A High-Density Whole-Genome Association Study Reveals That APOE Is the Major Susceptibility Gene for Sporadic Late-Onset Alzheimer's Disease
Abstract
OBJECTIVE: While the apolipoprotein E (APOE) epsilon allele is a well-established risk factor for late-onset Alzheimer's disease (AD), initial genome scans using microsatellite markers in late-onset AD failed to identify this locus on chromosome 19. Recently developed methods for the simultaneous assessment of hundreds of thousands of single nucleotide polymorphisms (SNPs) promise to help more precisely identify loci that contribute to the risk of AD and other common multigenic conditions. We sought here to demonstrate that more precise identification of loci that are associated with complex, multi-genic genetic disorders can be achieved using ultra-high-density whole-genome associations by demonstrating their ability to identify the APOE locus as a major susceptibility gene for late-onset AD, despite the absence of SNPs within the APOE locus itself, as well as to refine odds ratios (ORs) based on gold-standard phenotyping of the study population. METHOD: An individualized genome-wide association study using 502,627 SNPs was performed in 1086 his-topathologically verified AD cases and controls to determine the OR associated with genes predisposing to Alzheimer's disease. RESULTS: As predicted, ultra-high-density SNP genotyping, in contrast to traditional microsatellite-based genome screening approaches, precisely identified the APOE locus as having a significant association with late-onset AD. SNP rs4420638 on chromosome 19, located 14 kilobase pairs distal to the APOE epsilon variant, significantly distinguished between AD cases and controls (Bonferroni corrected p value = 5.30 x 10(-34), OR = 4.01) and was far more strongly associated with the risk of AD than any other SNP of the 502,627 tested. CONCLUSION: This study provides empirical support for the suggestion that the APOE locus is the major susceptibility gene for late-onset AD in the human genome, with an OR significantly greater than any other locus in the human genome. It also supports the feasibility of the ultra-high-density whole-genome association approach to the study of AD and other heritable phenotypes. These whole-genome association studies show great promise to identify additional genes that contribute to the risk of AD.
Integrity signals
Registry
Cites
Statistics
Claims the paper makes
Claims other papers make about this one
Each is checked against this paper’s own text: does it say what the citing paper says it does?
Previous studies of clinically and neuropathologically characterized cases and controls may have been too small to demonstrate that APOE2 homozygotes have an even lower odds ratio than the relatively low-risk APOE2/3 group due to the paucity of APOE2 homozygotes, who comprise <1% of the general population.
“Also, previous studies of clinically and neuropathologically characterized cases and controls may have been too small to demonstrate that APOE2 homozygotes have an even lower OR than the relatively low-risk APOE2/3 group due to the paucity of APOE2 homozygotes, who comprise <1% of the general population1,4.”
From Exceptionally low likelihood of Alzheimer’s dementia in APOE2 homozygotes from a 5,000-person neuropathological study (2020) · cites this paper as [1]
The presence of one or two copies of the APOE2 allele is associated with a lower risk of Alzheimer's dementia and an older mean age at dementia onset.
“while the presence of one or two copies of the APOE2 allele is associated with a lower risk of Alzheimer’s dementia and an older mean age at dementia onset1–4.”
From Exceptionally low likelihood of Alzheimer’s dementia in APOE2 homozygotes from a 5,000-person neuropathological study (2020) · cites this paper as [1]
Compared to the APOE3/3 genotype, each additional copy of the APOE4 allele is associated with a higher risk of Alzheimer's dementia and a younger mean age at dementia onset.
“Compared to the most common APOE3/3 genotype, each additional copy of the APOE4 allele is associated with a higher risk of Alzheimer’s dementia and a younger mean age at dementia onset, such that APOE4 homozygotes are at the highest risk”
From Exceptionally low likelihood of Alzheimer’s dementia in APOE2 homozygotes from a 5,000-person neuropathological study (2020) · cites this paper as [1]
APOE4 homozygotes are at the highest risk of Alzheimer's dementia.
“such that APOE4 homozygotes are at the highest risk”
From Exceptionally low likelihood of Alzheimer’s dementia in APOE2 homozygotes from a 5,000-person neuropathological study (2020) · cites this paper as [1]
APOE is the major susceptibility gene for late-onset Alzheimer's disease.
“Apolipoprotein E (APOE), the major susceptibility gene for late-onset Alzheimer’s disease (AD), has three common alleles (APOE2, 3, and 4), giving rise to six genotypes (APOE2/2, 2/3, 3/3, 2/4, 3/4, and 4/4).”
From Exceptionally low likelihood of Alzheimer’s dementia in APOE2 homozygotes from a 5,000-person neuropathological study (2020) · cites this paper as [1]
Prior genome-wide association studies of AD all identified strong evidence for association to APOE but less convincing evidence implicating other genes.
“All have identified strong evidence for association to APOE, but less convincing evidence implicating other genes2 -9 .”
From Genome-wide association study identifies variants at CLU and PICALM associated with Alzheimer's disease (2009) · cites this paper as [6]
The first association studies covering most of the genome were published in 2007.
“The first association studies covering most of the genome were published in 2007 [81, 82].”
From Genetic architecture of Alzheimer's disease (2020) · cites this paper as [81]
Cites
Haploview: analysis and visualization of LD and haplotype maps
Barrett, J., Fry, B., Maller, J., & Daly, M. (2005) · Bioinform. · doi:10.1093/bioinformatics/bth457 · Cited by 15,086 · see citing works
Corder, E. H., Saunders, A. M., Strittmatter, W. J., Schmechel, D. E., Gaskell, P. C., Small, G. W., Roses, A. D., Haines, J. L., & Pericak-Vance, M. A. (1993) · Science · doi:10.1126/science.8346443 · Cited by 9,429 · see citing works
Association of apolipoprotein E allele ϵ4 with late‐onset familial and sporadic Alzheimer's disease
Saunders, A. M., Strittmatter, W. J., Schmechel, D., St. George-Hyslop, P. H., Pericak-Vance, M. A., Joo, S. H., Rosi, B. L., Gusella, J. F., Crapper-MacLachlan, D. R., Alberts, M. J., et al. (1993) · Neurology · doi:10.1212/wnl.43.8.1467 · Cited by 3,786 · see citing works
Systematic meta-analyses of Alzheimer disease genetic association studies: the AlzGene database
Bertram, L., McQueen, M. B., Mullin, K., Blacker, D., & Tanzi, R. E. (2007) · Nature Genetics · doi:10.1038/ng1934 · Cited by 1,857 · see citing works
Prospects for whole-genome linkage disequilibrium mapping of common disease genes
Kruglyak, L. (1999) · Nature Genetics · doi:10.1038/9642 · Cited by 1,416 · see citing works
Staging of Alzheimer-Related Cortical Destruction
Braak, H., Braak, E., & Bohl, J. (2008) · European Neurology · doi:10.1159/000116984 · Cited by 836 · see citing works
Single-Nucleotide Polymorphism Analysis by Pyrosequencing
Ahmadian, A., Gharizadeh, B., Gustafsson, A. C., Sterky, F. H., Nyrén, P., Uhlén, M., & Lundeberg, J. (2000) · Analytical Biochemistry · doi:10.1006/abio.2000.4493 · Cited by 433 · see citing works
A full genome scan for late onset Alzheimer's disease
Kehoe, P. G. (1999) · Human Molecular Genetics · doi:10.1093/hmg/8.2.237 · Cited by 356 · see citing works
Deciphering the Genetic Basis of Alzheimer's Disease
Selkoe, D. J., & Podlisny, M. B. (2002) · Annual Review of Genomics and Human Genetics · doi:10.1146/annurev.genom.3.022502.103022 · Cited by 293 · see citing works
Studies of familial type III hyperlipoproteinemia using as a genetic marker the apoE phenotype E2/2
Breslow, J. L., Zannis, V. I., SanGiacomo, T. R., Third, J. L., Tracy, T., & Glueck, C. J. (1982) · Journal of Lipid Research · doi:10.1016/s0022-2275(20)38060-3 · Cited by 174 · see citing works
A 4-Mb High-Density Single Nucleotide Polymorphism-Based Map around Human APOE
Lai, E., Riley, J., Purvis, I. J., & Roses, A. D. (1998) · Genomics · doi:10.1006/geno.1998.5581 · Cited by 161 · see citing works
Farrer, L. A. (1997) · JAMA · doi:10.1001/jama.1997.03550160069041 · Cited by 124 · see citing works
Genetics, Transcriptomics, and Proteomics of Alzheimers Disease
Papassotiropoulos, A., Fountoulakis, M., Dunckley, T. L., Stephan, D. A., & Reiman, E. M. (2006) · The Journal of Clinical Psychiatry · doi:10.4088/jcp.v67n0418 · Cited by 103 · see citing works
Self-citationNeuropathological diagnostic criteria for Alzheimer's disease
Murayama, S., & Saito, Y. (2004) · Neuropathology · doi:10.1111/j.1440-1789.2004.00571.x · Cited by 92 · see citing works
Jianping Hua, A., Craig, D. W., Marcel Brun, A., Webster, J., Zismann, V., Tembe, W., Joshipura, K. D., Huentelman, M. J., Dougherty, E. R., & Stephan, D. A. (2006) · Bioinformatics · doi:10.1093/bioinformatics/btl536 · Cited by 47 · see citing works
Self-citation
Flagged first, then by citations
Cited by
Sorted by citations
Harold, D., Abraham, R., Hollingworth, P., Sims, R., Gerrish, A., Hamshere, M. L., Pahwa, J. S., Moskvina, V., Dowzell, K., Williams, A., et al. (2009) · Nature Genetics · doi:10.1038/ng.440 · Cited by 3,326 · see citing works
Self-citationThe personal and clinical utility of polygenic risk scores
Torkamani, A., Wineinger, N. E., & Topol, E. J. (2018) · Nature Reviews Genetics · doi:10.1038/s41576-018-0018-x · Cited by 1,605 · see citing works
Genome-wide Analysis of Genetic Loci Associated With Alzheimer Disease
Seshadri, S. (2010) · JAMA · doi:10.1001/jama.2010.574 · Cited by 1,219 · see citing works
Molecular and cellular mechanisms underlying the pathogenesis of Alzheimer’s disease
Guo, T., Zhang, D., Zeng, Y., Huang, T. Y., Xu, H., & Zhao, Y. (2020) · Molecular Neurodegeneration · doi:10.1186/s13024-020-00391-7 · Cited by 994 · see citing works
Review Article: Genetics of Alzheimer Disease
Bekris, L. M., Yu, C.-E., Bird, T. D., & Tsuang, D. W. (2010) · Journal of Geriatric Psychiatry and Neurology · doi:10.1177/0891988710383571 · Cited by 1,029 · see citing works
Johnson, E. C. B., Dammer, E. B., Duong, D. M., Ping, L., Zhou, M., Yin, L., Higginbotham, L. A., Guajardo, A., White, B., Troncoso, J. C., et al. (2020) · Nature Medicine · doi:10.1038/s41591-020-0815-6 · Cited by 1,001 · see citing works
Self-citationThe diploid genome sequence of an Asian individual
Wang, J., Wang, W., Li, R., Li, Y., Tian, G., Goodman, L., Fan, W., Zhang, J., Li, J., Zhang, J., et al. (2008) · Nature · doi:10.1038/nature07484 · Cited by 924 · see citing works
How to Interpret a Genome-wide Association Study
Pearson, T. A. (2008) · JAMA · doi:10.1001/jama.299.11.1335 · Cited by 964 · see citing works
The Genetics of Alzheimer Disease: Back to the Future
Bertram, L., Lill, C. M., & Tanzi, R. E. (2010) · Neuron · doi:10.1016/j.neuron.2010.10.013 · Cited by 834 · see citing works
The amyloid hypothesis for Alzheimer’s disease: A critical reappraisal
Hardy, J. (2009) · Journal of Neurochemistry · doi:10.1111/j.1471-4159.2009.06181.x · Cited by 814 · see citing works
Self-citationReiman, E. M., Chen, K., Liu, X., Bandy, D., Yu, M., Lee, W., Ayutyanont, N., Keppler, J., Reeder, S. A., Langbaum, J. B. S., et al. (2009) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.0900345106 · Cited by 785 · see citing works
Self-citationThe Genetics of Alzheimer's Disease
Bertram, L., & Tanzi, R. E. (2012) · Progress in molecular biology and translational science · doi:10.1016/b978-0-12-385883-2.00008-4 · Cited by 784 · see citing works
Thirty years of Alzheimer's disease genetics: the implications of systematic meta-analyses
Bertram, L., & Tanzi, R. E. (2008) · Nature Reviews Neuroscience · doi:10.1038/nrn2494 · Cited by 747 · see citing works
Weller, R. O., Subash, M., Preston, S., Mazanti, I., & Carare, R. O. (2008) · Brain Pathology · doi:10.1111/j.1750-3639.2008.00133.x · Cited by 682 · see citing works
Age, APOE and sex: triad of risk of Alzheimer’s disease.
Riedel, B. C., Thompson, P. M., & Brinton, R. D. (2016) · The Journal of Steroid Biochemistry and Molecular Biology · doi:10.1016/j.jsbmb.2016.03.012 · Cited by 627 · see citing works
Seyfried, N. T., Dammer, E. B., Swarup, V., Nandakumar, D., Duong, D. M., Yin, L., Deng, Q., Nguyen, T., Hales, C. M., Wingo, T., et al. (2017) · Cell Systems · doi:10.1016/j.cels.2016.11.006 · Cited by 477 · see citing works
Reiman, E. M., Arboleda-Velasquez, J. F., Quiroz, Y. T., Huentelman, M. J., Beach, T. G., Caselli, R. J., Chen, Y., Su, Y., Myers, A. J., Hardy, J., et al. (2020) · Nature Communications · doi:10.1038/s41467-019-14279-8 · Cited by 473 · see citing works
Self-citationCandidate single-nucleotide polymorphisms from a genomewide association study of Alzheimer disease
Li, H., Wetten, S., Li, L., St. Jean, P. L., Upmanyu, R., Surh, L., Hosford, D., Barnes, M. R., Briley, J. D., Borrie, M., et al. (2008) · Archives of Neurology · doi:10.1001/archneurol.2007.3 · Cited by 499 · see citing works
A survey of genetic human cortical gene expression
Myers, A. J., Gibbs, J. R., Webster, J. A., Rohrer, K., Zhao, A., Marlowe, L., Kaleem, M., Leung, D., Bryden, L., Nath, P., et al. (2007) · Nature Genetics · doi:10.1038/ng.2007.16 · Cited by 479 · see citing works
Self-citationGAB2 Alleles Modify Alzheimer's Risk in APOE ɛ4 Carriers
Reiman, E. M., Webster, J. A., Myers, A. J., Hardy, J., Dunckley, T., Zismann, V. L., Joshipura, K. D., Pearson, J. V., Hu-Lince, D., Huentelman, M. J., et al. (2007) · Neuron · doi:10.1016/j.neuron.2007.05.022 · Cited by 487 · see citing works
Self-citationAge-Specific Epigenetic Drift in Late-Onset Alzheimer's Disease
Wang, S.-C., Oelze, B., & Schumacher, A. (2008) · PLoS ONE · doi:10.1371/journal.pone.0002698 · Cited by 467 · see citing works
Jun, G. (2010) · Archives of Neurology · doi:10.1001/archneurol.2010.201 · Cited by 422 · see citing works
A TOMM40 variable-length polymorphism predicts the age of late-onset Alzheimer's disease
Roses, A. D., Lutz, M. W., Amrine‐Madsen, H., Saunders, A. M., Crenshaw, D. G., Sundseth, S. S., Huentelman, M. J., Welsh-Bohmer, K. A., & Reiman, E. M. (2009) · The Pharmacogenomics Journal · doi:10.1038/tpj.2009.69 · Cited by 391 · see citing works
Self-citationAPOE genotype-specific differences in the innate immune response
Vitek, M. P., Brown, C. M., & Colton, C. A. (2009) · Neurobiology of Aging · doi:10.1016/j.neurobiolaging.2007.11.014 · Cited by 362 · see citing works
Genetic, environmental, and epigenetic factors involved in CAKUT
Nicolaou, N., Renkema, K. Y., Bongers, E. M. H. F., Giles, R. H., & Knoers, N. V. A. M. (2015) · Nature Reviews Nephrology · doi:10.1038/nrneph.2015.140 · Cited by 344 · see citing works
Expression of Novel Alzheimer’s Disease Risk Genes in Control and Alzheimer’s Disease Brains
Karch, C. M., Jeng, A. T., Nowotny, P., Cady, J., Cruchaga, C., & Goate, A. M. (2012) · PLoS ONE · doi:10.1371/journal.pone.0050976 · Cited by 328 · see citing works
Sharma, P., Srivastava, P., Seth, A., Tripathi, P. N., Banerjee, A. G., & Shrivastava, S. K. (2019) · Progress in Neurobiology · doi:10.1016/j.pneurobio.2018.12.006 · Cited by 331 · see citing works
The complexity of Alzheimer’s disease: an evolving puzzle
Ferrari, C., & Sorbi, S. (2021) · Physiological Reviews · doi:10.1152/physrev.00015.2020 · Cited by 324 · see citing works
Genetic Control of Human Brain Transcript Expression in Alzheimer Disease
Webster, J. A., Gibbs, J. R., Clarke, J., Ray, M., Zhang, W., Holmans, P., Rohrer, K., Zhao, A., Marlowe, L., Kaleem, M., et al. (2009) · The American Journal of Human Genetics · doi:10.1016/j.ajhg.2009.03.011 · Cited by 304 · see citing works
Self-citationThe Therapeutic Potential of Metformin in Neurodegenerative Diseases
Rotermund, C., Machetanz, G., & Fitzgerald, J. C. (2018) · Frontiers in Endocrinology · doi:10.3389/fendo.2018.00400 · Cited by 310 · see citing works
Astrogliosis: An integral player in the pathogenesis of Alzheimer's disease
Osborn, L. M., Kamphuis, W., Wadman, W. J., & Hol, E. M. (2016) · Progress in Neurobiology · doi:10.1016/j.pneurobio.2016.01.001 · Cited by 312 · see citing works
The genetic architecture of Alzheimer's disease: beyond APP, PSENs and APOE
Guerreiro, R. J., Gustafson, D. R., & Hardy, J. (2012) · Neurobiology of Aging · doi:10.1016/j.neurobiolaging.2010.03.025 · Cited by 285 · see citing works
Self-citationRole of Environmental Contaminants in the Etiology of Alzheimer’s Disease: A Review
Yegambaram, M., Manivannan, B., Beach, T. G., & Halden, R. U. (2015) · Current Alzheimer Research · doi:10.2174/1567205012666150204121719 · Cited by 277 · see citing works
Self-citationThe <i>MS4A</i> gene cluster is a key modulator of soluble TREM2 and Alzheimer’s disease risk
Deming, Y., Filipello, F., Cignarella, F., Cantoni, C., Hsu, S., Mikesell, R., Li, Z., Del-Aguila, J. L., Dube, U., Farias, F. G., et al. (2019) · Science Translational Medicine · doi:10.1126/scitranslmed.aau2291 · Cited by 271 · see citing works
“Association of MS4A SNPs and APOE genotype with CSF sTREM2 and A42 concentrations The APOE genotype is the strongest genetic risk factor for AD (33), and APOE4 is the strongest genetic association for increased A42 and tau in CSF (31, 34).”
Genome Wide Association Studies for Milk Production Traits in Chinese Holstein Population
Jiang, L., Liu, J., Sun, D., Ma, P., Ding, X., Yu, Y., & Zhang, Q. (2010) · PLoS ONE · doi:10.1371/journal.pone.0013661 · Cited by 272 · see citing works
Family-based designs for genome-wide association studies
Ott, J., Kamatani, Y., & Lathrop, M. G. (2011) · Nature Reviews Genetics · doi:10.1038/nrg2989 · Cited by 268 · see citing works
Air Pollution, Oxidative Stress, and Alzheimer's Disease
Moulton, P. V., & Yang, W. (2012) · Journal of Environmental and Public Health · doi:10.1155/2012/472751 · Cited by 265 · see citing works
Genome-wide Association Study Implicates a Chromosome 12 Risk Locus for Late-Onset Alzheimer Disease
Beecham, G. W., Martin, E. R., Li, Y.-J., Slifer, M. A., Gilbert, J. R., Haines, J. L., & Pericak-Vance, M. A. (2009) · The American Journal of Human Genetics · doi:10.1016/j.ajhg.2008.12.008 · Cited by 260 · see citing works
Genome-wide association studies in Alzheimer’s disease
Bertram, L., & Tanzi, R. E. (2009) · Human Molecular Genetics · doi:10.1093/hmg/ddp406 · Cited by 257 · see citing works
Genetics of familial and sporadic Alzheimer s disease
Piaceri, I. (2013) · Frontiers in Bioscience · doi:10.2741/e605 · Cited by 256 · see citing works
Risk Factors for β-Amyloid Deposition in Healthy Aging: Vascular and Genetic Effects
Rodrigue, K. M., Rieck, J. R., Kennedy, K. M., Devous, M. D., Diaz-Arrastia, R., & Park, D. C. (2013) · JAMA Neurology · doi:10.1001/jamaneurol.2013.1342 · Cited by 249 · see citing works
Genome-wide association study of Alzheimer's disease
Kamboh, M. I., Demirci, F. Y., Wang, X., Minster, R. L., Carrasquillo, M. M., Pankratz, V. S., Younkin, S. G., Saykin, A. J., Initiative, A. D. N., Jun, G., et al. (2012) · Translational Psychiatry · doi:10.1038/tp.2012.45 · Cited by 242 · see citing works
The genetics and neuropathology of Alzheimer’s disease
Schellenberg, G. D., & Montine, T. J. (2012) · Acta Neuropathologica · doi:10.1007/s00401-012-0996-2 · Cited by 242 · see citing works
Corneveaux, J. J., Myers, A. J., Allen, A. N., Pruzin, J. J., Ramirez, M., Engel, A., Nalls, M. A., Chen, K., Lee, W., Chewning, K., et al. (2010) · Human Molecular Genetics · doi:10.1093/hmg/ddq221 · Cited by 237 · see citing works
Self-citationCurrent and Emerging Drug Treatment Options for Alzheimerʼs Disease
Herrmann, N., Chau, S. A., Kircanski, I., & Lanctôt, K. L. (2011) · Drugs · doi:10.2165/11595870-000000000-00000 · Cited by 238 · see citing works
Genome-Wide Association Studies in Alzheimer Disease
Waring, S. C., & Rosenberg, R. N. (2008) · Archives of Neurology · doi:10.1001/archneur.65.3.329 · Cited by 238 · see citing works
Genotype Imputation from Large Reference Panels
Das, S., Abecasis, G. R., & Browning, B. L. (2018) · Annual Review of Genomics and Human Genetics · doi:10.1146/annurev-genom-083117-021602 · Cited by 221 · see citing works
Wijsman, E. M., Pankratz, N., Choi, Y., Rothstein, J. H., Faber, K. M., Cheng, R., Lee, J. H., Bird, T. D., Bennett, D. A., Diaz-Arrastia, R. R., et al. (2011) · PLoS Genetics · doi:10.1371/journal.pgen.1001308 · Cited by 223 · see citing works
Epidemiology and Etiology of Alzheimer’s disease: From Genetic to Non- Genetic Factors
Jiang, T., Yu, J., Tian, Y., & Tan, L. (2013) · Current Alzheimer Research · doi:10.2174/15672050113109990155 · Cited by 224 · see citing works
Physical activity and the brain: A review of this dynamic, bi-directional relationship
Loprinzi, P. D., Herod, S. M., Cardinal, B. J., & Noakes, T. D. (2013) · Brain Research · doi:10.1016/j.brainres.2013.10.004 · Cited by 222 · see citing works
The Utility of Cerebral Blood Flow as a Biomarker of Preclinical Alzheimer’s Disease
Hays, C. C., Zlatar, Z. Z., & Wierenga, C. E. (2016) · Cellular and Molecular Neurobiology · doi:10.1007/s10571-015-0261-z · Cited by 213 · see citing works
APOE ε4 Genotype and Longitudinal Changes in Cerebral Blood Flow in Normal Aging
Thambisetty, M., Beason‐Held, L. L., An, Y., Kraut, M. A., & Resnick, S. M. (2010) · Archives of Neurology · doi:10.1001/archneurol.2009.913 · Cited by 211 · see citing works
Genetics of Alzheimer’s Disease
Chouraki, V. A., & Seshadri, S. S. (2014) · Advances in genetics · doi:10.1016/b978-0-12-800149-3.00005-6 · Cited by 208 · see citing works
Molecular genetics of Alzheimer's disease: An update
Brouwers, N., Sleegers, K., & Broeckhoven, C. V. (2008) · Annals of Medicine · doi:10.1080/07853890802186905 · Cited by 208 · see citing works
Noncoding RNAs in Alzheimer's disease
Idda, M. L., Munk, R. B., Abdelmohsen, K., & Gorospe, M. (2018) · Wiley Interdisciplinary Reviews - RNA · doi:10.1002/wrna.1463 · Cited by 206 · see citing works
Nebel, A., Kleindorp, R., Caliebe, A., Nothnagel, M., Blanché, H., Junge, O., Wittig, M., Ellinghaus, D., Flachsbart, F., Wichmann, H. ‐., et al. (2011) · Mechanisms of Ageing and Development · doi:10.1016/j.mad.2011.06.008 · Cited by 201 · see citing works
Murabito, J. M., Yuan, R., & Lunetta, K. L. (2012) · The Journals of Gerontology Series A · doi:10.1093/gerona/gls089 · Cited by 200 · see citing works
A genome-wide genotyping study in patients with ischaemic stroke: initial analysis and data release
Matarín, M., Brown, W. M., Scholz, S. W., Simón‐Sánchez, J., Fung, H., Hernandez, D. G., Gibbs, J. R., Vrieze, F. W. D., Crews, C. K., Britton, A. F., et al. (2007) · The Lancet Neurology · doi:10.1016/s1474-4422(07)70081-9 · Cited by 196 · see citing works
Self-citationA genome-wide association study for late-onset Alzheimer's disease using DNA pooling
Abraham, R., Moskvina, V., Sims, R., Hollingworth, P., Morgan, A., Georgieva, L., Dowzell, K., Cichon, S., Hillmer, A. M., O'Donovan, M. C., et al. (2008) · BMC Medical Genomics · doi:10.1186/1755-8794-1-44 · Cited by 195 · see citing works
Lee, J. H., Cheng, R., Barral, S., Reitz, C., Medrano, M., Lantigua, R., Jiménez-Velazquez, I. Z., Rogaeva, E., St. George-Hyslop, P. H., & Mayeux, R. (2011) · Archives of Neurology · doi:10.1001/archneurol.2010.292 · Cited by 190 · see citing works
Autophagic and endo-lysosomal dysfunction in neurodegenerative disease
Malik, B. R., Maddison, D. C., Smith, G. A., & Peters, O. M. (2019) · Molecular Brain · doi:10.1186/s13041-019-0504-x · Cited by 180 · see citing works
The pursuit of genome-wide association studies: where are we now?
Ku, C., Loy, E. Y., Yudi Pawitan, Y., & Chia, K. S. (2010) · Journal of Human Genetics · doi:10.1038/jhg.2010.19 · Cited by 181 · see citing works
Genomic variants, genes, and pathways of Alzheimer's disease: An overview
Naj, A. C., & Schellenberg, G. D. (2016) · American Journal of Medical Genetics Part B Neuropsychiatric Genetics · doi:10.1002/ajmg.b.32499 · Cited by 178 · see citing works
Pharmacogenetics in drug discovery and development: a translational perspective
Roses, A. D. (2008) · Nature Reviews Drug Discovery · doi:10.1038/nrd2593 · Cited by 174 · see citing works
The genetics of Alzheimer's disease
Bagyinszky, E., Youn, Y. C., An, S. S. A., & Kim, S. (2014) · Clinical Interventions in Aging · doi:10.2147/cia.s51571 · Cited by 173 · see citing works
Current status on Alzheimer disease molecular genetics: from past, to present, to future
Bettens, K., Sleegers, K., & Broeckhoven, C. V. (2010) · Human Molecular Genetics · doi:10.1093/hmg/ddq142 · Cited by 167 · see citing works
Angiotensins in Alzheimer's disease – friend or foe?
Kehoe, P. G., Miners, J. S., & Love, S. (2009) · Trends in Neurosciences · doi:10.1016/j.tins.2009.07.006 · Cited by 166 · see citing works
The genetic relationship between handedness and neurodevelopmental disorders
Brandler, W. M., & Paracchini, S. (2013) · Trends in Molecular Medicine · doi:10.1016/j.molmed.2013.10.008 · Cited by 164 · see citing works
Hu, X., Pickering, E. H., Liu, Y. C., Hall, S., Fournier, H., Katz, E., DeChairo, B. M., John, S., Eerdewegh, P. V., Soares, H. D., et al. (2011) · PLoS ONE · doi:10.1371/journal.pone.0016616 · Cited by 161 · see citing works
GWAS for executive function and processing speed suggests involvement of the CADM2 gene
Ibrahim-Verbaas, C. A., Bressler, J., Debette, S., Schuur, M., Smith, A. V., Bis, J. C., Davies, G., Trompet, S., Smith, J. A., Wolf, C., et al. (2016) · Molecular Psychiatry · doi:10.1038/mp.2015.37 · Cited by 147 · see citing works
Thompson, P. M., Ge, T., Glahn, D. C., Jahanshad, N., & Nichols, T. E. (2013) · NeuroImage · doi:10.1016/j.neuroimage.2013.05.013 · Cited by 155 · see citing works
Can Infections Cause Alzheimer's Disease?
Mawanda, F., & Wallace, R. B. (2013) · Epidemiologic Reviews · doi:10.1093/epirev/mxs007 · Cited by 151 · see citing works
Naj, A. C., Beecham, G. W., Martin, E. R., Gallins, P. J., Powell, E. H., Konidari, I., Whitehead, P. L., Cai, G., Haroutunian, V. H., Scott, W. K., et al. (2010) · PLoS Genetics · doi:10.1371/journal.pgen.1001130 · Cited by 147 · see citing works
Genome-wide association studies: progress and potential for drug discovery and development
Kingsmore, S. F., Lindquist, I. E., Mudge, J., Gessler, D. D. G., & Beavis, W. D. (2008) · Nature Reviews Drug Discovery · doi:10.1038/nrd2519 · Cited by 143 · see citing works
Genetic association study on in and around the APOE in late-onset Alzheimer disease in Japanese
Takei, N., Miyashita, A., Tsukie, T., Arai, H., Asada, T., Imagawa, M., Shoji, M., Higuchi, S., Urakami, K., Kimura, H., et al. (2009) · Genomics · doi:10.1016/j.ygeno.2009.01.003 · Cited by 142 · see citing works
Chaperone signalling complexes in Alzheimer's disease
Koren, J., Jinwal, U. K., Lee, D. C., Jones, J. R., Shults, C. L., Johnson, A. G., Anderson, L. J., & Dickey, C. A. (2008) · Journal of Cellular and Molecular Medicine · doi:10.1111/j.1582-4934.2008.00557.x · Cited by 140 · see citing works
Molecular Genetics of Addiction and Related Heritable Phenotypes
Uhl, G. R., Drgon, T., Johnson, C., Li, C., Contoreggi, C. S., Hess, J., Naiman, D. Q., & Liu, Q. (2008) · Annals of the New York Academy of Sciences · doi:10.1196/annals.1441.018 · Cited by 139 · see citing works
On Jim Watson's APOE status: genetic information is hard to hide
Nyholt, D. R., Yu, C., & Visscher, P. M. (2008) · European Journal of Human Genetics · doi:10.1038/ejhg.2008.198 · Cited by 139 · see citing works
Genetics of Alzheimer's disease: recent advances
Avramopoulos, D. (2009) · Genome Medicine · doi:10.1186/gm34 · Cited by 136 · see citing works
Kehoe, P. G. (2018) · Journal of Alzheimer’s Disease · doi:10.3233/jad-171119 · Cited by 133 · see citing works
Associations between amyloid β and white matter hyperintensities: A systematic review
Roseborough, A. D., Ramirez, J., Black, S. E., & Edwards, J. D. (2017) · Alzheimer s & Dementia · doi:10.1016/j.jalz.2017.01.026 · Cited by 134 · see citing works
Genetics of Alzheimer’s Disease
Vilatela, M. E. A., López, M., & Yescas, P. (2012) · Archives of Medical Research · doi:10.1016/j.arcmed.2012.10.017 · Cited by 129 · see citing works
Genome-Wide Scan of Copy Number Variation in Late-Onset Alzheimer's Disease
Heinzen, E. L., Need, A. C., Hayden, K. M., Chiba‐Falek, O., Roses, A. D., Strittmatter, W. J., Burke, J. R., Hulette, C. M., Welsh-Bohmer, K. A., & Goldstein, D. B. (2010) · Journal of Alzheimer s Disease · doi:10.3233/jad-2010-1212 · Cited by 129 · see citing works
The pursuit of susceptibility genes for Alzheimer's disease: progress and prospects
Sleegers, K., Lambert, J.-C., Bertram, L., Cruts, M., Amouyel, P., & Van Broeckhoven, C. (2010) · Trends in Genetics · doi:10.1016/j.tig.2009.12.004 · Cited by 129 · see citing works
Genome-Wide Association Study for Wool Production Traits in a Chinese Merino Sheep Population
Wang, Z., Zhang, H., Yang, H., Wang, S., Rong, E., Pei, W., Li, H., & Wang, N. (2014) · PLoS ONE · doi:10.1371/journal.pone.0107101 · Cited by 127 · see citing works
Genetic architecture of Alzheimer's disease
Neuner, S. M., TCW, J., & Goate, A. M. (2020) · Neurobiology of Disease · doi:10.1016/j.nbd.2020.104976 · Cited by 126 · see citing works
“The first association studies covering most of the genome were published in 2007 [81, 82].”
BackgroundChildhood Lead Exposure and Adult Neurodegenerative Disease
Reuben, A. (2018) · Journal of Alzheimer s Disease · doi:10.3233/jad-180267 · Cited by 129 · see citing works
Use of next-generation sequencing and other whole-genome strategies to dissect neurological disease
Brás, J., Guerreiro, R. J., & Hardy, J. (2012) · Nature reviews. Neuroscience · doi:10.1038/nrn3271 · Cited by 124 · see citing works
Self-citation25-Hydroxycholesterol amplifies microglial IL-1β production in an apoE isoform-dependent manner
Wong, M. Y., Lewis, M., Doherty, J. J., Shi, Y., Cashikar, A. G., Amelianchik, A., Tymchuk, S., Sullivan, P. M., Qian, M., Covey, D. F., et al. (2020) · Journal of Neuroinflammation · doi:10.1186/s12974-020-01869-3 · Cited by 121 · see citing works
How to Use an Article About Genetic Association
Attia, J., Ioannidis, J. P. A., Thakkinstian, A., McEvoy, M., Scott, R. J., Minelli, C., Thompson, J. R., Infante‐Rivard, C., & Guyatt, G. H. (2009) · JAMA · doi:10.1001/jama.2008.901 · Cited by 121 · see citing works
Role of Cholesterol in APP Metabolism and Its Significance in Alzheimer’s Disease Pathogenesis
Maulik, M., Westaway, D. A., Jhamandas, J. H., & Kar, S. (2012) · Molecular Neurobiology · doi:10.1007/s12035-012-8337-y · Cited by 117 · see citing works
Dhiman, K., Blennow, K., Zetterberg, H., Martins, R. N., & Gupta, V. B. (2019) · Cellular and Molecular Life Sciences · doi:10.1007/s00018-019-03040-5 · Cited by 114 · see citing works
Discovery and replication of gene influences on brain structure using LASSO regression
Omid Kohannim, A. (2012) · Frontiers in Neuroscience · doi:10.3389/fnins.2012.00115 · Cited by 114 · see citing works
The application of naive Bayes model averaging to predict Alzheimer's disease from genome-wide data
Wei, W., Visweswaran, S., & Cooper, G. F. (2011) · Journal of the American Medical Informatics Association · doi:10.1136/amiajnl-2011-000101 · Cited by 108 · see citing works
Culqui, D. R., Linares, C., Ortíz, C., Carmona, R., & Díaz, J. (2017) · The Science of The Total Environment · doi:10.1016/j.scitotenv.2017.03.089 · Cited by 105 · see citing works
A decade in psychiatric GWAS research
Horwitz, T. B., Lam, K., Chen, Y., Xia, Y., & Liu, C. (2018) · Molecular Psychiatry · doi:10.1038/s41380-018-0055-z · Cited by 103 · see citing works
Plourde, M., Vohl, M., Vandal, M., Couture, P., Lemieux, S., & Cunnane, S. C. (2009) · British Journal Of Nutrition · doi:10.1017/s000711450938215x · Cited by 107 · see citing works
Sanders, A. E. (2010) · JAMA · doi:10.1001/jama.2009.1988 · Cited by 107 · see citing works
Genetics of Alzheimer disease in the pre- and post-GWAS era
Ertekin‐Taner, N. (2010) · Alzheimer s Research & Therapy · doi:10.1186/alzrt26 · Cited by 107 · see citing works
BIN1 is a key regulator of proinflammatory and neurodegeneration-related activation in microglia
Sudwarts, A., Ramesha, S., Gao, T., Ponnusamy, M., Wang, S., Hansen, M. T., Kozlova, A., Bitarafan, S., Kumar, P., Beaulieu‐Abdelahad, D., et al. (2022) · Molecular Neurodegeneration · doi:10.1186/s13024-022-00535-x · Cited by 107 · see citing works
- Authors
- Coon, K. D., Myers, A. J., Craig, D. W., Webster, J. A., Pearson, J. V., Lince, D. H., Zismann, V. L., Beach, T. G., Leung, D., Bryden, L., Halperin, R. F., Marlowe, L., Kaleem, M., Walker, D. G., Ravid, R., Heward, C. B., Rogers, J., Papassotiropoulos, A., Reiman, E. M., Hardy, J., & Stephan, D. A.
- Affiliations
- Translational Genomics Research Institute (US)
- University of Miami (US)
- Banner Sun Health Research Institute (US)
- National Institutes of Health (US)
- ORCID
- Venue
- The Journal of Clinical Psychiatry
- Publisher
- Physicians Postgraduate Press, Inc
- Published
- 2007-04-15
- Volume
- 68
- Issue
- 04
- Pages
- 613-618
- ISSN
- 0160-6689 (ISSN-L)
- OpenAlex
- W2017581860
- Cited by
- 569
- References
- 15
- Citations by year
- 2026: 4 · 2025: 18 · 2024: 15 · 2023: 37 · 2022: 32 · 2021: 26 · 2020: 23 · 2019: 23 · 2018: 28 · 2017: 20 · 2016: 21 · 2015: 22 · 2014: 29 · 2013: 28 · 2012: 42
- FWCI
- 36.06
- Type
- journal article
- Language
- en
- Open access
- closed
- Locations
- The Journal of Clinical Psychiatry (publishedVersion)
- PubMed (publishedVersion)
- UCL Discovery (University College London) (submittedVersion)
- Zurich Open Repository and Archive (University of Zurich) (submittedVersion)
- Funders
- National Institute on Aging (U01AG016976)
- Topics
- Health Sciences › Medicine › Physiology › Alzheimer's disease research and treatments
- Health Sciences › Medicine › Psychiatry and Mental health › Dementia and Cognitive Impairment Research
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Genetic Associations and Epidemiology
- Keywords
- late-onset Alzheimer's disease, apolipoprotein E, genetic susceptibility, single nucleotide polymorphisms, whole-genome association studies, chromosome 19, odds ratio, genetic susceptibility loci
- MeSH terms
- Aged, Aged, 80 and over, Alzheimer Disease, Apolipoproteins E, Brain, Chromosome Mapping, Chromosomes, Human, Pair 19, Female, Humans, Male, Risk Factors, Odds Ratio, Case-Control Studies, Age of Onset, Genetic Predisposition to Disease, Polymorphism, Single Nucleotide
About these checks
Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.
Statistics and arithmetic are recomputed, not judged.
Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.
What counts as a claim ›How we measure confidence ›How we check this ›
Are you an author, or do you see a problem with this page? Request a review
