Sudha Seshadri - US grants

No abstract provided

Cerebral Small Vessel Disease (SVD) is an important, potentially modifiable factor for clinical dementia. Recent data suggest that the age-specific incidence of dementia may be decreasing, partly as a result of better management of vascular risk factors, lending urgency to dementia prevention trials but a major impediment is the absence of circulating biomarkers for tracking onset and progression of SVD. Brain MRI imaging markers are the current gold standard for SVD but are too expensive and burdensome for repeated assessments. Recent genetic studies, including from the Cohorts for Heart & Aging Research in Genomic Epidemiology (CHARGE) consortium, implicate microglial inflammation and astroglia in the biology of SVD and dementia. We propose to measure 2 circulating biomarkers of microglial inflammation (sCD-14 and YKL-40) and a marker of astroglial injury (GFAP) in ~17,000 persons (including 4000 minority participants, 6000 with >2 MRI) across 5 CHARGE population-based cohorts. Specifcally, we will (1) examine the association of the novel biomarkers with (a) previously collected MRI-defined SVD (white matter hyperintensities, lacunar infarcts and cerebral microbleeds), and in persons under age 70, sensitive MRI measures of early, preclinical SVD such as fractional anisotropy on diffusion- weighted imaging, regional cortical thinning and perivascular spaces; (b) previously collected measures of cognitive function; and (c) neurocognitive and vascular consequences of SVD (dementia and stroke). We will use a Mendelian Randomization framework and existing genetic data to examine causal relationships between the novel biomarkers and MRI, neurocognitive, and clinical outcomes. (2) We will assess the incremental predictive utility of the novel biomarkers over (a) vascular risk factor profiles such as the Framingham Stroke Risk Prediction score; (b) over a panel of previously measured `candidate' biomarkers for SVD including CRP, IL6, TNF-alpha, fibrinogen, BNP, urine albumin, tHcy, ST2, GDF15, TnI, BDNF, VEGF, MMP-9, beta-amyloid, clusterin and APOE and (c) we will identify a parsimonious set of biomarkers that best predict presence of SVD and risk of cognitive decline, stroke and dementia. In summary we propose to leverage extensive available data to identify and validate a novel circulating biomarker profile of glial cell dysfunction that will improve our understanding of SVD biology and help in the prediction of SVD and its associated adverse neurological outcomes.

Project Summary The fastest growing demographic at risk of, and suffering from dementia, is the oldest-old, persons over age 80 or 90 years. By 2030, 1 in 2 incident cases of Alzheimer dementia (AD) will likely occur in this age group. The underlying biology and the impact of vascular and lifestyle risk factors on risk of dementia appear to be different in the young-old and oldest-old. Further, these factors likely interact with each other, with the impact of early and midlife risk exposure as reflected by the state of the brain (on MRI) when individuals enter old age (age 65±5 years), and with the multiple systemic illnesses that also manifest with aging. There is however, limited longitudinal data on the same individuals, followed for over 10-25 years from their 60s to their 80s and beyond. We propose a Cross-Cohort collaboration (CCC) across 8 large population studies (the Framingham Heart Study (FHS), The Cardiovascular Health Study (CHS), the Age, Genes/ Susceptibility study- Reykjavik, (AGES-RS), the Three Cities study (3C), the Rotterdam Study (RS), the Atherosclerosis Risk in Communities study (ARIC), the Austrian Study of Stroke Prevention (ASPS) and the Study of Health in Pomerania (SHIP). These studies, which obtained brain MRI and cognitive assessments between 1990-2001, continue to follow participants, and collectively have over 15,000 participants in whom initial brain MRI and cognitive assessments were obtained prior to age 70 and subsequent cognitive, dementia status and/or MRI assessments have been obtained until they died, developed dementia, or reached an age of 80+ free of dementia. These participants also have detailed, repeated assessments of vascular, metabolic and lifestyle risk factors, stroke, and the health of other organ systems at and after age 60 years, and after age 80 yrs. Finally, over 27,000 participants have cognition data beyond age 80 (>5000 with MRI) to study the proximate and remote determinants of incident dementia and AD in the oldest-old. We propose the following aims: Aim 1: To relate various measures such as established and novel MRI markers of brain injury (infarcts, WMH, microbleeds, hippocampal volumes, cortical atrophy patterns, microinfarcts, enlarged perivascular spaces etc.) dysfunction or disease in other organ system, and vascular, metabolic, social and lifestyle measures, gathered at age 60-70 to probability of reaching age 85 (+/- 5) years alive and dementia free. Aim 2 (a-c): To relate the same MRI, organ function and risk factors examined in Aim 1, as recorded at ages 60-70 and 70-80 to probability of developing clinical dementia after age 80. Aim 3: To examine if, how, and to what extent systemic organ dysfunction and risk factors beyond age 60 modified the association between brain injury markers and probabilities of cognitively healthy aging versus clinical dementia in the oldest-old. Aim 4: To examine if key AD related genes (such as APOE, BDNF, BIN1) modify the associations seen in Aims 1 and 2, or the interactions explored in Aim 3. Our findings will facilitate more effective, targeted efforts at prevention of dementia in the oldest-old, a key component of any public health strategy to reduce AD burden and costs.

? DESCRIPTION (provided by applicant): The proposed renewal application, entitled MRI, Cognitive, Genetic and Biomarker Precursors of AD & Dementia in Young Adults seeks to extend the study of preclinical dementia to a community-based sample of younger aged adults decades before possible onset of clinical symptoms. In the previous grant cycle, the Framingham Heart Study Generation 3 and its smaller multi-ethnic Omni Generation 2 cohorts were administered a neuropsychological test battery (NP; n=2498) and a brain MRI scan (n=2279). These cohorts had been previously characterized in detail through their participation in two health examinations, administered between 2002-2009, in which numerous lifestyle, genetic and circulating biomarkers have been measured. By proposing a repeat administration of the NP and MRI protocols we will establish the first population cohort able to estimate the heterogeneity of change in detectable differences in cognitive performance and brain structure. To meet this primary aim of earlier detection, we have incorporated novel cognitive indices that include error responses and latency metrics acquired through participant use of a digital pen and predict that for persons in whom change is evident, we will observe at least three distinct cognitive phenotypes - amnestic, executive function, and mixed, based on traditional and novel neuropsychological test performance measures. For detecting MRI changes, we will not only evaluate longitudinal measures but also construct a measure of brain structural health based on combined measures of white matter hyperintensities, gray matter regional volumes, cortical thickness and fractional anisotropy measures in specified regions. Another central aim of this proposal is to determine whether early vascular risk and other health measures, genetic factors and newer biomarkers are predictive of incident decline in cognition and brain morphology previously linked to increased risk of AD. Finally, we will test novel computational analytic methods to construct multi-marker preclinical risk scores predictive of cognitive and neuroimaging changes. Dementia is not an inevitable consequence of brain aging and determining the earliest age in which brain aging is detectable and the risk factors related to these early signs of change may lead to new pathways for intervention and prevention.

The Framingham Heart Study (FHS) is a prospective, community-based 3-generational study that enrolled participants between ages 20-50 and has examined them every 2-4 years to collect extensive lifestyle, vascular, biomarker data; 9300 have GWAS. Embedded in this cohort are 1036 multigenerational families. Surveillance for AD dementia (and MCI) has been ongoing for over 4 decades. We have identified 1421 incident AD, 1767 MCI, enrolled 800+ in a brain donation program, obtained 7000+ 1.5T brain MRI, and repeated, detailed neuropsychological assessments. We have recently obtained extensive omics in ~6000 (gene expression, methylation, miRNA, metabolomics and proteomics) and genomics (50X whole genome sequences [WGS] in 4197 with pedigree-based imputation to 6554) through the NHLBI funded SABRe CVD (omics) and TOPMed (WGS) programs. We seek to leverage these rich resources (>$25 million). We propose these specific aims: AIM 1 is to examine and explain temporal trends in clinical AD dementia in the FHS cohorts. The age-specific incidence of dementia has declined over the past 4 decades among FHS participants (in press). However, the reasons for this decline remain unclear. We thus propose to continue tracking temporal trends in AD dementia and MCI through intensive surveillance, and verifying diagnoses at autopsy. We hypothesize that better education, treatment of some vascular factors and protective lifestyle changes (diet, activity, social engagement) may partially explain these trends. AIM 2 is to identify the patterns and predictors of preclinical AD within FHS families by obtaining (i) a novel circulating biomarker (plasma tau on 8000+ persons, using samples collected 5-15 years ago and repeat assay in 450) to supplement 1000+ biomarkers already available, and (ii) brain imaging with tau- and amyloid- PET, 3TMRI, including assessment of functional connectivity, tractography and blood flow, in 450 dementia- and stroke-free, FHS participants age 35-75 on whom we have (a) directly verified familial cognition and AD dementia status (both parents and all 4 grandparents were FHS participants), and also (b) have WGS and omics data. AIM 3 is to utilize the available WGS and extensive `omics' data for deep molecular phenotyping of AD. We will undertake conventional family-based WGS analyses of AD dementia and preclinical AD endophenotypes and novel high dimensional (co-expression, network, systems-based) analyses in collaboration with Drs. DeJager (PI of Accelerated Medicine Partnerships-AD, with omics data in 1200 brains), Witten (award-winning mathematician in applying graphical analysis to omics) and Levy (PI of SABRe-CVD at FHS). We will validate our findings in unrelated and multi-ethnic (Omni) FHS participants, through collaborations with other cohorts, and share all data through dbGaP and BioLINCC for analyses by others. We expect to identify new biologic pathways, drug targets and biomarkers for AD, especially those applicable to the preclinical stage of AD and those explaining promising trends in AD risk; such pathways should prove most useful for AD prevention.

DESCRIPTION (provided by applicant): The Framingham Heart Study (FHS) has, during the 33 years that the Precursors of Stroke Incidence and Prognosis (PSIP) grant has been funded, prospectively identified 2290 incident stroke and TIA events in 15,442 participants and made landmark contributions to the our understanding of stroke risk factors. It has also described 50-year temporal trends in stroke risk, and crafted a widely used Framingham Stroke Risk Profile (FSRP). In parallel, FHS has prospectively accrued data on incident mild cognitive impairment and dementia, 1-3 rounds of brain MRI and detailed cognitive assessment (N~7000 persons) and a wealth of genomic, lifestyle, vascular risk factor and biomarker data. In this renewal we propose to continue stroke surveillance, to identify additional stroke risk factors and temporal trends, especially in adults <55 years, and to use the rich data available in FHS to understand vascular contributions to dementia. The burden of stroke is dwarfed by the burden of subclinical vascular brain injury (VBI). VBI assessed with objective imaging measures, is a risk factor for stroke and for vascular cognitive impairment and dementia (VCID). However, there is considerable heterogeneity in the association between conventional MRI measures of VBI and cognitive performance. We hypothesize that some of this discrepancy will be due to differences in brain blood flow (imaged with pseudocontinuous arterial spin labeling [pCASL]), white matter integrity (detectable by diffusion tensor imaging [DTI]), functional connectivity (assessed by fcMRI) and concomitant AD pathology (assessed using PIB-PET amyloid burden). We also posit that variability in risk of VCID might be further explained by exploring individual differences in genetic susceptibility, lifestyle and exposure to risk factors. Finally, we postulate that factors determining VCID in persons with and without stroke will overlap. We propose the following Specific Aims: Aim 1: To continue surveillance for stroke and transient ischemic attack (TIA) in surviving FHS participants (n~8000, aged 28-107 years), using existing standardized protocols and introducing web-based physician examinations. We will further explore clinical, risk factor, biomarker and (in conjunction with large consortia) genetic risk factors associated with stroke allowing us to expand and refine the FSRP. We propose to especially focus on young stroke and the study of TIA with diffusion-weighted abnormalities. Aim 2: To examine the burden of VBI after stroke/TIA using 3TMRI, MRA, pCASL, fcMRI and PIB-PET at 6 months and 2 years after the event in 75 cases, and in 75 age- and sex-matched controls. We will relate these measures to VCID assessed with a 60 min detailed cognitive assessment, repeatedly used in prior FHS exams. Aim 3: To assess the range of VBI and VCI in 200 persons without clinical stroke, selecting 100 each from the two extremes of the stroke risk (FSRP) spectrum, using the same imaging and cognitive measures as in Aim 2. Aim 4: To identify genetic, lifestyle, vascular and biomarker determinants of VBI, VCI, VCID among FHS participants, utilizing traditional and novel, targeted and exploratory statistical modeling.

DESCRIPTION (provided by applicant): The ADSP discovery phase will identify putative novel AD genes/variants. Nevertheless, to convincingly establish new late-onset AD (LOAD) loci, replication is essential and NHGRI will fund replication sequencing in 14,000 to 30,000 persons. Sample selection and analytical strategies will be determined by the ADSP Steering Committee in conjunction with grant awardees of RFA http://grants.nih.gov/grants/guide/rfa-files/RFA- AG-16-002.html. Here, we propose a cost-effective strategy to leverage phenotypic, endophenotypic, genomic and multi-dimensional omics data available through the Cohorts for Heart and Aging Research in Genomic Epidemiology (CHARGE) and its large network of collaborators. In Aim 1, we will perform harmonization of phenotypic and genetic data from discovery and replication phases for validation of variant- and gene-level AD associations, and for novel gene discovery, supplementing U54 efforts. Samples will be drawn from community-based cohorts of African, Hispanic, Asian, and European ancestry (>15,000 cases & 100,000 controls, of whom >60,000 are over age 65). One quarter of the sample already has sequence data (whole exome, whole genome) available; the others will be eligible for the NHGRI replication sequencing. Genome- wide array data are available in >65,000 and we propose to use the Illumina Multi-Ethnic Genotype Array (MEGA) chip, with custom AD content, to genotype an additional ~10,000 richly phenotyped samples, selected for being non-European or European but with unique measures (e.g., with amyloid PET scans). We will integrate array- and sequence data to perform imputation of common and moderately rare variants using improved reference panels that represent the ancestral diversity of the study samples. In Aim 2, we will leverage fine-scale population structure in multi-ethnic and admixed samples to validate and fine-map discovery phase loci, and also identify novel AD loci through trans-ethnic meta-analyses and admixture mapping. In addition, we will identify novel AD-relevant associations and interrogate biological pathways by studying previously-harmonized and new, sensitive endophenotypes including (1) Brain MRI: hippocampal volumes, white matter microstructural injuries and `AD signature' patterns of cortical atrophy; (2) Cognition: general cognitive performance and verbal memory; (3) Biomarker: PET amyloid burden and circulating beta- amyloid levels. In Aim 3, we will gain additional insight into biology and prioritize loci for experimental follow-up and drug development. Specifically, we will utilize bioinformatic tools and omics data, including available DNA methylation, gene expression, miRNA and metabolomics from CHARGE and through the Accelerated Medicine Partnerships-AD (AMP-AD) project to create and validate an AD-specific Combined Annotation Dependent Depletion tool (AD-CADD), finally, we will parse the most promising loci for further functional exploration using Drosophila knockdown models.

? DESCRIPTION (provided by applicant): The pathology of Alzheimer's disease (AD) starts >2-4 decades prior to onset of clinical dementia. Therefore it is critical to identify persons with preclinical AD, who may be most responsive to preventive interventions, and also risk factors and biomarkers for preclinical AD which may lead to new, effective AD prevention strategies. We propose to study, in a community-based cohort, heterogeneity of cognitive change at mean age 45, and (in a subset) 3 markers of preclinical AD: amyloid (PIB)-PET, resting state functional connectivity MRI, and tau (F18T807) PET at age 45-65. Such data are not currently available. Framingham Gen 3 participants are grandchildren of the Original cohort (followed since 1948) and children of the Offspring (Gen 2, followed since 1971). Omni 1 & 2 are multiethnic cohorts corresponding to Gen 2 & 3. All cohorts have genetic/epigenetic (GWAS, exome chip and sequencing, blood expression, methylome), lifestyle (diet, mood, hip accelerometry, etc.), vascular/metabolic risk factor and circulating biomarker (e.g., beta-amyloid, clusterin, inflammatory, lipids, adipokines, growth factors) data, verified clinical dementia statu, structural brain MRI (including diffusion tensor imaging [DTI]) and detailed cognitive assessments. Gen 3/Omni 2 (n=4200) participants have already been examined twice (2002-2005 and 2008-2011). These exams included 2 brief cognitive tests (of memory [CERAD word list], and of executive function [Victoria Stroop]) and a brain MRI. We have previously shown that hypertension and diabetes have a greater adverse impact in younger Gen 3 than in Gen 2 participants (2 & 6 years of brain aging in Gen 2, versus 7 & 23 years in Gen 3, respectively). We now propose the following Specific Aims: Aim 1: Obtain a brief subjective (AD8) and objective (Montreal Cognitive Assessment [MOCA], repeat Stroop and CERAD word list) cognitive assessment in all Gen 3/Omni 2 (N~3800) at exam 3 (2015-2018) and assess each person's change from 6-7 years earlier. We hypothesize that persons with a high vascular burden and/or high genetic burden of AD will experience the greatest decline in cognition. Aim 2: Obtain amyloid & tau PET and brain structural and fcMRI in 200 persons, aged 45-65 years, with prior MRI, and carefully selected to represent the entire spectrum of vascular risk. We will: assess (2-i) prevalence of amyloid, tau and fcMRI abnormalities at this age and their correlation with cognition, both directly and via an interaction with vascular brain injury; (2-ii) risk factorand circulating biomarker associations with these preclinical imaging markers of AD; also extend/validate the risk factor & biomarker associations with PET/ fcMRI (noted in Gen 3) in subjects >65 yrs with PET/ fcMRI via 4 international collaborations (N~2500). Aim 3: Examine genes, risk factors and biomarkers that we find are associated with PET/ fcMRI for additional association with: (3-i) structural MRI and cognitive measures already available in Gen 1, 2 & 3, e.g., hippocampal volumes, cortical thickness, logical memory (N=4,700); and (3-ii) with risk of developing clinical AD in Gen 1 & 2 participants (up to 1300 AD cases, 750 incident in >7500 persons).

Abstract The burden of cognitive impairment and Alzheimer disease (AD) is increasing rapidly with the aging of the US population. Accordingly, it is critical to identify molecular signatures of the long pre-symptomatic phase of AD to identify and target its clinically silent phase. New criteria of preclinical AD use structural and molecular imaging (MRI and PET) and cerebrospinal fluid (CSF) assays, which are expensive, invasive and not scalable for population-based screening. Hence, there is a quest for blood biomarkers of pre-symptomatic stages, mild cognitive impairment (MCI), and dementia that could (i) elucidate the biology of `normal' brain aging, AD and AD-related dementias (ADRD), (ii) improve risk prediction of AD, and iii) permit risk stratification and subject selection for enrollment in targeted clinical trials of early preclinical disease. AD is an archetypal proteinopathy characterized by protein misfolding and formation of neurotoxic protein aggregates. Damaged cerebral proteins leak into the CSF and can enter the blood. Therefore, ultra-sensitive proteomic profiling has been used to identify blood biomarkers of pre-dementia and AD. Yet, initial studies have been small, limited by suboptimal designs, and an absence of analytical validation and replication. We will characterize the plasma proteome (1310 SomaScan proteins) at two critical time points (mid-life and older age) in 1874 middle-aged-to-elderly individuals in the Framingham Offspring Study (FOS) spanning the spectrum of normal and abnormal cognition. Participants have serial neurocognitive and brain imaging data (including PET scans in a subset) and are under surveillance for AD. We hypothesize that the plasma proteome changes with the aging and with early changes in cognition. We posit that longitudinal patterns of blood biomarkers can distinguish normal aging from presence of comorbidities, pre-dementia, MCI and AD. Our specific aims are: Aim 1. Characterize the plasma proteome in 1874 elderly FOS participants at their tenth exam (2019-2021), and relate the proteome cross-sectionally to risk factors, lifestyle and medications; function of body systems and comorbidities; and structural/cognitive endophenotypes of AD. Aim 2. Evaluate longitudinal changes in plasma proteins with aging over a 25-yr follow-up period (between the 5th and 10th exams; using extant protein data at former), and relate protein changes to longitudinal trajectories of neurocognitive and brain imaging measures. Aim 3. Relate the plasma proteome at exam 10 (and changes between exams) to the incidence of cognitive decline, stroke and AD prospectively. Aim 4. Relate the top proteomic findings in Aims 1-3 to brain amyloid and tau on PET scans in a subset. We will validate our findings with mass spectrometry, and replicate them in independent cohorts. Our multidisciplinary team will identify novel longitudinal proteomic signatures of AD and ADRD; construct biological protein networks associated with AD that may be targeted in clinical trials for preventing cognitive decline and AD in middle age and beyond.

Project Summary/Abstract: The Alzheimer Disease Sequencing Project (ADSP) seeks to identify new genomic variants contributing to increased risk for and protection from Alzheimer's Disease in multi-ethnic populations, and to identify new pathways for disease treatment and prevention. Whole genome and whole exome sequencing data (WGS and WES) are available from ADSP Discovery and Discovery-Extension Phases and WGS in diverse ethnic groups will be generated for the Follow-up Study (FUS). The investigators of this proposal have diverse but complementary expertise across the range of bioinformatics, applied statistics and methodological development, admixture and ethnic diversity, rare variant association, network modeling, preclinical validation of targets, and clinical expertise in AD and have been involved in the ADSP since its inception. Further they bring expertise on endophenotypes and additional WGS data through their role within the CHARGE (Cohorts for Heart and Aging Research in Genomic Epidemiology) and TOPMed (Trans-Omics for Precision Medicine) consortia. We now propose the following aims to meet ADSP goals. Aim 1: To fully characterize known AD loci and to identify novel protective and risk variants for AD by exploiting the full range of genetic variability revealed by WGS including single nucleotide polymorphisms, small insertion/deletions, and structural variants. Analyses will include expanded association analyses of AD and endophenotypes, identification of novel protective variants via carefully selected ?Wellderly? samples, and integration of findings across analyses. Aim 2: To leverage ethnically-diverse and admixed populations to identify novel variants for AD and endophenotypes. This will be achieved by estimating and accounting for global-scale population structure in association analyses across the three phases of ADSP. We additionally propose to perform admixture mapping in samples of admixed ancestry and to perform ethnic-specific analyses and trans-ethnic meta- analyses. Aim 2 analyses will be performed for AD, AD endophenotypes, and Wellderly status. Aim 3: To functionally characterize genes, gene networks, and systems, via bioinformatics and omics integrative analyses to identify putative therapeutic targets. The investigators will work closely with the Accelerating Medicines Partnership (AMP) projects. We propose to use a combination of bioinformatics tools and analysis of ?omics? data, including DNA methylation, gene expression, miRNA and metabolomics data within AMP and in the CHARGE cohorts to predict function of specific variants or groups of variants, to apply network approaches across gene sets, to utilize a systems approach to understand the ADSP sequencing data in the larger context of human biology and to identify putative therapeutic targets. Our proposal provides a comprehensive, integrated plan, which we will implement within the existing ADSP infrastructure and in coordination with ADSP investigators.

Alzheimer?s-focused Administrative Supplement to Enhance the Imaging Genomics of the Aging Brain Project Project Summary/Abstract We request an administrative supplement for our ?Imaging Genomics of the Aging Brain? study (R01 AG058464). The goal of this administrative supplement is to extend our existing study to include a focus on Alzheimer?s disease and related dementias (ADRD). Currently our NIA funded project is designed to characterize the genetic influences on normal aging-related changes in neuroanatomic, neurophysiologic and neurocognitive indices in randomly selected Mexican American pedigrees. This supplement will support additional work, planned and performed by original and new project investigators, to advance the primary goal of our study: elucidating the genetic architecture underlying normal and pathologic brain aging. Our requested administrative supplement is in response to NOT-AG-20-008, as we integrate ADRD specific procedures and biomarkers into a project previously focused more on normal brain aging. In our currently funded project, we are re-phenotyping the oldest 700 Mexican American individuals ~10 years after their initial assessment as part of a pedigree-based, mixed longitudinal design. While our current study takes advantage of more powerful methods for the detection of genetic and environmental influences of healthy aging in longitudinal data, it does not include a formal assessment of Alzheimer?s disease or related dementias, nor are biomarkers associated with Alzheimer?s disease indexed. Thus, as part of this supplement, we aim to (1) integrate a culturally appropriate diagnostic screening into our existing protocol, (2) index ADRD related blood-based biomarkers using ultrasensitive methods for the quantitation of low abundance proteins (SIMOA technology), and (3) for each biomarker estimate the effect size on ARDR risk, the heritability, and the extent to which the biomarkers and ADRD share genetic factors. To achieve these aims, we partnered with Drs. Sudha Seshadri and Gladys Maestre, both world renowned experts in Alzheimer?s disease who will directly oversee our diagnostic aim. Although we will expand our brain aging genomics project to include diagnostic procedures and measure Alzheimer?s disease related biomarkers, the work proposed in this administrative supplement is within the scope of our originally supported research given the prevalence rates for dementia among individuals 70 years of age or older. Given the dearth of Alzheimer?s research involving the Mexican American community and evidence that this under-represented group is at increased risk for Alzheimer?s disease and related dementias, our supplement has the potential to help minimize this growing health disparity. This administrative supplement will provide pilot data for large-scale ADRD research projects in this underserved population. Dr. David Glahn, Boston Children?s Hospital, and Dr. John Blangero, University of Texas Rio Grande Valley School of Medicine, are co-principal investigators on this application. Our administrative supplement is in response to NOT-AG-20-008, as we integrate Alzheimer?s specific procedures and biomarkers into a project focused on normal brain aging.

ABSTRACT Cerebral small vessel disease (CSVD) contributes considerably to the global burden of dementia. As vascular diseases can be both prevented and safely treated, there is a great potential for interventions to reduce the burden of dementia. However, more research is needed to develop suitable biomarkers of cerebral small vessel contributions to cognitive impairment and dementia (VCID). The National Institute of Neurological Disorders and Stroke (NINDS) has supported the MarkVCID initiative to advance the identification and validation of biomarkers for VCID across seven sites and a coordinating center. As one contributing site, our team has led the development of two candidate biomarkers, helped define and harmonize all protocols, and joined multisite validation with the recruitment of the largest Hispanic sample from a single site. In this proposal, we seek to include a more diverse population across South Texas, including Hispanic and African Americans, from Houston and San Antonio, stroke and dementia clinics, primary care, and population studies. We further propose additional validation of candidate biomarkers in the rich datasets of four cohorts in the Cohorts for Heart and Aging Research in Genomic Epidemiology (CHARGE) Consortium that have legacy data (MRI, dementia) and biospecimens (plasma, serum, brain autopsy). As a MarkVCID site, we aim to perform a comprehensive, longitudinal validation of candidate biomarkers of CSVD in a diverse sample. We aim to recruit 400 participants over age 55 years with subjective cognitive complaints, mild cognitive impairment, or early dementia of presumed vascular etiology and retain at least 320 of them over the 5-year follow-up; ~60 will be persons seen in the UH3 phase and will have 7 years of follow- up. We will perform a comprehensive examination to collect medical history, biospecimens (blood, CSF), imaging (MRI with cerebrovascular reactivity, optical coherence tomography angiography), and neuropsychological data (cognition, CDR) following the protocols developed during the UH2/UH3 phases of the MarkVCID consortium. We will perform a follow-up examination with interim phone screenings for cognitive status and continuous dementia surveillance via consensus conferences. Further, we will offer brain autopsies to consenting participants for the assessment of clinicopathological correlates of VCID biomarkers. We will measure selected fluid and imaging biomarkers following established kit protocols and perform longitudinal clinical validation of biomarkers according to their pre-specified hypotheses. Finally, we will perform additional validation in four cohorts of the CHARGE consortium. Data, biospecimens, and results will be shared with the consortium and external qualified investigators through the designated MarkVCID coordinating center. Our team will have strong leadership with the PIs of the UH3 Seshadri, Fornage (multiple PI), Tracy (Co-I), a proven, young Co-I now taking over as Contact PI (Satizabal), and the addition of an exceptional stroke trials leader (Savitz).

SARS-CoV-2 virus displays neurotropism in some infected patients with reports of viral invasion, inflammation, meningoencephalitis, microvascular injury, stroke, delirium and delayed cognitive and psychiatric symptoms. It is unclear if there is any acceleration of neurodegenerative processes and increased risk of Alzheimer?s disease and related dementias (ADRD). Race-, ethnic- minorities and men are known to have a higher risk of dying from COVID and may also have a greater susceptibility to long-term neuropsychiatric sequelae. Ultrahigh field (7T) MRI has increased sensitivity and spatial resolution, compared to 3T MRI and can detect small changes in cortical and white matter structure, integrity and connectivity, inflammation, iron deposition, hippocampal subfields, venular injury and the locus coeruleus. The 7T MRI COVID Consortium is an international collaboration across 5 sites to enroll a diverse, multi-ethnic cohort of 780 persons, aged 55-80. Of these 260 persons will have well-documented SARS-CoV-2 infection (cases) and 260 will be ?illness? controls with a clinically similar non-COVID illness (e.g. pneumonia). Cases and controls will include >25% Hispanic and >25% African-Americans. Both groups will be compared to 260 healthy controls with documented normal cognition and no hospitalization in preceding 2 years. Additional data will be drawn from 40 persons with autosomal dominant early-onset AD and 180 population controls, all imaged with the same 7T MRI protocol. All participants will undergo 2 annual 7T MRI scans and 4 detailed exams comprising neurological, cognitive and psychiatric assessments, smell, gait, blood biomarkers of neurodegeneration (p-tau181, NFL, GFAP, amyloid) and systemic inflammation (CRP, IL6, IL10, TNF-alpha, IL1R) and surveillance for incident MCI, ADRD dementia. These exams will occur at the time of each MRI, and at 36, 48 months post-illness. We propose the following specific aims: Aim 1: Detail the range of (Aim 1a) Early (6-12 months) brain pathology in COVID survivors (Aim 1b) assess if early changes improve, persist or worsen at a delayed 7T MRI (12-18 months) and (Aim 1c) Compare findings in COVID survivors to MRI in preclinical EOAD. Aim 2: Compare cross-sectional prevalence of pre-illness ADRD and vascular injury (VCID) and of cognitive, behavioral, mood and functional outcomes across 3 groups. Aim 3: Relate early and delayed 7T MRI measures to subsequent risk of MCI, dementia and cognitive and gait trajectories. Aim 4: Explore if race/ethnic-, sex- differences, blood biomarkers, genetics, or early SARS-CoV-2 ?treatments? are effect-modifiers, mediators, or neither, of the associations noted in Aims 1-3. Investigators leading this grant are also members of other larger, less detailed COVID consortia permitting harmonized data analyses. Our study will permit a better biological understanding of mechanisms and modifiers of long-term neurological and psychiatric sequelae of COVID. It could also help illuminate the role of viral infections, inflammation and immune response in ADRD.

Alzheimer´s disease (AD) and related disorders (ADRD) disproportionally impacts Hispanics/Latinos, who exhibit higher rates, earlier onset and face unique challenges due to cultural, linguistic, socioeconomic or healthcare access problems. Moreover, there is a shortage of researchers focused on ADRD in Mexican- American (MA) Hispanics, the fastest growing minority in the US. Addressing the heterogeneity of ADRD presentation and biology, using precision medicine approaches to improve risk prediction, target prevention and treatment is likely to improve outcomes for MA and others. The proposed South Texas Alzheimer disease Center (STAC) will exploit its unique geographic location in South Texas, a region of ~5 million, underserved MA to develop infrastructure and data/biosample collections that will support researchers from multiple disciplines to conduct research to diminish the burden of AD in Hispanics. We have 6 specific aims: (1) Collecting and sharing longitudinal data from patients, controls and caregivers (2) Exploring the biological heterogeneity of preclinical and clinical dementia, through deep phenotyping with clinical, imaging, genetic, omic, CSF, blood and sensory-motor biomarkers and autopsy of all these enrollees (3) Focusing especially for Aims #1 and #2 on Hispanic/Latino individuals (4) Identifying novel predictors/ biomarkers of dementia risk and resilience, including for poorly understood clinic-pathologic subgroups such as Suspected Non-Alzheimer (amyloid negative, neurodegeneration positive) Pathology [SNAP] in Hispanics with/without diabetes, (5) To recruit, train, mentor and support a diverse research workforce, largely women and minorities, to become leaders in multidisciplinary, team-based, ADRD research, (6) Bidirectional community education and engagement, research into knowledge, attitudes and practices/preferences. The STAC will develop and share culturally sensitive deep phenotyping methods beyond the Uniform Dataset (including novel cognitive, behavioral, vascular, lifestyle factors, biomarkers), genetics and multi- dimensional omics within community- based and patient and caregiver (dyadic) cohorts. Using state of the art clinical informatics and statistical methods, these rich data should permit an exploration of the molecular heterogeneity of ADRD and uncover novel biology and drug targets, treatment approaches. Finally we will collaborate, share data/samples and expertise with other institutions in Texas and around the world, especially other ADRC Centers, the NACC, NCRAD, NIAGADS. We will achieve these aims through creation of six required Cores and one component: Administrative, Clinical, Data Management and Statistical, Neuropathology, Outreach, Recruitment and Engagement, Biomarker Cores and the Research Education Component. In addition, we propose three Optional Cores: Population Neuroscience, Imaging and Genetics and Multiomics Cores. The STAC will serve as a national resource for disruptive, transformative and innovative research and the design, development, testing and implementation of practical strategies to diminish the burden of AD in Hispanics.

PROJECT SUMMARY/ABSTRACT ? Administrative Core The South Texas Alzheimer?s Disease Center (STAC) Administrative Core (AC), part of the collaborative effort of University of Texas Health Science Center at San Antonio (UTHSA) and the University of Texas Rio Grande Valley (UTRGV), will provide the overarching leadership and governance for the STAC along with directing new initiatives aimed at training and supporting innovative research approaches with the goal of reducing health disparities in Alzheimer´s disease and related disorders (ADRD). The AC will serve as an integral administrative hub for each Core by acting as the central resource for financial review, human resources management, contract management, grants management, and data/biospecimen /resources sharing. The Specific Aims of the AC are: 1) Lead the overall direction of the STAC by holding continuous strategic planning sessions with national and international experts in AD research; 2) Review, fund and oversee novel AD developmental projects from across South Texas with input from the STAC advisory committees and NIA with the goal to provide seed funding to new investigators that will advance the field and ultimately result in greater funding through other NIH opportunities, foundations, or philanthropy; 3)Identify and support mentees involved in transformative AD research, community engagement, and education with the focus of advancing careers centered around the ADRD research and education; 4) Engage in routine financial review and analysis of all STAC functions to ensure maximal ROI of existing Cores and projects as well as to support new initiatives. 5) Serve as the integral administrative hub for each Core and collaborative site by acting as the central repository for resources such as contract management, finance, HR, and grants management. Ensure compliance with human subjects, scientific integrity, data sharing, and fiscal policy requirements of the NIH. 6) Promote integration of all STAC Cores by holding regular meetings between all Core leaders and scientific advisory members to discuss strategy and progress of each Core. 7) Recruit and retain faculty and staff who are underrepresented in neuroscience by fostering an inclusive environment with the aid; 8) Encourage national, state, and local collaboration through interaction with other ADC?s, NIH, the data coordinating center, and engage AD clinicians and scientists at UTHSA/UTRGV and externally; 9) Bolster STAC funding and resources through actively engaging in philanthropic initiatives and seeking public private partnerships; 10) Ensure the STAC is promoted as the premier AD resource in South Texas by routinely publicizing research, community engagement and educational initiatives to the state and local community with guidance from NIA. The AC will provide an effective and efficient administrative infrastructure for the STAC to establish, maintain, and grow a robust, interdisciplinary, cross- institution education and research enterprise that will advance the goal of reducing the burden of ADRD in our nation, and particularly addressing health disparities for Hispanics with ADRD in Texas.

Dementia in older adults is clinically, genetically and pathologically heterogeneous. Understanding this heterogeneity and addressing all the biological pathways that increase risk and lower resilience, will be required to provide precision prevention, diagnosis and treatment. Genome wide association studies (GWAS) have implicated over 40 genes, multiple cell and varied biological pathways (amyloid, tau, endolysosomal, mitochondrial function, inflammation). Genetic and multiomic characterization of ADRD in individuals, and in groups of patients, could exploit this heterogeneity towards more effective, precise, personalized prevention and treatment of dementia. Whereas, most of these biological discoveries have been in non-Hispanic whites, there is a paucity of data on Mexican American (MA) Hispanics, who are the fastest growing segment of older adults in the US. The Genetics and Multiomics Core (GMC) of the South Texas Alzheimer Disease Consortium (STAC) has the following specific aims: Aim 1: Identifying causal genetic variation underlying ADRD in CC enrollees through a combination of routine clinical sequencing and a ?Undiagnosed Disease Network? approach to identifying novel genetic variation that may be causal or contributory. To achieve this, we will record results of clinical sequencing and genetic counseling in proband and relatives. Aim 2: Genetically characterize all CC enrollees (using APOE and GWAS) to expand our understanding of genetic variation modifying risk, resilience and disease progression. We will aim to refine and improve genetic risk estimates for late onset AD, PD, DLB permitting more accurate risk stratification in MA Hispanics, better targeting for recruitment in clinical trials. Aim 3: Serve as a resource for STAC investigators, trainees, and the national ADRD research community for deeply phenotyped Hispanic MA samples, genomic data and innovative analysis methods. To achieve this (i) GMC will share DNA, genetic and phenotypic data (clinical, MRI and PET imaging, blood and CSF -amyloid, tau, inflammation, metabolomic, lipidomic- and sensory-motor biomarkers) and digital and conventional neuropathology, through NCRAD, NIAGADS, NACC; (ii) GMC will serve as a STAC resource for providing methylation, transcriptomics (blood, brain, CSF), ATAC-Seq, single-cell omics data and for generating usable iPSCs and organoids; (iii) GMC will develop and share innovative genetic and multiomic association analyses methods, especially for use in large families; (iv) GMC will facilitate collaborations with consortia such as the Alzheimer Disease Genetics Consortium (ADGC), the International Genomics of AD Project (IGAP), Cohorts for Heart and Aging Research in Genomic Epidemiology (CHARGE) and Transomics in Precision Medicine (TOPMed); (v) GMC faculty and resources will support the Research Education Core in developing a diverse workforce, well-trained in applying genetic and multiomic research methods.

Persons with similar amount of Alzheimer's or vascular brain pathology on imaging or autopsy may have had very different clinical and functional experiences during life. One possible reason could be varying amounts of cognitive reserve, or brain health which protects them from clinical manifestations. Thus, just as a healthy bone mass through life protects from osteoporosis and fractures, having a healthy brain at age 65-85, a consequence of genetic propensity and lifelong environmental, behavioral and disease-related factors, will protect from development of AD, dementia and stroke. How do we define a healthy brain phenotype? Brain health is typically characterized using quantitative measurements MRI and PET brain imaging, cognitive testing and at autopsy. Other dimensions of brain health, often altered in aging, prior to cognition, include retinal structure and vasculature, olfactory, visual, auditory, tactile and sensory perception and motor abilities. Sensory-motor measures are promising early biomarkers of AD and may play a causal role in the development or progression of dementia. An NIA workshop titled ?Sensory and Motor dysfunctions in Aging and AD? concluded that comprehensive sensory motor testing would provide key mechanistic insights into AD pathogenesis. We propose to incorporate multiple such sensory-motor measures in the recently funded 10th exam for 1874 Framingham Heart Study (FHS) Offspring and Omni 1 cohort participants and develop a multi-dimensional sensory-motor Brain Health Index (smBHI), as well as a composite BHI (cBHI) that additionally includes brain MRI and cognitive measures. Predictors and outcomes related to the BHI will be identified using the extensive profiling of risk factors, repeated measures of brain structure and function, information on MCI, dementia (AD and VCID) and stroke outcomes already available in FHS. It will be validated in 3 additional population samples, 200 African- Americans in Jackson, MS, 400 Hispanic participants in San Antonio, Texas and 1650 European ancestry participants in the Great Age Study in Barri, Italy (LOS only, will collect and analyze data with Italian funding. Aim 1: To characterize individual brain health using a multidimensional sensory-motor `Brain Health Index' by assessing olfaction, retina, vision, auditory function, vestibular function, touch sensation, motor function, and examine its association with (i) cross-sectional MRI, PET and cognitive function and (ii) incident mild cognitive impairment (MCI), dementia including AD, VCID, TIA, stroke and all-cause mortality over 3-5 years and subsequent follow-up Aim 2: To investigate the effect of lifelong (20-40+ years) social, behavioral and vascular/metabolic factors, measured previously on these participants, on individual sensory-motor functions, smBHI and cBHI and brain reserve (difference between BH age and chronological age) Aim 3: To examine the association between (1) genetic, (2) putative circulating biomarkers and (3) epigenetic aging and `brain health' Aim 4: To replicate the associations observed in Aims 1, 2 and 3 in our three replication samples.