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
Listed by year
2023 CADRE Collaborations:
Chemparathy A, Guen YL, Chen S, et al. APOE loss-of-function variants: Compatible with longevity and associated with resistance to Alzheimer’s Disease pathology. Preprint. medRxiv. 2023
Kang M, Ang TFA, Devine SA, 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
Lee WP, Choi SH, Shea MG, et al. Association of Common and Rare Variants with Alzheimer’s Disease in over 13,000 Diverse Individuals with Whole-Genome Sequencing from the Alzheimer’s Disease Sequencing Project. Preprint. medRxiv. 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
Logue MW, Dasgupta S, Farrer LA. Genetics of Alzheimer’s Disease in the African American Population. J Clin Med. 2023
Mantyh WG, Cochran JN, Taylor JW, et al. Early-onset Alzheimer’s disease explained by polygenic risk of late-onset disease?. Alzheimers Dement (Amst). 2023
O’Neill NK, Stein TD, Hu J, et al. Bulk brain tissue cell-type deconvolution with bias correction for single-nuclei RNA sequencing data using DeTREM. BMC Bioinformatics. 2023
Rajabli F, Tosto G, Hamilton-Nelson KL, et al. Admixture mapping identifies novel Alzheimer’s disease risk regions in African Americans. Alzheimers Dement. 2023
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, Dombroski BA, Cheng PL, et al. Structural Variation Detection and Association Analysis of Whole-Genome-Sequence Data from 16,905 Alzheimer’s Diseases Sequencing Project Subjects. Preprint. medRxiv. 2023
2022 CADRE Collaborations:
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
Clark K, Leung YY, Lee WP, Voight B, Wang LS. Polygenic Risk Scores in Alzheimer’s Disease Genetics: Methodology, Applications, Inclusion, and Diversity. J Alzheimers Dis. 2022
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
Kuksa PP, Liu CL, Fu W, et al. Alzheimer’s Disease Variant Portal: A Catalog of Genetic Findings for Alzheimer’s Disease. J Alzheimers Dis. 2022
Olayinka OA, O’Neill NK, Farrer LA, Wang G, Zhang X. Molecular Quantitative Trait Locus Mapping in Human Complex Diseases. Curr Protoc. 2022
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
You Y, Hersh SW, Aslebagh R, et al. Alzheimer’s disease associated AKAP9 I2558M mutation alters posttranslational modification and interactome of tau and cellular functions in CRISPR-edited human neuronal cells. Aging Cell. 2022
Zhang X, Farrell JJ, Tong T, et al. Association of mitochondrial variants and haplogroups identified by whole exome sequencing with Alzheimer’s disease. Alzheimers Dement. 2022
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 Diagnosis. J 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 Disease. Neurol 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
2103 Cornell Road, Suite 2500
Cleveland, Ohio 44106