Publications by authors named "Richard Mayeux"

333 Publications

Genome-wide association identifies the first risk loci for psychosis in Alzheimer disease.

Mol Psychiatry 2021 Jun 10. Epub 2021 Jun 10.

Neuroscience Department, Istituto di Ricerche Farmacologiche Mario Negri IRCCS, Milan, Italy.

Psychotic symptoms, defined as the occurrence of delusions or hallucinations, are frequent in Alzheimer disease (AD with psychosis, AD + P). AD + P affects ~50% of individuals with AD, identifies a subgroup with poor outcomes, and is associated with a greater degree of cognitive impairment and depressive symptoms, compared to subjects without psychosis (AD - P). Although the estimated heritability of AD + P is 61%, genetic sources of risk are unknown. We report a genome-wide meta-analysis of 12,317 AD subjects, 5445 AD + P. Results showed common genetic variation accounted for a significant portion of heritability. Two loci, one in ENPP6 (rs9994623, O.R. (95%CI) 1.16 (1.10, 1.22), p = 1.26 × 10) and one spanning the 3'-UTR of an alternatively spliced transcript of SUMF1 (rs201109606, O.R. 0.65 (0.56-0.76), p = 3.24 × 10), had genome-wide significant associations with AD + P. Gene-based analysis identified a significant association with APOE, due to the APOE risk haplotype ε4. AD + P demonstrated negative genetic correlations with cognitive and educational attainment and positive genetic correlation with depressive symptoms. We previously observed a negative genetic correlation with schizophrenia; instead, we now found a stronger negative correlation with the related phenotype of bipolar disorder. Analysis of polygenic risk scores supported this genetic correlation and documented a positive genetic correlation with risk variation for AD, beyond the effect of ε4. We also document a small set of SNPs likely to affect risk for AD + P and AD or schizophrenia. These findings provide the first unbiased identification of the association of psychosis in AD with common genetic variation and provide insights into its genetic architecture.
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http://dx.doi.org/10.1038/s41380-021-01152-8DOI Listing
June 2021

Common variants in Alzheimer's disease and risk stratification by polygenic risk scores.

Nat Commun 2021 06 7;12(1):3417. Epub 2021 Jun 7.

Servei de Neurologia, Hospital Universitari i Politècnic La Fe, Valencia, Spain.

Genetic discoveries of Alzheimer's disease are the drivers of our understanding, and together with polygenetic risk stratification can contribute towards planning of feasible and efficient preventive and curative clinical trials. We first perform a large genetic association study by merging all available case-control datasets and by-proxy study results (discovery n = 409,435 and validation size n = 58,190). Here, we add six variants associated with Alzheimer's disease risk (near APP, CHRNE, PRKD3/NDUFAF7, PLCG2 and two exonic variants in the SHARPIN gene). Assessment of the polygenic risk score and stratifying by APOE reveal a 4 to 5.5 years difference in median age at onset of Alzheimer's disease patients in APOE ɛ4 carriers. Because of this study, the underlying mechanisms of APP can be studied to refine the amyloid cascade and the polygenic risk score provides a tool to select individuals at high risk of Alzheimer's disease.
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http://dx.doi.org/10.1038/s41467-021-22491-8DOI Listing
June 2021

Polygenic risk score for Alzheimer's Disease in Caribbean Hispanics.

Ann Neurol 2021 May 26. Epub 2021 May 26.

Taub Institute for Research on Alzheimer's Disease and the Aging Brain, College of Physicians and Surgeons, Columbia University., 630 West 168th Street, New York, NY, 10032.

Objective: Polygenic risk scores (PRSs) assess the individual genetic propensity to a condition by combining sparse information scattered across genetic loci, often displaying small effect sizes. Most PRSs are constructed in European-ancestry populations, limiting their use in other ethnicities. Here we constructed and validated a PRS for late-onset Alzheimer's Disease (LOAD) in Caribbean Hispanics (CH).

Methods: We employed a CH discovery (N=4,312) and independent validation sample (N=1,850) to construct an ancestry-specific PRS ("CH-PRS") and evaluated its performance alone and with other predictors using the area under curve (AUC) and logistic regression (strength of association with LOAD and statistical significance). We tested if CH-PRS predicted conversion to LOAD in a subsample with longitudinal data (N=1,239). We also tested the CH-PRS in an independent replication CH cohort (N=200) and brain autopsy cohort (N=33). Finally, we tested the effect of ancestry on PRS by employing European and African American discovery cohorts to construct alternative PRSs ("EUR-PRS", "AA-PRS").

Results: The full model (LOAD ~ CH-PRS + sex + age + APOE-&ip.eop;4), achieved an AUC=74% (OR =1.51 95%CI=1.36-1.68), raising to >75% in APOE-&ip.eop;4 non-carriers. CH-PRS alone achieved an AUC=72% in the autopsy cohort, raising to AUC=83% in full model. Higher CH-PRS was significantly associated with clinical LOAD in the replication CH cohort (OR=1.61, 95%CI=1.19-2.17) and significantly predicted conversion to LOAD (HR=1.93, CI=1.70-2.20) in the longitudinal subsample. EUR-PRS and AA-PRS reached lower prediction accuracy (AUC=58% and 53%, respectively).

Interpretation: Enriching diversity in genetic studies is critical to provide an effective PRS in profiling LOAD risk across populations. This article is protected by copyright. All rights reserved.
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http://dx.doi.org/10.1002/ana.26131DOI Listing
May 2021

Social network characteristics moderate associations between cortical thickness and cognitive functioning in older adults.

Alzheimers Dement 2021 May 18. Epub 2021 May 18.

Department of Psychology, University of Michigan, Ann Arbor, Michigan, USA.

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 from the Washington Heights-Inwood Columbia Aging Project to examine whether social network characteristics (i.e., total size, spouse/partner, number of children, other relatives, friends) moderate associations between cortical thickness in regions implicated in AD and cognitive performance.

Results: Lower cortical thickness was associated with worse global cognition among individuals with smaller friend networks, but not among individuals with larger friend networks. This pattern of results was most prominent for language and speed/executive functioning.

Discussion: Longitudinal and intervention studies are needed to determine whether these cross-sectional findings reflect a protective effect of later-life friendships for maintaining cognitive performance in the context of poorer brain health.
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http://dx.doi.org/10.1002/alz.12383DOI Listing
May 2021

Association of Life's Simple 7 with incident dementia and its modification by the apolipoprotein E genotype.

Alzheimers Dement 2021 May 2. Epub 2021 May 2.

The Taub Institute for Research in Alzheimer's Disease and the Aging Brain, Columbia University, New York, USA.

Introduction: There is limited and inconsistent reporting on the association between Life's Simple 7 (LS7) and dementia in the elderly population.

Methods: Based on the Washington Heights-Inwood Columbia Aging Project (WHICAP), LS7 scores were estimated to assess cardiovascular health status. Associations between LS7 scores and incident dementia were investigated by Cox proportional hazards models.

Results: Among 1987 subjects, 291 incident cases of dementia were identified over a median follow-up of 5.84 years. Compared with subjects in the poor cardiovascular health group (scores 0 to 5), those in intermediate (6 to 9) and optimal (10 to 14) groups had lower dementia risk, with the hazard ratio (HR; 95% confidence interval) being 0.74 (0.54 to 1.00) and 0.59 (0.38 to 0.91), respectively. These results were significant in apolipoprotein E genotype ε4 (APOE ε4) allele non-carriers but not in carriers.

Discussion: Higher LS7 scores are protective for dementia, especially among the APOE ε4 noncarriers.
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http://dx.doi.org/10.1002/alz.12359DOI Listing
May 2021

Linkage of Alzheimer disease families with Puerto Rican ancestry identifies a chromosome 9 locus.

Neurobiol Aging 2021 Feb 28. Epub 2021 Feb 28.

John P. Hussman Institute for Human Genomics, University of Miami Miller School of Medicine, Miami, FL, USA; Dr. John T. Macdonald Foundation Department of Human Genetics, University of Miami Miller School of Medicine, Miami, FL, USA.

The genetic admixture of Caribbean Hispanics provides an opportunity to discover novel genetic factors in Alzheimer disease (AD). We sought to identify genetic variants for AD through a family-based design using the Puerto Rican (PR) Alzheimer Disease Initiative (PRADI). Whole-genome sequencing (WGS) and parametric linkage analysis were performed for 100 individuals from 23 multiplex PRADI families. Variants were prioritized by minor allele frequency (<0.01), functional potential [combined annotation dependent depletion score (CADD) >10], and co-segregation with AD. Variants were further ranked using an independent PR case-control WGS dataset (PR10/66). A genome-wide significant linkage peak was found in 9p21 with a heterogeneity logarithm of the odds score (HLOD) >5.1, which overlaps with an AD linkage region from two published independent studies. The region harbors C9orf72, but no expanded repeats were observed in the families. Seven variants prioritized by the PRADI families also displayed evidence for association in the PR10/66 (p < 0.05), including a missense variant in UNC13B. Our study demonstrated the importance of family-based design and WGS in genetic study of AD.
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http://dx.doi.org/10.1016/j.neurobiolaging.2021.02.019DOI Listing
February 2021

Automated detection of cerebral microbleeds on T2*-weighted MRI.

Sci Rep 2021 Feb 17;11(1):4004. Epub 2021 Feb 17.

Taub Institute for Research on Alzheimer's Disease and the Aging Brain, Vagelos College of Physicians and Surgeons, Columbia University, New York, NY, USA.

Cerebral microbleeds, observed as small, spherical hypointense regions on gradient echo (GRE) or susceptibility weighted (SWI) magnetic resonance imaging (MRI) sequences, reflect small hemorrhagic infarcts, and are associated with conditions such as vascular dementia, small vessel disease, cerebral amyloid angiopathy, and Alzheimer's disease. The current gold standard for detecting and rating cerebral microbleeds in a research context is visual inspection by trained raters, a process that is both time consuming and subject to poor reliability. We present here a novel method to automate microbleed detection on GRE and SWI images. We demonstrate in a community-based cohort of older adults that the method is highly sensitive (greater than 92% of all microbleeds accurately detected) across both modalities, with reasonable precision (fewer than 20 and 10 false positives per scan on GRE and SWI, respectively). We also demonstrate that the algorithm can be used to identify microbleeds over longitudinal scans with a higher level of sensitivity than visual ratings (50% of longitudinal microbleeds correctly labeled by the algorithm, while manual ratings was 30% or lower). Further, the algorithm identifies the anatomical localization of microbleeds based on brain atlases, and greatly reduces time spent completing visual ratings (43% reduction in visual rating time). Our automatic microbleed detection instrument is ideal for implementation in large-scale studies that include cross-sectional and longitudinal scanning, as well as being capable of performing well across multiple commonly used MRI modalities.
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http://dx.doi.org/10.1038/s41598-021-83607-0DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7889861PMC
February 2021

Plasma p-tau181, p-tau217, and other blood-based Alzheimer's disease biomarkers in a multi-ethnic, community study.

Alzheimers Dement 2021 Feb 13. Epub 2021 Feb 13.

Taub Institute for Research on Alzheimer's Disease and the Aging Brain, Vagelos College of Physicians and Surgeons, Columbia University, New York, New York, USA.

Introduction: Blood-based Alzheimer's disease (AD) biomarkers provide opportunities for community studies and across ethnic groups. We investigated blood biomarker concentrations in the Washington Heights-Inwood Columbia Aging Project (WHICAP), a multi-ethnic community study of aging and dementia.

Methods: We measured plasma amyloid beta (Aβ)40, Aβ42, total tau (t-tau), phosphorylated tau (p-tau)181, and p-tau217, and neurofilament light chain (NfL) in 113 autopsied participants (29% with high AD neuropathological changes) and in 300 clinically evaluated individuals (42% with clinical AD). Receiver operating characteristics were used to evaluate each biomarker. We also investigated biomarkers as predictors of incident clinical AD.

Results: P-tau181, p-tau217, and NfL concentrations were elevated in pathologically and clinically diagnosed AD. Decreased Aβ42/Aβ40 ratio and increased p-tau217 and p-tau181 were associated with subsequent AD diagnosis.

Discussion: Blood-based AD biomarker concentrations are associated with pathological and clinical diagnoses and can predict future development of clinical AD, providing evidence that they can be incorporated into multi-ethnic, community-based studies.
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http://dx.doi.org/10.1002/alz.12301DOI Listing
February 2021

Amyloid PET Imaging in Self-Identified Non-Hispanic Black Participants of the Anti-Amyloid in Asymptomatic Alzheimer's Disease (A4) Study.

Neurology 2021 03 10;96(11):e1491-e1500. Epub 2021 Feb 10.

From the Department of Neurology and Neurological Sciences (K.D.D., V.N., M.D.G., E.C.M.), Stanford University School of Medicine, Palo Alto, CA; Department of Neurology (R.A.S.), Brigham and Women's Hospital, Massachusetts General Hospital, Boston; Department of Neurology, The Taub Institute for Research on Alzheimer's Disease and The Aging Brain, and The Institute for Genomic Medicine (R.M.), Columbia University Medical Center and The New York Presbyterian Hospital, New York; and Vanderbilt Memory and Alzheimer's Center and Vanderbilt Genetics Institute (T.H.), Nashville, TN.

Objective: To examine whether amyloid PET in cognitively normal (CN) individuals screened for the Anti-Amyloid in Asymptomatic Alzheimer's Disease (A4) study differed across self-identified non-Hispanic White and Black (NHW and NHB) groups.

Methods: We examined 3,689 NHW and 144 NHB participants who passed initial screening for the A4 study and underwent amyloid PET. The effect of race on amyloid PET was examined using logistic (dichotomous groups) and linear (continuous values) regression controlling for age, sex, and number of ε4 and ε2 alleles. Associations between amyloid and genetically determined ancestry (reflecting African, South Asian, East Asian, American, and European populations) were tested within the NHB group. Potential interactions with were assessed.

Results: NHB participants had lower rates of amyloid positivity and lower continuous amyloid levels compared to NHW participants. This race effect on amyloid was strongest in the ε4 group. Within NHB participants, those with a lower percentage of African ancestry had higher amyloid. A greater proportion of NHB participants did not pass initial screening compared to NHW participants, suggesting potential sources of bias related to race in the A4 PET data.

Conclusion: Reduced amyloid was observed in self-identified NHB participants who passed initial eligibility criteria for the A4 study. This work stresses the importance of investigating AD biomarkers in ancestrally diverse samples as well as the need for careful consideration regarding study eligibility criteria in AD prevention trials.
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http://dx.doi.org/10.1212/WNL.0000000000011599DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8032379PMC
March 2021

Assessment of Leisure Time Physical Activity and Brain Health in a Multiethnic Cohort of Older Adults.

JAMA Netw Open 2020 11 2;3(11):e2026506. Epub 2020 Nov 2.

Taub Institute for Research in Alzheimer's Disease and the Aging Brain, Columbia University, New York, New York.

Importance: Results from longitudinal studies suggest that regular leisure time physical activity (LTPA) is associated with reduced risk of dementia or Alzheimer disease. Data on the association between LTPA and brain magnetic resonance imaging (MRI) measures remain scarce and inconsistent.

Objective: To examine the association of LTPA and MRI-assessed brain aging measures in a multiethnic elderly population.

Design, Setting, And Participants: This cross-sectional study included 1443 older (≥65 years) adults without dementia who were participants of the Washington/Hamilton Heights-Inwood Columbia Aging Project study. LTPA, from self-reported questionnaire, was calculated as metabolic equivalent of energy expenditure. Both moderate to vigorous LTPA, assessed as meeting Physical Activity Guidelines for Americans (≥150 minutes/week) or not, and light-intensity LTPA were also examined.

Exposures: LTPA.

Main Outcomes And Measures: Primary outcomes included total brain volume (TBV), cortical thickness, and white matter hyperintensity volume, all derived from MRI scans with established methods and adjusted for intracranial volume when necessary. We examined the association of LTPA with these imaging markers using regression models adjusted for demographic, clinical, and vascular risk factors.

Results: The 1443 participants of the study had a mean (SD) age of 77.2 (6.4) years; 921 (63.8%) were women; 27.0%, 34.4%, and 36.3% were non-Hispanic White, non-Hispanic African American, and Hispanic individuals, respectively; and 27.3% carried the apolipoprotein E (APOE) ɛ4 allele. Compared with the LTPA of nonactive older adults, those with the most LTPA had larger (in cm3) TBV (β [SE], 13.17 [4.42] cm3; P = .003; P for trend = .006) and greater cortical thickness (β [SE], 0.016 [0.008] mm; P = .05; P for trend = .03). The effect size comparing the highest LTPA level with the nonactive group was equivalent to approximately 3 to 4 years of aging (β for 1 year older, -3.06 and -0.005 for TBV and cortical thickness, respectively). A dose-response association was found and even the lowest LTPA level had benefits (eg, TBV: β [SE], 9.03 [4.26] cm3; P = .03) compared with the nonactive group. Meeting Physical Activity Guidelines for Americans (TBV: β [SE], 18.82 [5.14] cm3; P < .001) and light-intensity LTPA (TBV: β [SE], 9.26 [4.29] cm3; P = .03) were also associated with larger brain measures. The association between LTPA and TBV was moderated by race/ethnicity, sex, and APOE status, but generally existed in all subgroups. The results remained similar after excluding participants with mild cognitive impairment.

Conclusions And Relevance: In this study, more physical activity was associated with larger brain volume in older adults. Longitudinal studies are warranted to explore the potential role of physical activity in brain health among older individuals.
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http://dx.doi.org/10.1001/jamanetworkopen.2020.26506DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7677758PMC
November 2020

Novel Alzheimer Disease Risk Loci and Pathways in African American Individuals Using the African Genome Resources Panel: A Meta-analysis.

JAMA Neurol 2021 Jan;78(1):102-113

Taub Institute for Research on Alzheimer's Disease and the Aging Brain, Columbia University, New York, New York.

Importance: Compared with non-Hispanic White individuals, African American individuals from the same community are approximately twice as likely to develop Alzheimer disease. Despite this disparity, the largest Alzheimer disease genome-wide association studies to date have been conducted in non-Hispanic White individuals. In the largest association analyses of Alzheimer disease in African American individuals, ABCA7, TREM2, and an intergenic locus at 5q35 were previously implicated.

Objective: To identify additional risk loci in African American individuals by increasing the sample size and using the African Genome Resource panel.

Design, Setting, And Participants: This genome-wide association meta-analysis used case-control and family-based data sets from the Alzheimer Disease Genetics Consortium. There were multiple recruitment sites throughout the United States that included individuals with Alzheimer disease and controls of African American ancestry. Analysis began October 2018 and ended September 2019.

Main Outcomes And Measures: Diagnosis of Alzheimer disease.

Results: A total of 2784 individuals with Alzheimer disease (1944 female [69.8%]) and 5222 controls (3743 female [71.7%]) were analyzed (mean [SD] age at last evaluation, 74.2 [13.6] years). Associations with 4 novel common loci centered near the intracellular glycoprotein trafficking gene EDEM1 (3p26; P = 8.9 × 10-7), near the immune response gene ALCAM (3q13; P = 9.3 × 10-7), within GPC6 (13q31; P = 4.1 × 10-7), a gene critical for recruitment of glutamatergic receptors to the neuronal membrane, and within VRK3 (19q13.33; P = 3.5 × 10-7), a gene involved in glutamate neurotoxicity, were identified. In addition, several loci associated with rare variants, including a genome-wide significant intergenic locus near IGF1R at 15q26 (P = 1.7 × 10-9) and 6 additional loci with suggestive significance (P ≤ 5 × 10-7) such as API5 at 11p12 (P = 8.8 × 10-8) and RBFOX1 at 16p13 (P = 5.4 × 10-7) were identified. Gene expression data from brain tissue demonstrate association of ALCAM, ARAP1, GPC6, and RBFOX1 with brain β-amyloid load. Of 25 known loci associated with Alzheimer disease in non-Hispanic White individuals, only APOE, ABCA7, TREM2, BIN1, CD2AP, FERMT2, and WWOX were implicated at a nominal significance level or stronger in African American individuals. Pathway analyses strongly support the notion that immunity, lipid processing, and intracellular trafficking pathways underlying Alzheimer disease in African American individuals overlap with those observed in non-Hispanic White individuals. A new pathway emerging from these analyses is the kidney system, suggesting a novel mechanism for Alzheimer disease that needs further exploration.

Conclusions And Relevance: While the major pathways involved in Alzheimer disease etiology in African American individuals are similar to those in non-Hispanic White individuals, the disease-associated loci within these pathways differ.
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http://dx.doi.org/10.1001/jamaneurol.2020.3536DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7573798PMC
January 2021

Reproducibility of serum cytokines in an elderly population.

Immun Ageing 2020 13;17:29. Epub 2020 Oct 13.

Taub Institute for Research in Alzheimer's Disease and the Aging Brain, Columbia University, New York, NY USA.

Background: It is important to assess the temporal reproducibility of circulating cytokines for their utility in epidemiological studies. However, existing evidence is limited and inconsistent, especially for the elderly population.

Methods: Sixty-five elderly (mean age = 77.89 ± 6.14 years) subjects were randomly selected from an existing prospective cohort study. Levels of 41 cytokines in 195 serum samples, collected at three separate visits that were up to 15.26 years apart, were measured by the Luminex technology. The temporal reproducibility of cytokines was estimated by the intraclass correlation coefficient (ICC) calculated using a mixed-effects model. In addition, data analyses were stratified by the median (4.49 years) of time intervals across sample collection. Sensitivity analyses were performed when excluding subjects with undetectable samples.

Results: A total of 23 cytokines were detectable in more than 60% of samples. Fair to good (ICC = 0.40 to 0.75) and excellent (ICC > 0.75) reproducibility was found in 10 (Eotaxin, VEGF, FGF-2, G-CSF, MDC, GM-CSF, TGFα, IP-10, MIP-1β, IL-1RA) and 5 (GRO, IFNγ, IL-17, PDGF-AA, IL-4) cytokines, respectively. The results were not changed dramatically in the stratification and sensitivity analyses.

Conclusions: Serum levels of the selected 15 cytokines measured with Luminex technology displayed fair to excellent within-person temporal reproducibility among elderly population.
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http://dx.doi.org/10.1186/s12979-020-00201-0DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7556943PMC
October 2020

APOE 4 and resting-state functional connectivity in racially/ethnically diverse older adults.

Alzheimers Dement (Amst) 2020 22;12(1):e12094. Epub 2020 Sep 22.

Taub Institute for Research on Alzheimer's Disease and the Aging Brain College of Physicians and Surgeons Columbia University New York New York USA.

Introduction: Numerous neuroimaging studies demonstrated an association between the apolipoprotein E (APOE) 4 allele and resting-state functional connectivity (rsFC) of regions within the default mode network (DMN), both in healthy populations and patients with AD. It remains unclear whether the APOE 4 allele differentially affects the brain's functional network architecture across race/ethnicity.

Methods: We investigated rsFC within DMN subsystems in 170 APOE 4 carriers compared to 387 APOE 4 non-carriers across three major racial/ethnic groups, including non-Hispanic Whites (n = 166), non-Hispanic Blacks (n = 185), and Hispanics (n = 206) from the Washington Heights-Inwood Columbia Aging Project.

Results: Compared to APOE 4 non-carriers, APOE 4 carriers had lower rsFC in temporal DMN, but only in non-Hispanic Whites. Non-Hispanic Black and Hispanic APOE 4 carriers had slightly higher or similar rsFC compared with non-Hispanic White APOE 4 non-carriers.

Discussion: These findings suggest that APOE 4 modulates DMN rsFC differently in non-Hispanic Whites compared with non-Hispanic Blacks and Hispanics.
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http://dx.doi.org/10.1002/dad2.12094DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7508460PMC
September 2020

Analysis of brain region-specific co-expression networks reveals clustering of established and novel genes associated with Alzheimer disease.

Alzheimers Res Ther 2020 09 2;12(1):103. Epub 2020 Sep 2.

Bioinformatics Graduate Program, Boston University, Boston, MA, USA.

Background: Identifying and understanding the functional role of genetic risk factors for Alzheimer disease (AD) has been complicated by the variability of genetic influences across brain regions and confounding with age-related neurodegeneration.

Methods: A gene co-expression network was constructed using data obtained from the Allen Brain Atlas for multiple brain regions (cerebral cortex, cerebellum, and brain stem) in six individuals. Gene network analyses were seeded with 52 reproducible (i.e., established) AD (RAD) genes. Genome-wide association study summary data were integrated with the gene co-expression results and phenotypic information (i.e., memory and aging-related outcomes) from gene knockout studies in Drosophila to generate rankings for other genes that may have a role in AD.

Results: We found that co-expression of the RAD genes is strongest in the cortical regions where neurodegeneration due to AD is most severe. There was significant evidence for two novel AD-related genes including EPS8 (FDR p = 8.77 × 10) and HSPA2 (FDR p = 0.245).

Conclusions: Our findings indicate that AD-related risk factors are potentially associated with brain region-specific effects on gene expression that can be detected using a gene network approach.
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http://dx.doi.org/10.1186/s13195-020-00674-7DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7469336PMC
September 2020

Genetic variants and functional pathways associated with resilience to Alzheimer's disease.

Brain 2020 08;143(8):2561-2575

Department of Neurology, Columbia University, New York, NY, USA.

Approximately 30% of older adults exhibit the neuropathological features of Alzheimer's disease without signs of cognitive impairment. Yet, little is known about the genetic factors that allow these potentially resilient individuals to remain cognitively unimpaired in the face of substantial neuropathology. We performed a large, genome-wide association study (GWAS) of two previously validated metrics of cognitive resilience quantified using a latent variable modelling approach and representing better-than-predicted cognitive performance for a given level of neuropathology. Data were harmonized across 5108 participants from a clinical trial of Alzheimer's disease and three longitudinal cohort studies of cognitive ageing. All analyses were run across all participants and repeated restricting the sample to individuals with unimpaired cognition to identify variants at the earliest stages of disease. As expected, all resilience metrics were genetically correlated with cognitive performance and education attainment traits (P-values < 2.5 × 10-20), and we observed novel correlations with neuropsychiatric conditions (P-values < 7.9 × 10-4). Notably, neither resilience metric was genetically correlated with clinical Alzheimer's disease (P-values > 0.42) nor associated with APOE (P-values > 0.13). In single variant analyses, we observed a genome-wide significant locus among participants with unimpaired cognition on chromosome 18 upstream of ATP8B1 (index single nucleotide polymorphism rs2571244, minor allele frequency = 0.08, P = 2.3 × 10-8). The top variant at this locus (rs2571244) was significantly associated with methylation in prefrontal cortex tissue at multiple CpG sites, including one just upstream of ATPB81 (cg19596477; P = 2 × 10-13). Overall, this comprehensive genetic analysis of resilience implicates a putative role of vascular risk, metabolism, and mental health in protection from the cognitive consequences of neuropathology, while also providing evidence for a novel resilience gene along the bile acid metabolism pathway. Furthermore, the genetic architecture of resilience appears to be distinct from that of clinical Alzheimer's disease, suggesting that a shift in focus to molecular contributors to resilience may identify novel pathways for therapeutic targets.
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http://dx.doi.org/10.1093/brain/awaa209DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7447518PMC
August 2020

Education differentially contributes to cognitive reserve across racial/ethnic groups.

Alzheimers Dement 2021 01 22;17(1):70-80. Epub 2020 Aug 22.

Taub Institute for Research on Alzheimer's Disease and the Aging Brain, College of Physicians and Surgeons, Columbia University, New York, New York, USA.

Introduction: We examined whether educational attainment differentially contributes to cognitive reserve (CR) across race/ethnicity.

Methods: A total of 1553 non-Hispanic Whites (Whites), non-Hispanic Blacks (Blacks), and Hispanics in the Washington Heights-Inwood Columbia Aging Project (WHICAP) completed structural magnetic resonance imaging. Mixture growth curve modeling was used to examine whether the effect of brain integrity indicators (hippocampal volume, cortical thickness, and white matter hyperintensity [WMH] volumes) on memory and language trajectories was modified by education across racial/ethnic groups.

Results: Higher educational attainment attenuated the negative impact of WMH burden on memory (β = -0.03; 99% CI: -0.071, -0.002) and language decline (β = -0.024; 99% CI:- 0.044, -0.004), as well as the impact of cortical thinning on level of language performance for Whites, but not for Blacks or Hispanics.

Discussion: Educational attainment does not contribute to CR similarly across racial/ethnic groups.
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http://dx.doi.org/10.1002/alz.12176DOI Listing
January 2021

A quantitative trait rare variant nonparametric linkage method with application to age-at-onset of Alzheimer's disease.

Eur J Hum Genet 2020 12 1;28(12):1734-1742. Epub 2020 Aug 1.

Center for Statistical Genetics, Baylor College of Medicine, Houston, TX, 77030, USA.

To analyze pedigrees with quantitative trait (QT) and sequence data, we developed a rare variant (RV) quantitative nonparametric linkage (QNPL) method, which evaluates sharing of minor alleles. RV-QNPL has greater power than the traditional QNPL that tests for excess sharing of minor and major alleles. RV-QNPL is robust to population substructure and admixture, locus heterogeneity, and inclusion of nonpathogenic variants and can be readily applied outside of coding regions. When QNPL was used to analyze common variants, it often led to loci mapping to large intervals, e.g., >40 Mb. In contrast, when RVs are analyzed, regions are well defined, e.g., a gene. Using simulation studies, we demonstrate that RV-QNPL is substantially more powerful than applying traditional QNPL methods to analyze RVs. RV-QNPL was also applied to analyze age-at-onset (AAO) data for 107 late-onset Alzheimer's disease (LOAD) pedigrees of Caribbean Hispanic and European ancestry with whole-genome sequence data. When AAO of AD was analyzed regardless of APOE ε4 status, suggestive linkage (LOD = 2.4) was observed with RVs in KNDC1 and nominally significant linkage (p < 0.05) was observed with RVs in LOAD genes ABCA7 and IQCK. When AAO of AD was analyzed for APOE ε4 positive family members, nominally significant linkage was observed with RVs in APOE, while when AAO of AD was analyzed for APOE ε4 negative family members, nominal significance was observed for IQCK and ADAMTS1. RV-QNPL provides a powerful resource to analyze QTs in families to elucidate their genetic etiology.
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http://dx.doi.org/10.1038/s41431-020-0703-zDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7785016PMC
December 2020

Synonymous variants associated with Alzheimer disease in multiplex families.

Neurol Genet 2020 Aug 8;6(4):e450. Epub 2020 Jun 8.

The Taub Institute for Research on Alzheimer's Disease and the Aging Brain (M.E.A., B.V., R.L., P.L.J., R.M., I.S.-M., C.R.); The Gertrude H. Sergievsky Center (M.T., D.R.-D., R.L., R.M., C.R.); Department of Neurology (P.L.J., R.M., C.R.); Department of Epidemiology (R.M., C.R.); Department of Psychiatry (R.M.), Columbia University, New York; Department of Pathology and Cell Biology (M.E.A., I.S.-M.), Columbia University, New York; Rush Alzheimer's Disease Center (D.A.B.); Department of Neurological Sciences (D.A.B.); Department of Pathology (D.A.B.), Rush University Medical Center, Chicago, IL; Center for Innovation in Brain Science , Departments of Pharmacology and Neurology , University of Arizona College of Medicine (M.T.), Tucson; Department of Medicine (R.L.), College of Physicians and Surgeons, Columbia University, New York, NY; School of Medicine (M.M.), Mother and Teacher Pontifical Catholic University, Santiago, Dominican Republic; and The Krembil Centre for Neuroinformatics (D.F.), Centre for Addiction and Mental Health, Toronto, Ontario, Canada.

Objective: Synonymous variants can lead to disease; nevertheless, the majority of sequencing studies conducted in Alzheimer disease (AD) only assessed coding variation.

Methods: To detect synonymous variants modulating AD risk, we conducted a whole-genome sequencing study on 67 Caribbean Hispanic (CH) families multiply affected by AD. Identified disease-associated variants were further assessed in an independent cohort of CHs, expression quantitative trait locus (eQTL) data, brain autopsy data, and functional experiments.

Results: Rare synonymous variants in 4 genes ( and ) segregated with AD status in multiplex families and had a significantly higher frequency in these families compared with reference populations of similar ancestry. In comparison to subjects without dementia, expression of (β = 0.53, = 0.006) and (β = 0.50, = 0.02) was increased, and expression of (β = -0.70, = 0.02) decreased in individuals with AD at death. In line with this finding, increased expression of (β = 0.26 ± 0.08, = 4.9E-4) and decreased expression of (β = -0.60 ± 0.12, = 5.5E-7) were related to brain amyloid load ( = 0.0025). expression was associated with burden of TDP43 pathology (β = 0.58 ± 0.17, = 5.9E-4). Using eQTL data, the variant was in linkage disequilibrium with variants modulating expression levels (top single nucleotide polymorphism: rs11000035, = 4.85E-6, D' = 1.0). Using minigene splicing assays, the and variants affected splicing efficiency.

Conclusions: These findings suggest that , and possibly , which are involved in synaptic function, the glutamatergic system, and innate immunity, contribute to AD etiology. In addition, this study supports the notion that synonymous variants contribute to AD risk and that comprehensive scrutinization of this type of genetic variation is warranted and critical.
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http://dx.doi.org/10.1212/NXG.0000000000000450DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7323483PMC
August 2020

Sex-dependent autosomal effects on clinical progression of Alzheimer's disease.

Brain 2020 07;143(7):2272-2280

Department of Radiology, University of California, San Diego, USA.

Sex differences in the manifestations of Alzheimer's disease are under intense investigation. Despite the emerging importance of polygenic predictions for Alzheimer's disease, sex-dependent polygenic effects have not been demonstrated. Here, using a sex crossover analysis, we show that sex-dependent autosomal genetic effects on Alzheimer's disease can be revealed by characterizing disease progress via the hazard function. We first performed sex-stratified genome-wide associations, and then applied derived sex-dependent weights to two independent cohorts. Relative to sex-mismatched scores, sex-matched polygenic hazard scores showed significantly stronger associations with age-at-disease-onset, clinical progression, amyloid deposition, neurofibrillary tangles, and composite neuropathological scores, independent of apolipoprotein E. Models without using hazard weights, i.e. polygenic risk scores, showed lower predictive power than polygenic hazard scores with no evidence for sex differences. Our results indicate that revealing sex-dependent genetic architecture requires the consideration of temporal processes of Alzheimer's disease. This has strong implications not only for the genetic underpinning of Alzheimer's disease but also for how we estimate sex-dependent polygenic effects for clinical use.
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http://dx.doi.org/10.1093/brain/awaa164DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7364740PMC
July 2020

Genome-wide association study of rate of cognitive decline in Alzheimer's disease patients identifies novel genes and pathways.

Alzheimers Dement 2020 08 23;16(8):1134-1145. Epub 2020 Jun 23.

Division of Genetics, Department of Medicine, Brigham and Women's Hospital, Boston, Massachusetts, USA.

Introduction: Variability exists in the disease trajectories of Alzheimer's disease (AD) patients. We performed a genome-wide association study to examine rate of cognitive decline (ROD) in patients with AD.

Methods: We tested for interactions between genetic variants and time since diagnosis to predict the ROD of a composite cognitive score in 3946 AD cases and performed pathway analysis on the top genes.

Results: Suggestive associations (P < 1.0 × 10 ) were observed on chromosome 15 in DNA polymerase-γ (rs3176205, P = 1.11 × 10 ), chromosome 7 (rs60465337,P = 4.06 × 10 ) in contactin-associated protein-2, in RP11-384F7.1 on chromosome 3 (rs28853947, P = 5.93 × 10 ), family with sequence similarity 214 member-A on chromosome 15 (rs2899492, P = 5.94 × 10 ), and intergenic regions on chromosomes 16 (rs4949142, P = 4.02 × 10 ) and 4 (rs1304013, P = 7.73 × 10 ). Significant pathways involving neuronal development and function, apoptosis, memory, and inflammation were identified.

Discussion: Pathways related to AD, intelligence, and neurological function determine AD progression, while previously identified AD risk variants, including the apolipoprotein (APOE) ε4 and ε2 variants, do not have a major impact.
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http://dx.doi.org/10.1002/alz.12106DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7924136PMC
August 2020

Association Between Common Variants in RBFOX1, an RNA-Binding Protein, and Brain Amyloidosis in Early and Preclinical Alzheimer Disease.

JAMA Neurol 2020 Oct;77(10):1288-1298

Department of Neurology, Columbia University Medical Center, New York, New York.

Importance: Genetic studies of Alzheimer disease have focused on the clinical or pathologic diagnosis as the primary outcome, but little is known about the genetic basis of the preclinical phase of the disease.

Objective: To examine the underlying genetic basis for brain amyloidosis in the preclinical phase of Alzheimer disease.

Design, Setting, And Participants: In the first stage of this genetic association study, a meta-analysis was conducted using genetic and imaging data acquired from 6 multicenter cohort studies of healthy older individuals between 1994 and 2019: the Anti-Amyloid Treatment in Asymptomatic Alzheimer Disease Study, the Berkeley Aging Cohort Study, the Wisconsin Registry for Alzheimer's Prevention, the Biomarkers of Cognitive Decline Among Normal Individuals cohort, the Baltimore Longitudinal Study of Aging, and the Alzheimer Disease Neuroimaging Initiative, which included Alzheimer disease and mild cognitive impairment. The second stage was designed to validate genetic observations using pathologic and clinical data from the Religious Orders Study and Rush Memory and Aging Project. Participants older than 50 years with amyloid positron emission tomographic (PET) imaging data and DNA from the 6 cohorts were included. The largest cohort, the Anti-Amyloid Treatment in Asymptomatic Alzheimer Disease Study (n = 3154), was the PET screening cohort used for a secondary prevention trial designed to slow cognitive decline associated with brain amyloidosis. Six smaller, longitudinal cohort studies (n = 1160) provided additional amyloid PET imaging data with existing genetic data. The present study was conducted from March 29, 2019, to February 19, 2020.

Main Outcomes And Measures: A genome-wide association study of PET imaging amyloid levels.

Results: From the 4314 analyzed participants (age, 52-96 years; 2478 participants [57%] were women), a novel locus for amyloidosis was noted within RBFOX1 (β = 0.61, P = 3 × 10-9) in addition to APOE. The RBFOX1 protein localized around plaques, and reduced expression of RBFOX1 was correlated with higher amyloid-β burden (β = -0.008, P = .002) and worse cognition (β = 0.007, P = .006) during life in the Religious Orders Study and Rush Memory and Aging Project cohort.

Conclusions And Relevance: RBFOX1 encodes a neuronal RNA-binding protein known to be expressed in neuronal tissues and may play a role in neuronal development. The findings of this study suggest that RBFOX1 is a novel locus that may be involved in the pathogenesis of Alzheimer disease.
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http://dx.doi.org/10.1001/jamaneurol.2020.1760DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7309575PMC
October 2020

Differences in plasma metabolites related to Alzheimer's disease, ε4 status, and ethnicity.

Alzheimers Dement (N Y) 2020 6;6(1):e12025. Epub 2020 May 6.

College of Physicians and Surgeons Taub Institute for Research on Alzheimer's Disease and the Aging Brain Columbia University New York New York.

Introduction: We investigated metabolites in plasma to capture systemic biochemical changes associated with Alzheimer's disease (AD).

Methods: Metabolites in plasma were measured in 59 AD cases and 60 healthy participants of African American (AA), Caribbean Hispanic (CH), and non-Hispanic white (NHW) ancestry using untargeted liquid-chromatography-based ultra-high-resolution mass spectrometry. Metabolite differences between AD and healthy, ethnic groups and apolipoprotein E gene () ε4 status were analyzed. Untargeted network analysis identified pathways enriched in AD-associated metabolites.

Results: A total of 5929 annotated metabolites were measured. Partial least squares discriminant analysis (PLS-DA) inferred that AD clustered separately from healthy controls (area under the curve [AUC] = 0.9816); discriminating pathways included glycerophospholipid, sphingolipid, and non-essential amino acid (alanine, aspartate, glutamate) metabolism. Metabolic features in AA clustered differently from CH and NHW (AUC = 0.9275), and differed between ε4 carriers and non-carriers (AUC = 0.9972).

Discussion: Metabolites, specifically lipids, were associated with AD, ε4, and ethnic group. Metabolite profiling can identify perturbed AD pathways, but genetic and ancestral background need to be considered.
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http://dx.doi.org/10.1002/trc2.12025DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7201178PMC
May 2020

Long-term exposure to air pollution and trajectories of cognitive decline among older adults.

Neurology 2020 04 8;94(17):e1782-e1792. Epub 2020 Apr 8.

From the Department of Epidemiology (E.R.K., G.A.W., N.R.J.), Brown University School of Public Health, Providence, RI; Departments of Neurology (E.R.K., A.K.B., N.S., M.S.V.E.) and Psychiatry (R.M.) and Gertrude H. Sergievsky Center (N.S., R.M., J.J.M., M.S.V.E.), Vagelos College of Physicians and Surgeons, Department of Epidemiology, Mailman School of Public Health (E.R.K., A.K.B., N.S., R.M., J.J.M., M.S.V.E.), and Taub Institute for Research on Alzheimer Disease and the Aging Brain (N.S., R.M., J.J.M.), Columbia University, New York, NY; Departments of Environmental and Occupational Health Sciences, Medicine, and Epidemiology (J.D.K.), University of Washington, Seattle; and Departments of Neurology, Public Health Sciences, and Human Genetics (R.L.S.), Evelyn McKnight Brain Institute, Miller School of Medicine, University of Miami, FL.

Objective: To evaluate the association between long-term exposure to ambient air pollution and cognitive decline in older adults residing in an urban area.

Methods: Data for this study were obtained from 2 prospective cohorts of residents in the northern Manhattan area of New York City: the Washington Heights-Inwood Community Aging Project (WHICAP) and the Northern Manhattan Study (NOMAS). Participants of both cohorts received in-depth neuropsychological testing at enrollment and during follow-up. In each cohort, we used inverse probability weighted linear mixed models to evaluate the cross-sectional and longitudinal associations between markers of average residential ambient air pollution (nitrogen dioxide [NO], fine particulate matter [PM], and respirable particulate matter [PM]) levels in the year prior to enrollment and measures of global and domain-specific cognition, adjusting for sociodemographic factors, temporal trends, and censoring.

Results: Among 5,330 participants in WHICAP, an increase in NO was associated with a 0.22 SD lower global cognitive score at enrollment (95% confidence interval [CI], -0.30, -0.14) and 0.06 SD (95% CI, -0.08, -0.04) more rapid decline in cognitive scores between visits. Results were similar for PM and PM and across functional cognitive domains. We found no evidence of an association between pollution and cognitive function in NOMAS.

Conclusion: WHICAP participants living in areas with higher levels of ambient air pollutants have lower cognitive scores at enrollment and more rapid rates of cognitive decline over time. In NOMAS, a smaller cohort with fewer repeat measurements, we found no statistically significant associations. These results add to the evidence regarding the adverse effect of air pollution on cognitive aging and brain health.
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http://dx.doi.org/10.1212/WNL.0000000000009314DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7274848PMC
April 2020

Preparing a neurology department for SARS-CoV-2 (COVID-19): Early experiences at Columbia University Irving Medical Center and the New York Presbyterian Hospital in New York City.

Neurology 2020 05 6;94(20):886-891. Epub 2020 Apr 6.

From the Department of Neurology (G.W., R.M., J.C., S.A., J.W., R.L., M.B., S.P., C.U., K.R., O.W., A.B.L., L.L., K.T.T.), Neurological Institute, Columbia University Irving Medical Center; and New York Presbyterian Hospital (G.W., R.M., J.C., S.A., J.W., E.A., P.P., R.L., M.B., S.P., C.U., K.R., O.W., A.B.L., L.L., K.T.T.), New York, NY.

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http://dx.doi.org/10.1212/WNL.0000000000009519DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7963356PMC
May 2020

Exceptionally low likelihood of Alzheimer's dementia in APOE2 homozygotes from a 5,000-person neuropathological study.

Nat Commun 2020 02 3;11(1):667. Epub 2020 Feb 3.

Department of Epidemiology, University of Washington, 1959 NE Pacific Street, Seattle, WA, 98195, USA.

Each additional copy of the apolipoprotein E4 (APOE4) allele is associated with a higher risk of Alzheimer's dementia, while the APOE2 allele is associated with a lower risk of Alzheimer's dementia, it is not yet known whether APOE2 homozygotes have a particularly low risk. We generated Alzheimer's dementia odds ratios and other findings in more than 5,000 clinically characterized and neuropathologically characterized Alzheimer's dementia cases and controls. APOE2/2 was associated with a low Alzheimer's dementia odds ratios compared to APOE2/3 and 3/3, and an exceptionally low odds ratio compared to APOE4/4, and the impact of APOE2 and APOE4 gene dose was significantly greater in the neuropathologically confirmed group than in more than 24,000 neuropathologically unconfirmed cases and controls. Finding and targeting the factors by which APOE and its variants influence Alzheimer's disease could have a major impact on the understanding, treatment and prevention of the disease.
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http://dx.doi.org/10.1038/s41467-019-14279-8DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6997393PMC
February 2020

Long-term exposure to ambient air pollution, APOE-ε4 status, and cognitive decline in a cohort of older adults in northern Manhattan.

Environ Int 2020 03 8;136:105440. Epub 2020 Jan 8.

Department of Epidemiology, Brown University School of Public Health, Providence, RI, USA.

Background: There is mounting evidence that long-term exposure to air pollution is related to accelerated cognitive decline in aging populations. Factors that influence individual susceptibility remain largely unknown, but may involve the apolipoprotein E genotype E4 (APOE-ε4) allele.

Objectives: We assessed whether the association between long-term exposure to ambient air pollution and cognitive decline differed by APOE-ε4 status and cognitive risk factors.

Methods: The Washington Heights Inwood Community Aging Project (WHICAP) is a prospective study of aging and dementia. Neuropsychological testing and medical examinations occur every 18-24 months. We used mixed-effects models to evaluate whether the association between markers of ambient air pollution (nitrogen dioxide [NO]), fine [PM], and coarse [PM] particulate matter) and the rate of decline in global and domain-specific cognition differed across strata defined by APOE-ε4 genotypes and cognitive risk factors, adjusting for sociodemographic factors and temporal trends.

Results: Among 4821 participants with an average of 6 years follow-up, higher concentrations of ambient air pollution were associated with more rapid cognitive decline. This association was more pronounced among APOE-ε4 carriers (p < 0.001). A one interquartile range increase in NO was associated with an additional decline of 0.09 standard deviations (SD) (95%CI -0.1, -0.06) in global cognition across biennial visits among APOE-ε4 positive individuals and a 0.07 SD (95%CI -0.09, -0.05) decline among APOE-ε4 negative individuals. Results for PM PM and cognitive domains were similar. The association between air pollutants and rate of cognitive decline also varied across strata of race-ethnicity with the association strongest among White non-Hispanic participants.

Conclusions: These results add to the body of evidence on the adverse impact of ambient air pollution on cognitive aging and brain health and provide new insights into the genetic and behavioral factors that may impact individual susceptibility.
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http://dx.doi.org/10.1016/j.envint.2019.105440DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7024003PMC
March 2020

Parental History of Dementia Is Associated with Increased Small Vessel Cerebrovascular Disease.

J Gerontol A Biol Sci Med Sci 2020 10;75(11):2156-2161

Taub Institute for Research on Alzheimer's Disease and the Aging Brain, College of Physicians and Surgeons, Columbia University, New York, New York.

Background: Small vessel cerebrovascular dysfunction that manifests on magnetic resonance imaging (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 strong heritable component; the examination of the extent to which parental history of dementia is associated with cerebrovascular disease could provide insight into the aggregation of AD and cerebrovascular disease.

Methods: This study included 481 community-dwelling older adults (mean age = 74.07 ± 5.81; 56% women) with available MRI scans. Participants were classified as having a parental history of dementia or having no parental history based on self-report. Total WMH values were calculated and compared between the two groups with general linear models, adjusting for relevant covariates. We also compared WMH volume between those with a reported sibling history of dementia and those without.

Results: One hundred twelve participants reported having a parental history of dementia and 369 reported no parental history. Those with parental history had greater total WMH volume than those without (F = 4.17, p = .042, partial η 2 = 0.009). Results were strongest for those with maternal versus paternal history (F = 2.43, p = .089, partial η 2 = 0.010 vs <0.001) and among Hispanic (F = 5.57, p = .020, partial η 2 = 0.038) and non-Hispanic White participants (F = 4.17, p = .042, partial η 2 = 0.009). Those with reported sibling history of dementia did not differ from those without.

Conclusions: Older adults with parental, particularly maternal, history of dementia have increased WMH. The results highlight the possibility that cerebrovascular changes are a core feature of AD, as WMH severity and parental history aggregate together.
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http://dx.doi.org/10.1093/gerona/glz291DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7566406PMC
October 2020

Intact global cognitive and olfactory ability predicts lack of transition to dementia.

Alzheimers Dement 2020 02 4;16(2):326-334. Epub 2020 Jan 4.

Taub Institute for Research on Alzheimer's Disease and the Aging Brain, College of Physicians and Surgeons, Columbia University, New York, NY, USA.

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 Identification Test, which includes the 12-item Brief Smell Identification Test (B-SIT). Data from 749 participants followed up for 4 years were analyzed.

Results: In covariate-adjusted survival analyses, impairment on the Blessed Orientation Memory Concentration Test and B-SIT each predicted dementia (n = 109), primarily Alzheimer's disease (n = 101). Among participants with intact olfactory (B-SIT ≥ 11/12 correct) and cognitive (Blessed Orientation Memory Concentration Test ≤ 5/28 incorrect) ability, 3.4% (4/117) transitioned to dementia during follow-up with no transitions in the 70-75 and 81-83 years age group quartiles.

Discussion: Odor identification testing adds value to global cognitive testing, and together can identify individuals who rarely transition to dementia, thereby avoiding unnecessary diagnostic investigation.
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http://dx.doi.org/10.1016/j.jalz.2019.08.200DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7007828PMC
February 2020

Secular trends in cognitive trajectories of diverse older adults.

Alzheimers Dement 2019 12 28;15(12):1576-1587. Epub 2019 Oct 28.

Taub Institute for Research on Alzheimer's Disease and the Aging Brain, Department of Neurology, College of Physicians and Surgeons, Columbia University, New York, NY, USA. Electronic address:

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 subdomains in two successive racially/ethnically and educationally diverse birth cohorts of a prospective cohort study.

Results: Later birth year was associated with higher initial cognitive levels for Whites and Blacks, but not Hispanics. Later birth year was also associated with less rapid rate of decline in all three racial/ethnic groups. More years of education, higher childhood socioeconomic status, and, to a smaller extent, greater cardiovascular disease burden accounted for higher intercepts in the later-born cohort, but did not account for attenuated slope of cognitive decline.

Discussion: Later birth year is related to a slower rate of age-related decline in some cognitive domains in some racial/ethnic groups. Our analyses suggest that racial/ethnic and social inequalities are part of the mechanisms driving secular trends in cognitive aging and dementia.
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http://dx.doi.org/10.1016/j.jalz.2019.06.4944DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6925643PMC
December 2019