
Richard MayeuxColumbia University | CU · Department of Neurology
Richard Mayeux
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1,253
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Introduction
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June 1979 - present
June 1998 - present
Publications
Publications (1,253)
INTRODUCTION
Clinical research in Alzheimer's disease (AD) lacks cohort diversity despite being a global health crisis. The Asian Cohort for Alzheimer's Disease (ACAD) was formed to address underrepresentation of Asians in research, and limited understanding of how genetics and non‐genetic/lifestyle factors impact this multi‐ethnic population.
MET...
BACKGROUND
Alzheimer's disease (AD) biomarkers can help differentiate cognitively unimpaired (CU) individuals from mild cognitive impairment (MCI) and dementia. The role of AD biomarkers in predicting cognitive impairment and AD needs examination.
METHODS
In 628 CU individuals from a multi‐ethnic cohort, amyloid beta (Aβ)42, Aβ40, phosphorylated t...
Alzheimer’s disease (AD) remains a complex challenge characterized by cognitive decline and memory loss. Genetic variations have emerged as crucial players in the etiology of AD, enabling hope for a better understanding of the disease mechanisms; yet the specific mechanism of action for those genetic variants remain uncertain. Animal models with re...
The risk of developing Alzheimer’s disease (AD) significantly increases in individuals carrying the APOEε4 allele. Elderly cognitively healthy individuals with APOEε4 also exist, suggesting the presence of cellular mechanisms that counteract the pathological effects of APOEε4 ; however, these mechanisms are unknown. We hypothesized that APOEε4 carr...
Background
Apolipoprotein E4 (APOE4) is common in the population yet is the strongest genetic risk factor for late‐onset Alzheimer’s disease (AD). Here, we sought to identify genetic effects that differ by APOE4 genotype leveraging stratified and APOE interaction analyses. We hypothesized that we could identify novel genetic associations with longi...
Background
A recently recognized subset of older individuals are an anomaly of cognitive decline; the “SuperAgers”, unsurprisingly named, achieve cognitive scores equivalent to much younger cognitively normal (CN) middle‐aged adults. Using longitudinal cognitive data harmonized across eight cohorts of aging and Alzheimer’s Dementia (AD), we investi...
Background
Genetic Studies of Alzheimer’s Disease in Caribbean Hispanics (CH) has been ongoing for over 20 years. Our primary goal was to identify genes in large well‐phenotyped, multiplex families, and sporadic cases and controls. This longitudinal collection of data represents a unique resource for the scientific community. The project is led by...
Background
Genetic Studies of Alzheimer’s Disease in Caribbean Hispanics (CH) has been ongoing for over 20 years. Our primary goal was to identify genes in large well‐phenotyped, multiplex families, and sporadic cases and controls. This longitudinal collection of data represents a unique resource for the scientific community. The project is led by...
Background
Recent studies increased the number of genes that are associated with the co‐existence of vascular pathologies and Alzheimer’s disease (AD). However, the biological functions and the mechanism of action by which they contribute to the disease pathology are still to be further elucidated. Therefore, animal models that allow streamlined la...
Background
The APOE ɛ4/ɛ4 genotype has the greatest risk for late‐onset Alzheimer disease (AD). However, modifying effects of other genes on AD risk in APOE ɛ4 homozygotes are not fully understood.
Methods
We conducted a genome‐wide association study (GWAS) for AD among 1,223 non‐Hispanic White APOE ɛ4/ɛ4 carriers assembled by the Alzheimer’s Dise...
Background
Although African Americans are twice as likely to develop Alzheimer’s Disease (AD), individuals with African ancestry are under‐represented in genetic research of the disease. In the largest AD genome‐wide association studies to date for African‐Americans (Reitz et al. JAMA 2013; Kunkle at al. JAMA Neurol 2021) we previously identified s...
Background
Energy, amino acid, and lipid metabolism are dysregulated in Alzheimer’s Disease. We investigated circulating plasma metabolites to capture systemic biochemical changes associated with Alzheimer’s disease (AD) using the clinical diagnosis and followed by the addition of plasma‐based biomarkers.
Method
Exogenous and endogenous metabolite...
Background
Alzheimer’s disease (AD) is clinically characterized by disabling cognitive impairment, though substantial variability in cognitive symptoms and trajectories is observed in AD individuals. However, genetic predictors of domain‐specific cognitive performance remain undiscovered. We investigated cross‐sectional and longitudinal genetic arc...
In order to provide a comprehensive evaluation of the non‐genetic factors involved in the development of Alzheimer’s disease and related disorders it is necessary to develop a systematic process to capture the range of environmental and social influences. Exposomics has emerged as an approach to do this. Using high‐resolution mass spectrometry and...
Background
Genetic analyses of cognitive endophenotypes have led to discoveries of novel loci contributing to Alzheimer’s disease (AD) risk. Sex differences are present in cognitive trajectories in aging and AD, and these may vary across cognitive domain. However, genetic drivers that may contribute to sex differences in cognitive trajectories have...
Background
More than 75 common variant loci account for only a portion of the heritability for Alzheimer’s disease (AD). A more complete understanding of the genetic basis of AD can be deduced by exploring associations with AD‐related endophenotypes.
Method
We conducted genome‐wide scans for cognitive domain performance using harmonized and co‐cal...
Background
Lack of diversity in expanding genomic studies has limited the identification of LOAD risk variants that may be more prevalent in non‐European ancestry groups with more modest power requirements for detection. To help reverse this trend, we constructed and analyzed a multi‐ancestry collection of GWAS datasets in the Alzheimer’s Disease G...
Background
Cardio and cerebrovascular diseases co‐exist in up to a third of the Alzheimer’s disease (AD) patients, and the presence of cardiovascular/cerebrovascular risk factors (CVRFs) are associated with the risk of AD in middle age and later. The relationship between CVRFs such as hypertension, body mass index, diabetes and coronary heart disea...
Background
Blood‐based biomarkers have the unique potential to make diagnoses along the Alzheimer’s Disease (AD) continuum. The value of these plasma‐based biomarkers in AD among different race and ethnicity, sex, and genetic status groups needs to be evaluated.
Method
The study included 603 participants of the Washington Heights Inwood Columbia A...
Background
The utility of plasma‐based Alzheimer’s biomarkers in differentiating cognitively healthy individuals from those with Mild Cognitive Impairment (MCI) or Alzheimer’s disease (AD) has been widely investigated in cross‐sectional studies. There are fewer data on longitudinal change of these biomarkers over time, particularly in multi‐ethnic...
Background
Cerebrovascular disease is associated with risk for dementia and possibly Alzheimer’s disease (AD) pathogenesis. Most people diagnosed with AD have mixed pathology, including plaques, tangles, and cerebrovascular disease. Because parental history of dementia is a strong risk factor for AD, studying the extent to which markers of cerebrov...
Background
Memory performance can serve as a strong endophenotype for Alzheimer’s disease (AD) that changes early and continues to decline with disease progression. Yet, the genetic architecture of memory is not well characterized in older adults. Here, we build on existing memory GWAS studies by performing predicted gene expression analysis (Predi...
Background
It is well‐established that telomeres shrink over the course of aging and that this process is genetically regulated. Work from our group and others has highlighted the complex interplay between measured leukocyte telomere length and Alzheimer’s Disease (AD) biomarkers over the course of AD. We expand on this work to explore whether a po...
Background
The ADSP‐FUS is a National Institute on Aging (NIA) initiative focused on identifying genetic risk and protective variants for Alzheimer Disease (AD) by expanding the ADSP beyond non‐Hispanic Whites of European Ancestry (NHW‐EA) populations. Given the lack of diversity in the ADSP, the ADSP‐FUS was designed to whole genome sequence (WGS)...
Background
Cardiovascular risk factors (CVRFs) increase the risk of cerebrovascular disease and AD, and over 30% of the patients with AD coincident cerebrovascular pathology. We previously found that FMNL2 interacts with CVRFs (p = 6.6e‐07) by altering the normal astroglial‐vascular mechanisms that underly amyloid clearance. The goal here was to id...
Background
Presence of the APOE‐ε4 allele is the most consistently confirmed genetic risk factor for late‐onset Alzheimer’s disease (AD) in white, non‐Hispanic populations, but the associated risks observed in African Americans and Hispanics are somewhat lower. The objective of this study was to identify protective variants that could modify or red...
Background
Intake of key nutrients is associated with improved cognitive performance and reduced risk of Alzheimer’s dementia (AD). We examined whether omega‐3 polyunsaturated fatty acid (O‐3 PUFA), omega‐6 (O‐6) PUFA, and monounsaturated fat (MUFA) from foods are associated with plasma biomarkers for AD.
Method
We selected 695 participants in a c...
Background
Inter‐cellular communication within the gliovascular unit (GVU) is critical for cerebral blood flow regulation, and maintenance of the blood‐brain‐barrier (BBB) properties. The breakdown of BBB in Alzheimer’s disease (AD) is well‐established, but precise underlying molecular changes remain unclear. Additionally, whether GVU molecular alt...
Background
Asian Americans and Canadians (ASACs) are the fastest growing minority group in the U.S. and Canada. However, ASACs are under‐sampled in Alzheimer’s disease (AD) research. To address the need of culturally appropriate clinical protocols and community‐based recruitment approaches for ASACs, the Asian Cohort for Alzheimer’s Disease (ACAD),...
Background
Small vessel cerebrovascular disease, often visualized as white matter hyperintensities (WMH) on T2‐weighted MRI scans, contributes to risk, progression, and, possibly, pathogenesis of Alzheimer’s disease (AD). When considered in the context of previous neuroimaging biomarker work in AD, WMH appear to colocalize with other markers of dis...
Objective
The current research framework recommends using biomarkers to further understand Alzheimer’s disease (AD) pathogenesis, including other contributing factors like cerebrovascular disease. In longitudinal studies of people with neuropathological examination after death, baseline loneliness was associated with lower cognition, faster cogniti...
PURPOSE. Few rare pathogenic variants have been identified in more than 70 genetic loci from genome wide association studies of late-onset Alzheimer's disease (AD), limiting research on underlying mechanisms, risk assessment, and genetic counseling.
METHODS. Using genome sequencing data from 197 families in The National Institute on Aging Alzheimer...
Many of the Alzheimer’s disease (AD) risk genes are specifically expressed in microglia and astrocytes, but how and when the genetic risk localizing to these cell types contributes to AD pathophysiology remains unclear. Here, we derive cell-type-specific AD polygenic risk scores (ADPRS) from two extensively characterized datasets and uncover the im...
BACKGROUND
Women demonstrate a memory advantage when cognitively healthy yet lose this advantage to men in Alzheimer's disease. However, the genetic underpinnings of this sex difference in memory performance remain unclear.
METHODS
We conducted the largest sex‐aware genetic study on late‐life memory to date (Nmales = 11,942; Nfemales = 15,641). Le...
INTRODUCTION
Although large‐scale genome‐wide association studies (GWAS) have been conducted on AD, few have been conducted on continuous measures of memory performance and memory decline.
METHODS
We conducted a cross‐ancestry GWAS on memory performance (in 27,633 participants) and memory decline (in 22,365 participants; 129,201 observations) by l...
Background
Long-term exposure to air pollution has been associated with changes in levels of metabolites measured in the peripheral blood. However, most research has been conducted in ethnically homogenous, young or middle-aged populations.
Objective
To study the relationship between the plasma metabolome and long-term exposure to three air pollut...
We built a genetic risk score (GRS) from the most complete landscape of the Alzheimer disease (AD) genetics. We extended its analysis in 16 European countries and observed a consistent association of this GRS with AD risk, age at onset and cerebrospinal fluid (CSF) AD biomarker levels regardless of the Apolipoprotein E (APOE) genotype. This GRS was...
Background: Comorbidities may influence the levels of blood-based biomarkers for Alzheimer’s disease (AD). We investigated whether differences in risk factors or comorbid conditions might explain the discordance between clinical diagnosis and biomarker classifications in a multi-ethnic cohort of elderly individuals. Aims: To evaluate the relationsh...
Background
We profiled circulating plasma metabolites to identify systemic biochemical changes in clinical and biomarker-assisted diagnosis of Alzheimer’s disease (AD).
Methods
We used an untargeted approach with liquid chromatography coupled to high-resolution mass spectrometry to measure small molecule plasma metabolites from 150 clinically diagn...
INTRODUCTION: Despite a two-fold increased risk, individuals of African ancestry have been significantly underrepresented in Alzheimers Disease (AD) genomics efforts.
METHODS: GWAS of 2,903 AD cases and 6,265 cognitive controls of African ancestry. Within-dataset results were meta-analyzed, followed by gene-based and pathway analyses, and analysis...
Background: We investigated systemic biochemical changes in Alzheimer's disease (AD) by investigating the relationship between circulating plasma metabolites and both clinical and biomarker-assisted diagnosis of AD.
Methods: We used an untargeted approach with liquid chromatography coupled to high-resolution mass spectrometry to measure exogenous a...
INTRODUCTION: Alzheimer's disease (AD) biomarkers can help differentiate cognitively unimpaired (CU) individuals from mild cognitive impairment (MCI) and dementia. The role of AD biomarkers in predicting cognitive impairment and AD needs examination.
METHODS: In 628 CU individuals from a multi-ethnic cohort, Aβ42, Aβ40, phosphorylated tau-181 (P-ta...
Background:
Queries for the presence of cardiovascular and cerebrovascular risk factors are typically assessed through self-report. However, the reliability and validity of self-reported cardiovascular and cerebrovascular risk factors remains inconsistent in aging research.
Objective:
To determine the reliability and validity of the most frequen...
Neurogenesis, crucial for brain resilience, is reduced in Alzheimer’s disease (AD) that induces astroglial reactivity at the expense of the pro-neurogenic potential, and restoring neurogenesis could counteract neurodegenerative pathology. However, the molecular mechanisms promoting pro-neurogenic astroglial fate despite AD pathology are unknown. In...
Limited ancestral diversity has impaired our ability to detect risk variants more prevalent in non-European ancestry groups in genome-wide association studies (GWAS). We constructed and analyzed a multi-ancestry GWAS dataset in the Alzheimer Disease (AD) Genetics Consortium (ADGC) to test for novel shared and ancestry-specific AD susceptibility loc...
Introduction:
Sequencing efforts to identify genetic variants and pathways underlying Alzheimer's disease (AD) have largely focused on late-onset AD although early-onset AD (EOAD), accounting for ∼10% of cases, is largely unexplained by known mutations, resulting in a lack of understanding of its molecular etiology.
Methods:
Whole-genome sequenc...
Background
More than 75 common variant loci account for only a portion of the heritability for Alzheimer’s disease (AD). A more complete understanding of the genetic basis of AD can be deduced by exploring associations with AD-related endophenotypes.
Methods
We conducted genome-wide scans for cognitive domain performance using harmonized and co-ca...
Background
Genome‐wide association studies (GWAS) for AD have identified numerous associated loci but have been focused only on the autosomes. We sought to identify novel AD‐associated genes on X‐Chromosome (X‐Chr).
Method
We evaluated the association of AD with X‐Chr variants in GWAS datasets assembled by the Alzheimer Disease Genetics Consortium...
Background
Early Onset Alzheimer Disease (EOAD, age at onset [AAO] < = 65) is a severe form of AD, often occurring when patients are still caring for children or adults. Despite this, most genetic studies of EOAD have focused on autosomal dominant forms, and there is little understanding of similarities and differences between early and late onset...
Background
Alzheimer’s disease (AD), the most common form of dementia, is a complex polygenic disease with genetic, cellular, pathologic, and clinical heterogeneity. Recently, significant attempts have been made for identifying AD biomarkers for reliably tracking disease progression in its early asymptomatic stages. To this end, amyloid PET imaging...
Alzheimer's disease (AD) heritability is enriched in glial genes, but how and when cell-type-specific genetic risk contributes to AD remains unclear. Here, we derive cell-type-specific AD polygenic risk scores (ADPRS) from two extensively characterized datasets. In an autopsy dataset spanning all stages of AD (n=1,457), astrocytic (Ast) ADPRS was a...
Introduction:
Most Alzheimer's disease (AD) loci have been discovered in individuals with European ancestry (EA).
Methods:
We applied principal component analysis using Gaussian mixture models and an Ashkenazi Jewish (AJ) reference genome-wide association study (GWAS) data set to identify Ashkenazi Jews ascertained in GWAS (n = 42,682), whole ge...
Objective:
To assess for TDP-43 deposits in brains with and without a LRRK2 G2019S mutation.
Background:
LRRK2 G2019S mutations have been associated with parkinsonism and a wide range of pathological findings. There are no systematic studies examining the frequency and extent of TDP-43 deposits in neuropathological samples from LRRK2 G2019S carr...
In normal aging, the cognitive domain of semantic memory remains preserved, while the domain of episodic memory declines to some extent. In Alzheimer's disease dementia, both semantic and episodic memory become impaired early in the disease process. Given the need to develop sensitive and accessible cognitive markers for early detection of dementia...
Fine-mapping is commonly used to identify putative causal variants at genome-wide significant loci. Here we propose a Bayesian model for fine-mapping that has several advantages over existing methods, including flexible specification of the prior distribution of effect sizes, joint modeling of summary statistics and functional annotations and accou...
Amyloid PET imaging has been crucial for detecting the accumulation of amyloid beta (Aβ) deposits in the brain and to study Alzheimer’s disease (AD). We performed a genome-wide association study on the largest collection of amyloid imaging data (N = 13,409) to date, across multiple ethnicities from multicenter cohorts to identify variants associate...
INTRODUCTION
The reliability and validity of self-reported cardiovascular and cerebrovascular risk factors remains inconsistent in aging research.
METHODS
We assessed the reliability, validity, sensitivity, specificity, and percent agreement of self-reported hypertension, diabetes, and heart disease, in comparison with direct measures of blood pre...
Background:
Haptoglobin (HP) is an antioxidant of apolipoprotein E (APOE), and previous reports have shown HP binds with APOE and amyloid beta (Aβ) to aid its clearance. A common structural variant of the HP gene distinguishes it into two alleles: HP1 and HP2.
Methods:
HP genotypes were imputed in 29 cohorts from the Alzheimer's Disease Genetics...
The risk of Alzheimer disease (AD) increases with age, family history and informative genetic variants. Sadly, there is still no cure or means of prevention. As in other complex diseases, uncovering genetic causes of AD could identify underlying pathological mechanisms and lead to potential treatments. Rare, autosomal dominant forms of AD occur in...
Importance:
Cerebrospinal fluid (CSF) and plasma biomarkers can detect biological evidence of Alzheimer disease (AD), but their use in low-resource environments and among minority ethnic groups is limited.
Objective:
To assess validated plasma biomarkers for AD among adults of Caribbean Hispanic ethnicity.
Design, setting, and participants:
In...
Objective:
To compute penetrance and recurrence risk using a genome-wide PRS (including and excluding the APOE region) in families with Alzheimer's disease.
Methods:
Genotypes from the National Institute on Aging Late-Onset Alzheimer's Disease Family-Based Study and a study of familial Alzheimer's disease in Caribbean Hispanics were used to comp...
The heterogeneity of the older population suggests the existence of subsets of individuals which share certain brain molecular features and respond differently to risk factors for Alzheimer’s disease, but this population structure remains poorly defined. Here, we performed an unsupervised clustering of individuals with multi-region brain transcript...
Neuroinflammation may be associated with global vascular dysfunction and damage. APOE‐ε4, a major genetic risk factor for late onset AD, is expressed in neuroinflammatory cells and may lead to increased pro‐inflammatory cytokine and nitric oxide production in response to injury. We examined the relationship of vascular dysfunction and damage with a...
Alzheimer’s disease (AD) pathophysiology (i.e., amyloid‐induced tau) and cerebrovascular disease drive neurodegeneration and cognitive impairment. Our objective was to investigate moderation and mediation pathways among amyloid PET, tau PET, vascular MRI, and structural MRI in a middle‐aged, racially and ethnically diverse sample. In an ongoing stu...
Previous studies identified associations of Alzheimer’s disease (AD) risk primarily in outbred European ancestry (EA) populations. We focused on Ashkenazi Jews (AJs) who descended from a founder population in eastern Europe. We discriminated AJs in the multiethnic Alzheimer’s Disease Genetic Consortium (ADGC) TOPMed imputed GWAS dataset (n = 53,502...
Haptoglobin (HP) is an antioxidant of apolipoprotein E (APOE) – the strongest risk gene for sporadic Alzheimer’s disease (AD). The HP gene has two functional alleles, HP2 and HP1, which contains a two‐exon deletion that changes its protein structure conformation. We hypothesize that this structural variation is associated with AD. To investigate th...
Increasing diversity in genomic studies is critical for defining the genetic architecture of LOAD by improving power to identify variants more prevalent in or specific to a given ancestry. In this study, we constructed and analyzed a multi‐ancestry collection of GWAS datasets in the Alzheimer’s Disease Genetics Consortium (ADGC) to identify novel L...
Genome‐wide association studies (GWAS) of Alzheimer’s disease (AD) have implicated microglia in AD pathogenesis, and microglia is a promising cellular therapeutic target in AD. However, it remains unclear when and how AD genetic risk localizing to microglia contributes to AD pathophysiology. Participants are from two community‐based cohorts (Religi...
The ADSP‐FUS is a National Institute on Aging (NIA) initiative focused on identifying genetic risk and protective variants for Alzheimer Disease (AD) by expanding the ADSP Discovery and Discovery Extension cohorts beyond non‐Hispanic Whites of European Ancestry (NHW‐EA). Given the lack of diversity in the ADSP, the ADSP‐FUS was designed to sequence...
Two‐thirds of Alzheimer’s disease (AD) patients are women and there are well‐established sex differences in the association between APOE and cognitive impairment in AD. However, it is not clear whether sex‐specific cognitive consequences of APOE emerge across all cognitive domains or in a domain‐specific manner. Data were obtained from 38,386 parti...
Alzheimer’s disease (AD) is more prevalent in women than men, and robust evidence shows sex differences in the biological response to the AD neuropathological cascade. However, there is a lack of large‐scale genetic studies on sex‐specific genetic predictors of AD‐related cognitive outcomes. Thus, we sought to elucidate the sex‐specific genetic eti...
Despite large genome‐wide association studies, only ∼30% of the heritability of Alzheimer’s disease is explained. The Alzheimer’s Disease Sequencing Project Whole Exome Sequencing (ADSP WES) has identified millions of genetic variants, over 97% of which are rare (MAF<1%), with 23% appearing in only one person. These rare variants could provide valu...
We completed a large genetic analysis of resilience to cognitive decline in Alzheimer’s Disease (AD) and discovered novel variants, genes, and complex traits associated with better‐than or worse‐than‐expected cognitive performance given an individual’s age, sex, and APOE genotype. Leveraging 15,933 non‐Hispanic white participants across four longit...
Plasma biomarkers for Alzheimer’s disease (AD) are becoming more widely available, with pTau181 emerging as among the most sensitive and specific. There is a lack of data characterizing plasma pTau181 concentration in diverse cohorts and in middle age. The purpose of this study was to examine the association of age, sex/gender, race/ethnicity, APOE...
In the largest Alzheimer disease (AD) genome‐wide association studies to date for African‐Americans (AA; Reitz et al. JAMA 2013; Kunkle at al. JAMA Neurol 2021) we previously identified in addition to APOE several novel susceptibility loci, including ABCA7, API5, RBFOX1 and IGF1R. We followed up these analyses with an increased sample size (2,913 c...
State‐level socioeconomic opportunity disparities have been linked to health outcomes. We examined whether early‐life exposure to state‐level socioeconomic opportunity disparities between women and men influences the pattern of sex/gender inequalities in cognitive decline. Participants were 2,394 U.S.‐born non‐Latinx Black and non‐Latinx White wome...
Asian Americans and Canadians (ASACs) are the fastest growing minority group in the US and Canada. ASACs are under‐sampled in Alzheimer’s disease (AD) research. Culturally appropriate, community‐based approaches to recruit these understudied communities are urgently needed, and in 2021 the Asian Cohort for Alzheimer’s Disease (ACAD) began recruitme...
The amyloid‐tau‐neurodegeneration (AT(N)) research framework uses a biomarker definition of Alzheimer’s disease (AD); neuroimaging has been the in vivo gold standard, but plasma‐based measures are becoming more widely available yet need to be characterized earlier in the life course and AD continuum, as well as in representative samples. Our object...
Alzheimer’s disease (AD), the leading cause of dementia, has an estimated heritability of approximately 70%1. The genetic component of AD has been mainly assessed using genome-wide association studies, which do not capture the risk contributed by rare variants2. Here, we compared the gene-based burden of rare damaging variants in exome sequencing d...
Importance
Neuroimaging studies have documented racial and ethnic disparities in brain health in old age. It remains unclear whether these disparities are apparent in midlife.
Objective
To assess racial and ethnic disparities in magnetic resonance imaging (MRI) markers of cerebrovascular disease and neurodegeneration in midlife and late life.
Des...