cohort, which is a community-based cohort of late middle-aged subjects without dementia, who are well phenotyped from a demographic, anthropometric, clinical history, cognitive, cerebrovascular disease and Amyloid, Tau, and Neurodegeneration (A/T/N) standpoint; (b) study whether we can reproduce the ADNI metabolomics signatures in mouse models of AD, diabetes, and appropriate controls, with and without stroke, with outcomes analogous to the human cohort, but with biospecimens from brain, gut and liver in addition to blood, which will allow to discern mechanisms and functional correlates through cross-species modeling. We will accomplish these goals through the following specific aims: 1. To discover the metabolomics signatures associated with Alzheimer?s disease (AD) with and without cerebrovascular disease (CVD) in humans and mice. For both humans and mice, we will use 2 targeted metabolomics platforms that have been informative in defining signatures related to cognition, cognitive decline and brain imaging changes in ADNI, Biocrates P180 and Biocrates Bile Acids. Biocrates P180 kits measure 180 metabolites covering lipids, acylcarnitines, and amines. Biocrates Bile Acids Kits measure 20 primary and secondary bile acids end products of cholesterol metabolism and clearance that involve gut microbiome human co-metabolism. 2. To explore in new experiments in sphingomyelin synthase (SMS) knockout mice, not included in the parent project, the functional impact of lowering SM levels, similar to those found in human AD. We will study mice with abnormalities of different grades in de novo synthesis of SM. We will relate the metabolomics profile of 2 brain structures (frontal cortex and cerebellum) and plasma.

PROJECT 1 SUMMARY There is growing emphasis on elucidating neurobiological and cognitive changes associated with Alzheimer s disease (AD) at the earliest point possible. In the absence of AD, however, cognition is also impacted by aging and subtle distinctions between normal and pathological processes are difficult to detect. The proposed project focuses on the complexity of the hippocampal circuit, regionally distributed white matter abnormalities, and refined neuropsychological instrumentation to understand differences between pathological aging and normal aging, defined as having cerebrospinal fluid evidence of AD or not. Recent studies suggest that two regions of the hippocampal circuit that seem to be most relevant in AD and aging are the entorhinal cortex, particularly its lateral extent, and the dentate gyrus. Postmortem, neuroimaging, and behavioral studies show that the dentate gyrus is differentially affected by aging and that pattern separation is the cognitive operation closely linked to normal aging and dentate gyrus function. In contrast, entorhinal cortex appears to be the region affected first in AD and retention of information over a brief interval is a cognitive metric strongly associated with entorhinal cortex function and commonly impacted early in AD. A parallel line of research implicates regionally-distributed white matter abnormalities, visualized as white matter hyperintensities on magnetic resonance imaging, in AD and severity of cognitive symptoms in aging. Whereas frontal lobe white matter hyperintensity volume is elevated among older adults with any cognitive impairment, parietal lobe white matter hyperintensities specifically appear to be implicated in AD. Human studies examining hippocampal subregion and regional white matter hyperintensities in AD and aging have been limited because they generally have not incorporated AD biological marker information. The goal of the proposed study is to use recently developed in vivo tools to determine whether the specific loci within the hippocampal circuitry and the regional distribution of white matter hyperintensities are linked to AD and aging. Participants (n=150) will receive a lumbar puncture and be classified as having cerebrospinal fluid evidence suggestive of AD. High resolution functional and structural magnetic resonance imaging will be used to quantify regional hippocampal function and regional white matter hyperintensities volume. Participants will be evaluated with a neuropsychological battery comprising tests that, studies suggest, appear sensitive to AD/entorhinal cortex and normal aging/dentate gyrus function. We will compare individuals with and without cerebrospinal evidence of AD, examine the relationship of AD biological markers with hippocampal function and white matter hyperintensities, test the degree to which hippocampal dysfunction and white matter abnormalities interact, and conduct preliminary longitudinal analysis to test the degree to which regional hippocampal dysfunction and regional WMH predict decline in performance on tests designed to evaluate changes due to aging and AD.

As the older segment of our population increases, Alzheimer?s disease (AD) has emerged as one of the most devastating international public health epidemics. There are currently no effective disease-modifying treatment or preventative strategies available. Current pathogenic models and newly implemented diagnostic criteria for AD emphasize a single pathway of disease pathogenesis, but underestimate the important contribution of vascular risk factors and of small vessel cerebrovascular disease, which manifests primarily as white matter hyperintensities (WMH) on T2-weighted magnetic resonance imaging (MRI). During the previous four years of this project (R01 AG034189), we confirmed our hypotheses that accumulation of WMH predicts incident AD, particularly when distributed in parietal regions, and is associated with the presence of cerebral microbleeds, an indicator of cerebral amyloid angiopathy (CAA) in a large multi-ethnic cohort of older adults. Accordingly, we extended our research to examine mechanistic interactions between cerebrovascular disease and AD. Our new preliminary data suggest that individuals with evidence of fibrillar amyloidosis have increased parietal lobe WMH and that hemodynamic markers of autoregulatory dysfunction are associated with both WMH and amyloid deposition, which in turn interact to promote the clinical expression of AD. This proposed competitive renewal will continue our systematic evaluation of the intersection between regional WMH and AD, and ask innovative and novel questions about the role of cerebral autoregulation and bloodbased lipid biomarkers. The aims of the project are: 1. To examine whether regional WMH and amyloid pathology confer independent or interactive risk for cognitive decline, clinical AD, mild cognitive impairment (MCI), and neurodegeneration, indexed by regional atrophy, across racial and ethnic groups; 2. To examine the relationship of autoregulation with WMH severity, amyloid pathology, and cognition and diagnosis; and 3. To explore established and newly-modeled blood-based lipidomic profiles and their association with WMH and amyloid pathology. Importantly, we will examine the extent to which small vessel cerebrovascular disease accounts for racial and ethnic disparities in cognitive decline, and diagnosis of MCI or AD. Beginning in 2012, 500 individuals from a newly-established ethnically and racially diverse older adult cohort received clinical evaluation, high-resolution structural MRI, and a subset (n=100) received positron emission tomography (PET) to quantify fibrillar forms of beta amyloid. The current study seeks to conduct longitudinal analysis on these individuals by repeating these procedures, in addition to collecting transcranial Doppler-derived measures of cerebral autoregulation and analyzing stored blood samples for lipid profiles. The study will provide novel mechanistic insight into the pathogenesis of AD and identify new targets for intervention.

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 overall aim of this longitudinal study is to identify new, modifiable mechanisms of racial/ethnic disparities in Alzheimer's disease (AD) among a multi-ethnic cohort of approximately 2,000 older adults. The incidence of AD is higher for African Americans and Hispanics, compared to non-Hispanic Whites, even after controlling for the ?usual suspects? in disparities research: traditional socioeconomic indicators and vascular health. Persistent and unexplained disparities suggest two possibilities that have not been well-examined: (1) known AD risk factors exhibit differential impact across race/ethnicity and/or (2) yet unmeasured factors increase AD risk for minorities. Our research team has identified multiple factors that have stronger cognitive impact among older African Americans or Hispanics, including depressive symptoms and MRI markers of brain pathology. These variables, along with poor vascular health and lower education/income, may be less impactful among Whites because membership in a majority group is associated with social-environmental resources that promote resilience. In the current proposal, resilience is conceptualized as better-than-expected outcomes given level of AD risk factors or brain pathology. This study will examine how resources that differ across race/ethnicity in our cohort (e.g., perceived social status, quality of education, and the perception that life outcomes are controllable) promote resilience at multiple points in the AD pathogenic pathway using repeat MRI and cognitive assessments across three time points. Because racial/ethnic minorities face unique stressors (e.g., acculturative stress, racial discrimination), we will also test whether these experiences influence the progression of MRI markers of brain pathology, cognitive decline, and incident AD. Our overarching hypothesis is that AD disparities persist because racial/ethnic minorities have depleted resources to adapt to known AD risk factors and brain pathology and/or unique, yet unmeasured AD risk factors. Specific aims are to (1) identify risk factors relevant to minority populations and examine whether they predict advancing brain pathology, cognitive decline, and incident AD among African Americans or Hispanics, (2) determine which resources explain racial/ethnic differences in the impact of known AD risk factors on advancing brain pathology (i.e., brain resilience), and (3) determine which resources explain racial/ethnic differences in the impact of advancing brain pathology on cognitive decline and incident AD (i.e., cognitive resilience).

PROJECT SUMMARY As the population of older adults increases dramatically, age-related illnesses such as Alzheimer?s disease (AD) and other degenerative disorders present a great public health burden, currently affecting an estimated to 5.4 million Americans. It is well documented that older adults from ethnic minority and lower socioeconomic backgrounds are at increased risk for AD and other disorders of aging. There is thus an urgent need to increase the number of scientists from diverse backgrounds who are committed to the study of aging and age- related health disparities. The proposed Summer of Translational Aging Research for Undergraduates (STAR U) program is guided by three axioms related to biomedical research on aging: 1. The diversity of the older adult population is increasing and there are systematic racial/ethnic disparities related to disorders of aging that are poorly understood; 2. Scientific advancement relies upon diversity of background, experience, ideas, and perspectives; increasing the diversity of scientists involved with biomedical research of aging is necessary to provide the cultural sensitivity and knowledge to understand sources of disparities in aging; and 3. Despite increases in the number of underrepresented minorities receiving higher education, a large percentage do not pursue careers in science. STAR U seeks to overcome historic barriers that have prevented such students from pursuing careers in scientific and aging research. Through a structured summer research program, STAR U will provide 10-12 students per year with: 1) individual, tailored research mentorships in the neuroscience of aging; 2) a range of translational learning opportunities; and 3) professional networking and social experiences. Research opportunities will span areas such as patient-oriented clinical research, cognitive neuroscience, basic science, and the epidemiological study of cognitive aging and its disorders. STAR U students will gather formally once per week for a two-hour seminar session that will include one hour devoted to a scientific topic, and one hour devoted to professional/academic development. Scientific training will focus on major themes in aging research, research methodologies, and general content areas relevant to developing scientific careers. Personal and professional development will be fostered through social gatherings as well as seminars on career development, learning how to find and work effectively with mentors, balance personal and professional demands, choosing the type of graduate training that is most appropriate for them, communicating effectively in science, and applying to graduate/medical school effectively. The long-term goal of the Summer of Translational Aging Research for Undergraduates is to enhance the field of aging and age-related disparities research by infusing it with diverse, well-trained scientists.!

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.

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.

Project Summary/Abstract The proposed ancillary study looks to better understand racial/ethnic disparities in Alzheimer's disease (AD) by investigating spontaneous speech as part of the Washington Heights/Inwood Columbia Aging Project (WHICAP) Offspring Study. Limitations of existing cognitive screening instruments is a known contributor to racial/ethnic disparities in AD and recent work suggests that speech analysis may be a sensitive marker of cognitive decline and future AD. New technological advances raise the possibility that automated speech analysis could be conducted using smartphones in community settings, creating an inexpensive and scalable approach to early detection. However, many challenges remain in developing this method, including a very limited understanding of the biological underpinnings of spontaneous speech in at-risk individuals (e.g., hippocampal volume, amyloid deposition, contribution of executive function vs. language). We propose to examine spontaneous speech as part of the ongoing WHICAP Offspring Study (RF1AG054070, RF1AG058067). This large project is enrolling a diverse cohort (>70% minorities) of pre-clinical participants with varying degrees of risk for AD using medical, genetic, and neuropsychological testing (N = 3000), structural MRI (N = 1000), and amyloid and tau PET imaging (N = 150 for each). Both English and Spanish speakers are included. One measure of spontaneous speech has been included since study onset and a second brief measure would be added. We hypothesize that spontaneous speech will reflect a combination of both biological and sociocultural risk factors to AD and that bilingualism will show protective effects. By leveraging the rich data collection of the WHICAP Offspring Study, this application would generate substantial new insight into the basic underpinnings of spontaneous speech in diverse pre-clinical samples, as well as determine the feasibility of using speech analysis as a novel biomarker of AD risk. Additionally, should the cohort be followed longitudinally, the ability of spontaneous speech to predict future incidence of AD in racially/ethnically diverse samples over time could also be evaluated.

BIOMARKER CORE PROJECT SUMMARY/ABSTRACT The ability to study Alzheimer?s disease (AD) and related disorders has been revolutionized by the development and application of in vivo biomarkers. Analysis of cerebrospinal fluid (CSF), positron emission tomography (PET), and magnetic resonance imaging (MRI) allow operational measurement of amyloid, tau, and neurodegeneration (A/T/N), the major pathophysiological changes that define AD. Moreover, improved sensitivity and specificity of instrumentation applied to biofluid data, of neuroimaging protocols, and of analytic approaches both enable and necessitate the development, refinement, and discovery of novel biomarkers in any comprehensive AD research program. The Columbia University ADRC Biomarker Core embraces these theme and will derive standard biofluid and MRI biomarkers for all ADRC participants; serve as a central hub for human biofluid, PET, and MRI-based biomarker research conducted within the cognitive aging and dementia community at Columbia University; develop and implement novel biomarkers; and provide training opportunities for investigators interested in incorporating AD-related biomarkers into their research. The Biomarker Core leverages unique data sources, infrastructural, and intellectual strengths already in place and comprises a team of close-collaborating investigators instrumental to the majority of ongoing AD biomarker studies at Columbia University. The Biomarker Core will analyze research grade MRI scans acquired from harmonized clinical scans, from ongoing studies, or de novo for neurodegenerative and cerebrovascular markers. The Core features a newly-acquired single molecule array (Simoa) Benchtop Multiplexed Biomarker Detection Analyzer and Mesoscale Discovery (MSD) platform for analysis of CSF and blood and development of novel biomarkers. These resources will be used to derive existing blood- and CSF-based biomarkers and to develop novel ones. The deep biomarker characterization of all ADRC participants and close interaction with the other Cores will increase understanding of disease etiology and heterogeneity. The Biomarker Core has the following aims: 1) To harmonize, bank, and disseminate fluid and neuroimaging biomarker data derived from participants enrolled by the Clinical Core; 2) To quantitate biofluid biomarkers and MRI markers of neurodegeneration and cerebrovascular disease, according to the A/T/N classification scheme; 3) To develop, optimize, and implement biomarkers of the three thematic biological pathways: immune response, cholesterol metabolism, and endosomal trafficking; 4) To provide intellectual, analytic, and infrastructural support to local investigators interested in incorporating blood-based, CSF, MRI, and PET imaging biomarkers into their Alzheimer?s-related research programs; and 5) To provide training and training opportunities for the next generation of diverse scientists interested in incorporating biomarkers into the study of cognitive aging and dementia.

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.

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.