publications

 

CADRE members lead and participate in US and international research consortia.  Our goal is to enhance understanding of the genetic architecture of this disease and to accelerate the search for new therapeutic targets. Our work is inclusive of populations that historically have not been represented in large genetic studies.   

Featured publication

 

FIGURE 3 Admixture mapping Manhattan plot of meta‐analysis African American datasets. Genomic coordinates are displayed along the X‐axis, with each color representing a different chromosome. Negative logarithm of the association p‐value for the ancestral allele is displayed on the Y‐axis. The red dotted horizontal line represents the significance threshold after multiple testing correction, that is, those dots falling above the line are considered study‐wise significant.

Rajabli F, Tosto G, Hamilton-Nelson KL, et al. Admixture mapping identifies novel Alzheimer’s disease risk regions in African Americans. Alzheimers Dement. 2023

Background: This study used admixture mapping to prioritize the genetic regions associated with Alzheimer’s disease (AD) in African American (AA) individuals, followed by ancestry-aware regression analysis to fine-map the prioritized regions.

Methods: We analyzed 10,271 individuals from 17 different AA datasets. We performed admixture mapping and meta-analyzed the results. We then used regression analysis, adjusting for local ancestry main effects and interactions with genotype, to refine the regions identified from admixture mapping. Finally, we leveraged in silico annotation and differential gene expression data to prioritize AD-related variants and genes.

Results: Admixture mapping identified two genome-wide significant loci on chromosomes 17p13.2 (p = 2.2 × 10-5 ) and 18q21.33 (p = 1.2 × 10-5 ). Our fine mapping of the chromosome 17p13.2 and 18q21.33 regions revealed several interesting genes such as the MINK1, KIF1C, and BCL2.

Discussion: Our ancestry-aware regression approach showed that AA individuals have a lower risk of AD if they inherited African ancestry admixture block at the 17p13.2 locus.

Highlights: We identified two genome-wide significant admixture mapping signals: on chromosomes 17p13.2 and 18q21.33, which are novel in African American (AA) populations. Our ancestry-aware regression approach showed that AA individuals have a lower risk of Alzheimer’s disease (AD) if they inherited African ancestry admixture block at the 17p13.2 locus. We found that the overall proportion of African ancestry does not differ between the cases and controls that suggest African genetic ancestry alone is not likely to explain the AD prevalence difference between AA and non-Hispanic White populations.

Publications

CADRE publications for 2023 

Bai H et al. A haptoglobin (HP) structural variant alters the effect of APOE alleles on Alzheimer’s disease. Alzheimers Dement. 2023; PMID: 37051669

Celis K et al. Neuropsychiatric features in a multi-ethnic population with Alzheimer disease and mild cognitive impairment. Int J Geriatr Psychiatry. 2023; PMID: 37655494

Chung J et al. Alzheimer’s disease heterogeneity explained by polygenic risk scores derived from brain transcriptomic profiles. Alz Dement. 2023; PMID: 37166019

Felsky D et al. The Caribbean-Hispanic Alzheimer’s disease brain transcriptome reveals ancestry-specific disease mechanisms. Neurobiol Dis. 2023; PMID: 36462719

Gao XR et al. Explainable machine learning aggregates polygenic risk scores and electronic health records for Alzheimer’s disease prediction. Sci Rep. 2023; PMID: 36624143

Kang M et al. A genome-wide search for pleiotropy in more than 100,000 harmonized longitudinal cognitive domain scores. Mol Neurodegener. 2023

Le Guen Y, Raulin AC, Logue MW, et al. Association of African Ancestry-Specific APOE Missense Variant R145C With Risk of Alzheimer Disease. JAMA. 2023

Li D, Farrell JJ, Mez J, et al. Novel loci for Alzheimer’s disease identified by a genome-wide association study in Ashkenazi Jews [published online ahead of print, 2023 Jun 1]. Alzheimers Dement. 2023

Li Y-J et al. Identification of novel genes for age-at-onset of Alzheimer’s disease by combining quantitative and survival trait analyses. Alzheimers Dement. 2023; PMID: 36738287

Logue MW, Dasgupta S, Farrer LA. Genetics of Alzheimer’s Disease in the African American Population. J Clin Med. 2023

Osterman MD et al. “Founder population-specific weights yield improvements in performance of polygenic risk scores for Alzheimer’s disease in the Midwestern Amish.” HGG Adv. 2023; PMID: 37742071

Prough MB et al. “Visuospatial and Verbal Memory Differences in Amish Individuals With Alzheimer Disease and Related Dementias.” Alzheimer Dis Assoc Disord. 2023; PMID: 37561946

Qiao M et al. Polygenic risk score penetrance & recurrence risk in familial Alzheimer disease. Ann Clin Transl Neurol. 2023; PMID: 36946865

Reitz C et al. A global view of the genetic basis of Alzheimer disease. Nat Rev Neurol. 2023; PMID: 37024647

Sherva R et al. African ancestry GWAS of dementia in a large military cohort identifies significant risk loci. Mol Psychiatry. 2023; MID: 36543923

Walters S, Contreras AG, Eissman JM, et al. Associations of Sex, Race, and Apolipoprotein E Alleles With Multiple Domains of Cognition Among Older Adults. JAMA Neurol. 2023

Wang H et al. “The role of structural variations in Alzheimer’s disease and other neurodegenerative diseases.” Front Aging Neurosci. 2023; PMID: 36846102

Zaman A et al. “Psychometric approaches to defining cognitive phenotypes in the Old Order Amish.” Int J Geriatr Psychiatry. 2023; PMID: 36929524

Zhang W et al. Distinct CSF biomarker-associated DNA methylation in Alzheimer’s disease and cognitively normal subjects. Alzheimers Res Ther. 2023; PMID: 37038196

Zhang X et al. Midlife lipid and glucose levels are associated with Alzheimer’s disease. Alzheimers Dement. 2023; PMID: 35319157

 

CADRE publications for 2022

Bellenguez C, Küçükali F, Jansen IE, et al. “New insights into the genetic etiology of Alzheimer’s disease and related dementias.” Nat Genet. 2022

Chung J, Das A, Sun X, et al. Genome-wide association and multi-omics studies identify MGMT as a novel risk gene for Alzheimer’s disease among women.” [published online ahead of print, 2022 Jun 30]. Alzheimers Dement. 2022

Eissman et al. “Sex differences in the genetic architecture of cognitive resilience to Alzheimer’s disease.” Brain. 2022; PMID: 35552371

Gardner OK et al. “Genetic architecture of RNA editing regulation in Alzheimer’s disease across diverse ancestral populations.” Hum Mol Genet. 2022; PMID: 35383839

Godrich D, et al. “Neuropathological lesions and their contribution to dementia and cognitive impairment in a heterogeneous clinical population.” Alzheimers Dement. 2022; PMID: 35142102

Heath L et al. “Manifestations of Alzheimer’s disease genetic risk in the blood are evident in a multiomic analysis in healthy adults aged 18 to 90.” Sci Rep. 2022; PMID: 35413975

Holstege et al. “Exome sequencing identified rare damaging variants in ATP8B4 and ABCA1 as risk factors for Alzhiemer’s disease.” Nature Genetics. 2022; PMID: 36411364

Jin B, Capra JA, Benchek P, et al. An association test of the spatial distribution of rare missense variants within protein structures identifies Alzheimer’s disease-related patterns. Genome Res. 2022

Jun GR, You Y, Zhu C, et al. “Protein phosphatase 2A and complement component 4 are linked to the protective effect of APOE ɛ2 for Alzheimer’s disease.” Alzheimers Dement. 2022

Kizil C et al. “Admixture Mapping of Alzheimer’s disease in Caribbean Hispanics identifies a new locus on 22q13.1.” Mol Psychiatry. 2022; PMID: 35365809

Nuytemans K et al. “Identifying differential regulatory control of APOE e4 on African versus European haplotypes as potential therapeutic targets.” Alzheimers Dement. 2022; PMID: 34978147

Olayinka OA, O’Neill NK, Farrer LA, Wang G, Zhang X. “Molecular Quantitative Trait Locus Mapping in Human Complex Diseases.” Curr Protoc. 2022

Osterman MD et al. “The genetic architecture of Alzheimer disease risk in the Ohio and Indiana Amish.” HGG Adv. 2022; PMID: 35599847

Panitch R, Hu J, Xia W, et al. “Blood and brain transcriptome analysis reveals APOE genotype-mediated and immune-related pathways involved in Alzheimer disease.” Alzheimers Res Ther. 2022

Rajabli F, Beecham GW, Hendrie HC, et al. “A locus at 19q13.31 significantly reduces the ApoE ε4 risk for Alzheimer’s Disease in African Ancestry.” PLoS Genet. 2022

Rajabli F et al. “Admixture mapping identifies novel Alzheimer’s disease risk regions in African Americans.” Alzheimers Dement. 2022; PMID: 36539198

Ramos J et al. “Genetic variants in the SHISA6 gene are associated with delayed cognitive impairment in two family datasets.” Alzheimers Dement. 2022; PMID: 35490390

Vardarajan BN et al. “Progranulin mutations in clinical and neuropathological Alzheimer’s disease.” Alzheimers Dement. 2022; PMID: 35258170

2021 CADRE Collaborations:  

Amlie-Wolf A, Kuksa PP, Lee CY, Mlynarski E, Leung YY, Wang LS. Using INFERNO to Infer the Molecular Mechanisms Underlying Noncoding Genetic Associations. Methods Mol Biol. 2021;2254:73-91. doi:10.1007/978-1-0716-1158-6_6

Griswold AJ, Celis K, Bussies PL, et al. Increased APOE ε4 expression is associated with the difference in Alzheimer’s disease risk from diverse ancestral backgrounds. Alzheimers Dement. 2021

Marca-Ysabel MV, Rajabli F, Cornejo-Olivas M, et al. Dissecting the role of Amerindian genetic ancestry and the ApoE ε4 allele on Alzheimer disease in an admixed Peruvian population. Neurobiol Aging. 2021

Panitch R, Hu J, Chung J, et al. Integrative brain transcriptome analysis links complement component 4 and HSPA2 to the APOE ε2 protective effect in Alzheimer disease. Mol Psychiatry. 2021

Patel D, Zhang X, Farrell JJ, Lunetta KL, Farrer LA. Set-Based Rare Variant Expression Quantitative Trait Loci in Blood and Brain from Alzheimer Disease Study Participants. Genes (Basel). 2021;12(3):419. Published 2021 Mar 15. doi:10.3390/genes12030419

Patel N, Bush WS. Modeling transcriptional regulation using gene regulatory networks based on multi-omics data sources. BMC Bioinformatics. 2021

Rajabli F, Feliciano-Astacio BE, Cukier HN, et al. Linkage of Alzheimer disease families with Puerto Rican ancestry identifies a chromosome 9 locus. Neurobiol Aging. 2021

Xue D, Bush WS, Renton AE, et al. Large-scale sequencing studies expand the known genetic architecture of Alzheimer’s disease. Alzheimers Dement (Amst). 2021

 

2021 CADRE Investigators’ other AD Publications:

Andrews et al. Causal Associations Between Modifiable Risk Factors and the Alzheimer’s Phenome. Ann Neurol 2021

Avila et al. Education differentially contributes to cognitive reserve across racial/ethnic groups Alzheimers Dement 2021

Ayodele et al. Early-Onset Alzheimer’s Disease: What Is Missing in Research? Curr Neurol Neurosci Rep 2021

Brickman et al. Plasma p-tau181, p-tau217, and other blood-based Alzheimer’s disease biomarkers in a multi-ethnic, community study.  Alzheimers Dement 2021

Damotte et al. Plasma amyloid b levels are driven by genetic variants near APOE, BACE1, APP, PSEN2: A genome-wide association study in over 12,000 non-demented participants. Alzheimers Dement 2021

DeMichele-Sweet et al. Genome-wide association identifies the first risk loci for psychosis in Alzheimer disease. Mol Psychiatry 2021  

Deters et al. Amyloid PET Imaging in Self-Identified Non-Hispanic Black Participants of the Anti-Amyloid in Asymptomatic Alzheimer’s Disease (A4) Study. Neurology 2021

Guo et al. Association of Life’s Simple 7 with incident dementia and its modification by the apolipoprotein E genotype. Alzheimers Dement 2021

Hong et al. In vitro amplification of pathogenic tau conserves disease-specific bioactive characteristics. Acta Neuropathol 2021

Laverde-Paz et al. Derivation of stem cell line UMi028-A-2 containing a CRISPR/Cas9 induced Alzheimer’s disease risk variant p.S1038C in the TCC3 gene. Stem Cell Res 2021

Lagomarsino et al.  Stem cell-derived neurons reflect features of protein networks, neuropathology, and cognitive outcome of their aged human donors. Neuron 2021

Pillai et al. TNFRSF1B Gene Variants and Related Soluble TNFR2 Levels Impact Resilience in Alzheimer’s Disease.  Front Aging Neurosci 2021

Ramos et al. Lower Levels of Education Are Associated with Cognitive Impairment in the Old Order Amish. J Alzheimers Dis 2021

Sariya et al. Polygenic Risk Score for Alzheimer’s Disease in Caribbean Hispanics. Ann Neurol. 2021;90(3):366-376. doi:10.1002/ana.26131

Sharifian et al. Social network characteristics moderate associations between cortical thickness and cognitive functioning in older adults.  Alzheimers Dement 2021

Zhang et al. Sex-specific DNA methylation differences in Alzheimer’s disease pathology.  Acta neruopathol Commun 2021

 

2019 – 2020 CADRE Collaborations:

Amlie-Wolf A, Tang M, Way J, et al. Inferring the Molecular Mechanisms of Noncoding Alzheimer’s Disease-Associated Genetic Variants. J Alzheimers Dis. 2019

Bis JC, Jian X, Kunkle BW, et al. Whole exome sequencing study identifies novel rare and common Alzheimer’s-Associated variants involved in immune response and transcriptional regulation [published correction appears in Mol Psychiatry. 2019 Oct 21;:]. Mol Psychiatry. 2020

Bush WS, Wheeler N, Beaulieu-Jones B, Darabos C. Packaging Biocomputing Software to Maximize Distribution and Reuse. Pac Symp Biocomput. 2020

Chen HH, Petty LE, Bush W, Naj AC, Below JE. GWAS and Beyond: Using Omics Approaches to Interpret SNP Associations. Curr Genet Med Rep. 2019

Dumitrescu L, Barnes LL, Thambisetty M, et al. Sex differences in the genetic predictors of Alzheimer’s pathology. Brain. 2019

Ma Y, Jun GR, Zhang X, et al. Analysis of Whole-Exome Sequencing Data for Alzheimer Disease Stratified by APOE Genotype. JAMA Neurol. 2019

Naj AC, Lin H, Vardarajan BN, et al. Quality control and integration of genotypes from two calling pipelines for whole genome sequence data in the Alzheimer’s disease sequencing project. Genomics. 2019

Tang ZZ, Sliwoski GR, Chen G, et al. PSCAN: Spatial scan tests guided by protein structures improve complex disease gene discovery and signal variant detection. Genome Biol. 2020

Wheeler NR, Benchek P, Kunkle BW, et al. Hadoop and PySpark for reproducibility and scalability of genomic sequencing studies. Pac Symp Biocomput. 2020

Zhang L, Silva TC, Young JI, et al. Epigenome-wide meta-analysis of DNA methylation differences in prefrontal cortex implicates the immune processes in Alzheimer’s disease. Nat Commun. 2020

Zhang X, Zhu C, Beecham G, et al. A rare missense variant of CASP7 is associated with familial late-onset Alzheimer’s disease. Alzheimers Dement. 2019

 

2020 CADRE Investigators’ other AD Publications:

Ajnakina et al. Interplay Between Socioeconomic Markers and Polygenic Predisposition on Timing of Dementia DiagnosisJ Am Geriatr Soc 2020

Andrews et al.  Association Between Alcohol Consumption and Alzheimer’s Disease: A Mendelian Randomization Study.  Alzheimers Dement 2020

Bussies et al.  Use of Local Genetic Ancestry to Assess TOMM40-523′ and Risk for Alzhiemer DiseaseNeurol Genet 2020

Fan et al.  Sex-dependent Autosomal Effects on Clinical Progression of Alzheimer’s Disease. Brain 2020

Griswold et al.  Immune and Inflammatory Pathways Implicated by Whole Blood Transcriptomic Analysis in a Diverse Ancestry Alzheimer’s Disease Cohort.  J Alzheimers Dis 2020

He et al.  Transmission of tauopathy strains is independent of their isoform composition.  Nat Commun.  2020

Kunkle et al.  Novel Alzheimer Disease Risk Loci and Pathways in African American Individuals Using the African Genome Resources Panel: A Meta-analysis.   JAMA Neurol 2020

Lancour et al.  Analysis of brain region-specific co-expression networks reveals clustering of established and novel genes associated with Alzheimer disease.  Alzheimers Res Ther 2020

Pathak et al. Two-stage Bayesian GWAS of 9576 Individuals Identifies SNP Regions that are Targeted by miRNAs Inversely Expressed in Alzheimer’s and Cancer.   Alzheimers Dement 2020

Raghavan et al.  Association Between Common Variants in RBFOX1, an RNA-Binding Protein, and Brain Amyloidosis in Early and Preclinical Alzheimer Disease.   JAMA Neurol 2020

Reiman et al.  Exceptionally low likelihood of Alzheimer’s dementia in APOE2 homozygotes from a 5,000-person neuropathological study.   Nat Commun. 2020

Strickland et al. MAPT Haplotype-stratified GWAS Reveals Differential Association for AD Risk Variants.   Alzheimers Dement 2020

Van Der Meer et al.  Association of Copy Number Variation of the 15q11.2 BP1-BP2 Region With Cortical and Subcortical Morphology and Cognition.  JAMA Psychiatry 2020

Vance et al.  Failure to Detect Synergy Between Variants in Transferrin and Hemochromatosis and Alzheimer’s Disease in Large Cohort.  Neurobiol Aging 2020

Vardarajan et al.  Differences in Plasma Metabolites Related to Alzheimer’s Disease, APOE e4 Status, and Ethnicity.   Alzheimers Dement 2020

Vergouw et al.  LRP10 variants in progressive supranuclear palsy. Neurobiol Aging 2020

Wang et al.  Circulating Vitamin D Levels and Alzheimer’s Disease: A Mendelian Randomization Study in the IGAP and UK Biobank.  J Alzheimers Dis 2020

Weitzman et al.  Insoluble Tau From Human FTDP-17 Cases Exhibit Unique Transmission Properties in Vivo J Neuropathol Exp Neurol 2020

 

2019 CADRE Investigators’ other AD Publications: 

Avila et al. Sex/gender differences in cognitive trajectories vary as a function of race/ethnicity. Alzheimers Dement. 2019

Baker et al. Gene-based analysis in HRC imputed genome wide association data indentifies three novel genes for Alzheimer’s disease. PLoS  One 2019 

Choi et al. APOE Promoter Polymorphism-219T/G is an Effect Modifier of the Influence of APOE e4 on Alzheimer’s Disease Risk in a Multiracial Sample. J Clin Med. 2019

Devanand et al.  Intact global cognitive and olfactory ability predicts lack of transition to dementia. Alzheimers Dement. 2019

Feliciano-Astacio et al. The Puerto Rico Alzheimer Disease Initiative (PRADI): A Multisource Ascertainment Approach. Front Genet. 2019

Gardner et al. RNA editing alterations in a multi-ethnic Alzheimer disease cohort converge on immune and endocytic molecular pathways. Hum Mol Genet. 2019

Goldschmidt-Clermont et al. Time for Well-Powered Controlled Prospective Studies to Test a Causal Role for Herpes Viruses in Alzheimer’s Disease Using Antiherpetic Drugs. J Gerontol A  Biol Sci Med Sci. 2019

Gutierrez et al. Brain arterial dilatation and the risk of Alzheimer’s disease. Alzheimers Dement. 2019

Kunkle et al. Genetic meta-analysis of diagnosed Alzheimer’s disease identifies new risk loci and implicates Ab, tau, immunity and lipid processing. Nat Genet. 2019

Leung et al. VCPA: genomic variant calling pipeline and data management tool for Alzheimer’s Disease Sequencing Project. Bioinformatics. 2019

Ma et al. CpG-related SNPs in the MS4A region have a dose-dependent effect on risk of late-onset Alzheimer disease. Aging Cell. 2019

Ogino et al. Current and past leisure time physical activity in relation to risk of Alzheimer’s disease in older adults. Alzheimers Dement. 2019

Patel et al. Association of Rare Coding Mutations With Alzheimer Disease and Other Dementias Among Adults of European Ancestry. JAMA Netw Open. 2019

Sariya et al. Rare Variants Imputation in Admixed Populations: Comparison Across Reference Panels and Bioinformatics Tools. Front Genet. 2019

Stamm et al. Parental History of Dementia Is Associated with Increased Small Vessel Cerebrovascular Disease. J Gerontol A Biol Sci Med Sci. 2019

Tosto et al. Association of Variants in PINX1 and TREM2 With Late-Onset Alzheimer Disease. JAMA Neurol. 2019

Vonk et al. Education Moderates the Relation Between APOE e4 and Memory in Nondemented Non-Hispanic Black Older Adults. J Alzheimers Dis. 2019

Vonk et al. Secular trends in cognitive trajectories of diverse older adults. Alzheimers Dement. 2019

Zhang et al. Genetic and epigenetic study of an Alzheimer’s disease family with monozygotic triplets. Brain. 2019

 

2017 – 2018 CADRE Collaborations:

Beecham GW, Vardarajan B, Blue E, et al. Rare genetic variation implicated in non-Hispanic white families with Alzheimer disease. Neurol Genet. 2018

Butkiewicz M, Blue EE, Leung YY, et al. Functional annotation of genomic variants in studies of late-onset Alzheimer’s disease. Bioinformatics. 2018

Rajabli F, Feliciano BE, Celis K, et al. Ancestral origin of ApoE ε4 Alzheimer disease risk in Puerto Rican and African American populations. PLoS Genet. 2018

Sims R, van der Lee SJ, Naj AC, et al. Rare coding variants in PLCG2, ABI3, and TREM2 implicate microglial-mediated innate immunity in Alzheimer’s disease. Nat Genet. 2017

Vardarajan BN, Barral S, Jaworski J, et al. Whole genome sequencing of Caribbean Hispanic families with late-onset Alzheimer’s disease. Ann Clin Transl Neurol. 2018

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Administratively housed at Case Western Reserve University with support from all participating academic institutions

Department of Population and Quantitative Health Sciences

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Cleveland, Ohio 44106