Richard Mayeux

Columbia University | CU · Department of Neurology

Introduction: Prior research suggests that the strength of association between Alzheimer's disease (AD) pathology and lower cognitive performance is influenced by modifiable psychosocial factors, such as social network size. However, little is known about distinct social relationship types. Methods: The current cross-sectional study used data fr...

INTRODUCTION: The National Institute on Aging Late-Onset Alzheimers Disease Family Based Study (NIA-LOAD FBS) was established to study the genetic etiology of Alzheimers disease (AD). METHODS: Recruitment focused on families with two living affected siblings and a third first degree relative similar in age with or without dementia. Uniform assessme...

A number of collaborators were not acknowledged for their contribution to this published article. The acknowledgements that were missing in this published article can now be found in the associated correction.

The Alzheimer's Disease Sequencing Project (ADSP) undertook whole exome sequencing in 5,740 late-onset Alzheimer disease (AD) cases and 5,096 cognitively normal controls primarily of European ancestry (EA), among whom 218 cases and 177 controls were Caribbean Hispanic (CH). An age-, sex- and APOE based risk score and family history were used to sel...

Background: Small vessel cerebrovascular dysfunction that manifests on MRI as white matter hyperintensities(WMH), is linked to increased risk and progression of Alzheimer's disease(AD), but there is considerable debate about whether it represents a core feature of the disease. Parental history of dementia is a risk factor for AD, suggesting a stro...

Age at onset of Alzheimer's disease is highly variable, and its modifiers (genetic or environmental) could act through epigenetic changes, such as DNA methylation at CpG sites. DNA methylation is also linked to ageing-the strongest Alzheimer's disease risk factor. DNA methylation age can be calculated using age-related CpGs and might reflect biolog...

Introduction: The associations between self-reported current and past leisure time physical activity (LTPA) and Alzheimer's disease (AD) incidence were determined using data from the multiethnic Washington/Hamilton Heights-Inwood Columbia Aging Project (WHICAP) study. Methods: The metabolic equivalent of LTPA energy expenditure was calculated fo...

To analyze family-based whole-genome sequence (WGS) data for complex traits, we developed a rare variant (RV) non-parametric linkage (NPL) analysis method, which has advantages over association methods. The RV-NPL differs from the NPL in that RVs are analyzed, and allele sharing among affected relative-pairs is estimated only for minor alleles. Ana...

Introduction: The present study sought to determine whether cognitive trajectories differ between men and women across and within racial/ethnic groups. Methods: Participants were 5258 non-Hispanic White (NHW), Black, and Hispanic men and women in the Washington/Hamilton Heights-Inwood Columbia Aging Project who were administered neuropsychologic...

Introduction: This study aimed to determine if later birth year influences trajectory of age-related cognitive decline across racial/ethnic groups and to test whether years of school, childhood socioeconomic status, and cardiovascular disease burden explain such secular trends. Methods: We compared cognitive trajectories of global cognition and...

Introduction: Odor identification deficits characterize Alzheimer's disease and other dementias. We examined if intact performance on brief cognitive and odor identification tests predicts lack of transition to dementia. Methods: In an urban community, 1037 older adults without dementia completed the 40-item University of Pennsylvania Smell Iden...

Objectives: Greater depressive symptoms are associated with cognitive decline in older adulthood, but it is not clear what underlying factors drive this association. One behavioral pathway through which depressive symptoms may negatively influence cognitive functioning is through activity engagement. Prior research has independently linked greater...

Variants in the APOE gene region may explain ethnic differences in the association of Alzheimer’s disease (AD) with ε4. Ethnic differences in allele frequencies for three APOE region SNPs (single nucleotide polymorphisms) were identified and tested for association in 19,398 East Asians (EastA), including Koreans and Japanese, 15,836 European ancest...

Educational attainment is associated with cognition among older adults, but this association is complex and not well understood. While associated with better cognition among healthy adults, more education predicts faster decline in older adults with cognitive impairment. Education may influence cognitive functioning through mechanisms involving bra...

Importance Previous genome-wide association studies of common variants identified associations for Alzheimer disease (AD) loci evident only among individuals with particular APOE alleles. Objective To identify APOE genotype-dependent associations with infrequent and rare variants using whole-exome sequencing. Design, Setting, and Participants The...

Importance Genetic causes of late-onset Alzheimer disease (LOAD) are not completely explained by known genetic loci. Whole-exome and whole-genome sequencing can improve the understanding of the causes of LOAD and provide initial steps required to identify potential therapeutic targets. Objective To identify the genetic loci for LOAD across differe...

CpG‐related single nucleotide polymorphisms (CGS) have the potential to perturb DNA methylation; however, their effects on Alzheimer disease (AD) risk have not been evaluated systematically. We conducted a genome‐wide association study using a sliding‐window approach to measure the combined effects of CGSes on AD risk in a discovery sample of 24 Eu...

Sex differences in the manifestations of Alzheimer's disease (AD) are under intense investigations. Despite the emerging importance of polygenic predictions for AD, the sex-dependent polygenic effects have not been demonstrated. Here, using a sex crossover analysis, we show that sex-dependent autosomal genetic effects on AD can be revealed by chara...

Background Imputation has become a standard approach in genome-wide association studies (GWAS) to infer in silico untyped markers. Although feasibility for common variants imputation is well established, we aimed to assess rare and ultra-rare variants’ imputation in an admixed Caribbean Hispanic population (CH). Methods We evaluated imputation acc...

Objective To determine the putative protective relationship of educational attainment on Alzheimer disease (AD) risk using Mendelian randomization and to test the hypothesis that by using genetic regions surrounding individually associated single nucleotide polymorphisms (SNPs) as the instrumental variable, we can identify genes that contribute to...

Importance Some of the unexplained heritability of Alzheimer disease (AD) may be due to rare variants whose effects are not captured in genome-wide association studies because very large samples are needed to observe statistically significant associations. Objective To identify genetic variants associated with AD risk using a nonstatistical approa...

Introduction: We tested the hypothesis that brain arterial dilatation increases the risk of Alzheimer's dementia (AD). Methods: We studied dementia-free participants in the Washington Heights-Inwood Columbia Aging Project who had a brain MRI and post-MRI dementia adjudication. We measured the axial T2-proton density diameters of the intracranial...

Cardiovascular (CV)- and lifestyle-associated risk factors (RFs) are increasingly recognized as important for Alzheimer’s disease (AD) pathogenesis. Beyond the ε4 allele of apolipoprotein E (APOE), comparatively little is known about whether CV-associated genes also increase risk for AD. Using large genome-wide association studies and validated too...

Objective This investigation aimed at examining whether circulating inflammatory biomarkers C-reactive protein (CRP), interleukin-6 (IL6), and alpha 1-antichymotrypsin (ACT) were related to cerebrovascular disease (CVD) assessed by MRI. Methods The study included nondemented elderly participants of a community-based, multiethnic cohort, who receiv...

Background Imputation has become a standard approach in genome-wide association studies (GWAS) to infer in silico untyped markers. Although feasibility for common variants imputation is well established, we aimed to assess rare and ultra-rare variants’ imputation in an admixed Caribbean Hispanic population (CH). Methods We evaluated imputation acc...

Objective: To identify genetic variation influencing late-onset Alzheimer disease (LOAD), we used a large data set of non-Hispanic white (NHW) extended families multiply-affected by LOAD by performing whole genome sequencing (WGS). Methods: As part of the Alzheimer Disease Sequencing Project, WGS data were generated for 197 NHW participants from...

Introduction: The genetic architecture of Alzheimer's disease (AD) is only partially understood. Methods: We conducted an association study for AD using whole sequence data from 507 genetically enriched AD cases (i.e., cases having close relatives affected by AD) and 4917 cognitively healthy controls of European ancestry (EA) and 172 enriched ca...

Age-related changes in memory are not uniform, even in the absence of dementia. Characterization of non-disease associated cognitive changes is crucial to gain a more complete understanding of brain aging. Episodic memory was investigated in 13,037 ethnically diverse elderly (ages 72 to 85 years) with two to 15 years of follow-up, and with known de...

Definition of episodic memory domain across study cohorts. BA corresponds to the episodic memory scores at baseline evaluation; LE corresponds to episodic memory scores at last evaluation. (DOCX)

Episodic memory trajectories (EMTs) stratified by sex across all study cohorts. A) only non-cognitively impaired subjects at baseline; B) all subjects at baseline. The X-axis correspond to the time of follow-up in years (ranging from 0 to 15); the Y-axis correspond to the residual episodic memory score (ranging from -6 to 4) after being adjusted fo...

Episodic memory trajectories (EMTs) stratified by ethnicity. A) only non-cognitively impaired subjects at baseline; B) all subjects at baseline. The X-axis correspond to the time of follow-up in years (ranging from 0 to 15); the Y-axis correspond to the residual episodic memory score (ranging from -6 to 4) after being adjusted for sex, age, educati...

Characteristics of the original study cohorts before exclusion criteria. (DOCX)

Episodic memory trajectories (EMTs) distribution under the two analyses models (NCI and AI baseline samples). (DOCX)

Parameters estimates from post-hoc linear mixed models using the trajectories from LCMM stratified by sex and ethnicity for all subjects at baseline. (DOCX)

Parameters estimates from post-hoc linear mixed models using the trajectories from LCMM for all subjects at baseline evaluation. (DOCX)

The incidence and prevalence of Alzheimer's disease (AD) dementia are higher among Caribbean Hispanics than among non-Hispanic Whites. The causes of this health disparity remain elusive, partially because of the relative limited capacity for biomedical research in the developing countries that comprise Caribbean Latin America. To begin to address t...

Subjective cognitive decline may reflect a dementia prodrome or modifiable risk factor such as sleep disturbance. What is the association between sleep and subjective cognitive decline? Cross‐sectional design, from two studies of older adults: the WHICAP in the USA and the HELIAD in Greece. A total of 1,576 WHICAP and 1,456 HELIAD participants, wit...

The G4C2-repeat expansion in C9orf72 is the most common known cause of amyotrophic lateral sclerosis and frontotemporal dementia. The high phenotypic heterogeneity of C9orf72 patients includes a wide range in age of onset, modifiers of which are largely unknown. Age of onset could be influenced by environmental and genetic factors both of which may...

Objective: To develop, replicate, and validate an MRI-based quantitative measure of both cerebrovascular and neurodegeneration in Alzheimer disease (AD) for clinical and potentially research purposes. Methods: We used data from a cross-sectional and longitudinal community-based study of Medicare-eligible residents in northern Manhattan followed...

Introduction ¹⁸F-fluorodeoxyglucose (FDG) positron emission tomography (PET) is commonly used to estimate neuronal injury in Alzheimer's disease (AD). Here, we evaluate the utility of dynamic PET measures of perfusion using ¹¹C-Pittsburgh compound B (PiB) to estimate neuronal injury in comparison to FDG PET. Methods FDG, early frames of PiB images...

Background: Elevated total tau (tTau), 181-phosphorylated phosphorylated tau (pTau), and low amyloid-β42 (Aβ42) in cerebrospinal fluid (CSF) represent a diagnostic biomarker for Alzheimer's disease (AD). Objective: The goal was to determine the overall accuracy of CSF Aβ42, tTau, pTau, and the Aβ42/total tau index (ATI) in a non-research, clinic...

Systematic epistasis analyses in multifactorial disorders are an important step to better characterize complex genetic risk structures. We conducted a hypothesis-free sex-stratified genome-wide screening for epistasis contributing to Alzheimer's disease (AD) susceptibility. We identified a statistical epistasis signal between the single nucleotide...

Verbal fluency tasks are generally thought to be mediated by frontal brain regions for letter fluency and temporal regions for category fluency. This idea, however, is primarily based on lesion studies and adapted versions of the fluency tasks in functional neuroimaging, without fundamental evidence from structural neuroimaging in healthy individua...

Multipoint linkage analysis is an important approach for localizing disease‐associated loci in pedigrees. Linkage analysis, however, is sensitive to misspecification of marker allele frequencies. Pedigrees from recently admixed populations are particularly susceptible to this problem because of the challenge of accurately accounting for population...

Objective The genetic bases of Alzheimer's disease remain uncertain. An international effort to fully articulate genetic risks and protective factors is underway with the hope of identifying potential therapeutic targets and preventive strategies. The goal here was to identify and characterize the frequency and impact of rare and ultra‐rare variant...

Table S2. Genes in which LoF variants reach P < 0.05 in Fisher's Exact Test between cases and controls.

Table S1. Broad Phenotypes of the external controls in study.