Genetic evidence implicates the immune system and cholesterol metabolism in the aetiology of Alzheimer’s disease
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BACKGROUND: Late Onset Alzheimer's disease (LOAD) is the leading cause of dementia. Recent large genome-wide association studies (GWAS) identified the first strongly supported LOAD susceptibility genes since the discovery of the involvement of APOE in the early 1990s. We have now exploited these GWAS datasets to uncover key LOAD pathophysiological processes. METHODOLOGY: We applied a recently developed tool for mining GWAS data for biologically meaningful information to a LOAD GWAS dataset. The principal findings were then tested in an independent GWAS dataset. PRINCIPAL FINDINGS: We found a significant overrepresentation of association signals in pathways related to cholesterol metabolism and the immune response in both of the two largest genome-wide association studies for LOAD. SIGNIFICANCE: Processes related to cholesterol metabolism and the innate immune response have previously been implicated by pathological and epidemiological studies of Alzheimer's disease, but it has been unclear whether those findings reflected primary aetiological events or consequences of the disease process. Our independent evidence from two large studies now demonstrates that these processes are aetiologically relevant, and suggests that they may be suitable targets for novel and existing therapeutic approaches.
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The enrichment of prioritized proteins in microglia and immune pathways supports a strong immunological role in AD, including TREM2, CD33, and IL34.
“supporting a strong immunological role in AD93–95 including TREM27,96, CD33, and IL34.”
From Proteogenomic analysis of human cerebrospinal fluid identifies neurologically relevant regulation and implicates causal proteins for Alzheimer’s disease (2024) · cites this paper as [93]
Recent large transcriptomic and AD GWAS network studies show involvement of microglial gene products and GWAS candidates in AD.
“These results echo recent large transcriptomic and AD GWAS network studies that show the involvement of microglial gene products and GWAS candidates in AD (Jones et al., 2010; Zhang et al., 2013).”
From A Multi-network Approach Identifies Protein-Specific Co-expression in Asymptomatic and Symptomatic Alzheimer’s Disease (2017) · cites this paper as Jones et al., 2010
The majority of late-onset Alzheimer's disease risk is due to sequence variability in genes expressed in the innate immune system, largely microglial genes.
“In contrast, despite some rare variants in APP processing enzymes (Kim et al., 2009; Marioni et al., 2018; Jansen et al., 2019; Kunkle et al., 2019), the majority of the risk in late-onset disease has been shown to be due to sequence variability in genes expressed in the innate immune system (largely microglial genes; Jones et al., 2010).”
From Genetic variability in response to amyloid beta deposition influences Alzheimer’s disease risk (2019) · cites this paper as Jones et al., 2010
Pathway analyses of AD implicate cholesterol metabolism and the innate immune response.
“Intriguingly, pathway analyses (Box 2) of AD implicate cholesterol metabolism and the innate immune response. 38”
From Genetic architectures of psychiatric disorders: the emerging picture and its implications (2012) · cites this paper as [38]
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PLINK: a tool set for whole-genome association and population-based linkage analyses.
Purcell, S., Neale, B., Todd-Brown, K., Thomas, L., Ferreira, M. A. R., Bender, D., Maller, J., Sklar, P., de Bakker, P. I. W., Daly, M. J., et al. (2007) · The American Journal of Human Genetics · doi:10.1086/519795 · Cited by 34,089 · see citing works
Genome-wide association study of 14,000 cases of seven common diseases and 3,000 shared controls
The Wellcome Trust Case Control Consortium, Management Committee, Burton, P. R., Clayton, D. G., Cardon, L. R., Craddock, N., Deloukas, P., Duncanson, A., Kwiatkowski, D. P., McCarthy, M. I., et al. (2007) · Nature · doi:10.1038/nature05911 · Cited by 9,442 · see citing works
Self-citationCorder, 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
Polazzi, E., Mengoni, I., Caprini, M., Peña‐Altamira, E., Kurtys, E., & Monti, B. (2012) · Neurosignals · doi:10.1159/000337115 · Cited by 9,023 · see citing works
The Gene Ontology (GO) database and informatics resource
Gene Ontology Consortium (2003) · Nucleic Acids Research · doi:10.1093/nar/gkh036 · Cited by 4,533 · see citing works
Common SNPs explain a large proportion of the heritability for human height
Yang, J., Benyamin, B., McEvoy, B. P., Gordon, S., Henders, A. K., Nyholt, D. R., Madden, P. A., Heath, A. C., Martin, N. G., Montgomery, G. W., et al. (2010) · Nature Genetics · doi:10.1038/ng.608 · Cited by 4,446 · see citing works
Hearing loss and cognitive decline in older adults
Lin, F. R., Yaffe, K., Xia, J., Xue, Q.-L., Harris, T. B., Purchase-Helzner, E., Satterfield, S., Ayonayon, H. N., Ferrucci, L., Simonsick, E. M., et al. (2013) · JAMA Internal Medicine · doi:10.1001/jamainternmed.2013.1868 · Cited by 4,017 · see citing works
Microglia: Active sensor and versatile effector cells in the normal and pathologic brain
Hanisch, U.-K., & Kettenmann, H. (2007) · Nature Neuroscience · doi:10.1038/nn1997 · Cited by 3,676 · see citing works
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-citationBlennow, K., de Leon, M. J., & Zetterberg, H. (2006) · The Lancet · doi:10.1016/s0140-6736(06)69113-7 · Cited by 3,134 · see citing works
From genomics to chemical genomics: new developments in KEGG
Kanehisa, M. I. (2005) · Nucleic Acids Research · doi:10.1093/nar/gkj102 · Cited by 3,126 · see citing works
An improved Bonferroni procedure for multiple tests of significance
SIMES, R. J. (1986) · Biometrika · doi:10.1093/biomet/73.3.751 · Cited by 2,396 · see citing works
Genome-wide association study identifies variants at CLU and CR1 associated with Alzheimer's disease
the European Alzheimer's Disease Initiative Investigators, Lambert, J.-C., Heath, S., Even, G., Campion, D., Sleegers, K., Hiltunen, M., Combarros, O., Zelenika, D., Bullido, M. J., et al. (2009) · Nature Genetics · doi:10.1038/ng.439 · Cited by 2,234 · see citing works
Alzheimer Disease in the US Population: Prevalence Estimates Using the 2000 Census
Hebert, L. E., Scherr, P. A., Bienias, J. L., Bennett, D. A., & Evans, D. A. (2003) · Archives of Neurology · doi:10.1001/archneur.60.8.1119 · Cited by 2,168 · see citing works
Cholinesterase inhibitors for Alzheimer's disease
Birks, J. S. (2006) · Cochrane Database of Systematic Reviews · doi:10.1002/14651858.cd005593 · Cited by 1,906 · see citing works
Role of Genes and Environments for Explaining Alzheimer Disease
Gatz, M., Reynolds, C. A., Fratiglioni, L., Johansson, B., Mortimer, J. A., Berg, S., Fiske, A., & Pedersen, N. L. (2006) · Archives of General Psychiatry · doi:10.1001/archpsyc.63.2.168 · Cited by 1,798 · see citing works
Wyss-Coray (2006) · doi:10.1038/nm1484 · Cited by 1,284 · see citing works
Apolipoprotein E and its receptors in Alzheimer's disease: pathways, pathogenesis and therapy
Bu, G. (2009) · Nature Reviews Neuroscience · doi:10.1038/nrn2620 · Cited by 1,168 · see citing works
ApoE Promotes the Proteolytic Degradation of Aβ
Jiang, Q., Lee, C. Y. D., Mandrekar, S., Wilkinson, B., Cramer, P., Zelcer, N., Mann, K., Lamb, B., Willson, T. M., Collins, J. L., et al. (2008) · Neuron · doi:10.1016/j.neuron.2008.04.010 · Cited by 876 · see citing works
Pathway-Based Approaches for Analysis of Genomewide Association Studies
Wang, K., Li, M., & Bućan, M. (2007) · The American Journal of Human Genetics · doi:10.1086/522374 · Cited by 858 · 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-citationGenomewide Association Studies — Illuminating Biologic Pathways
Hirschhorn, J. N. (2009) · New England Journal of Medicine · doi:10.1056/nejmp0808934 · Cited by 510 · see citing works
Anstey, K. J., Lipnicki, D. M., & Low, L. (2008) · American Journal of Geriatric Psychiatry · doi:10.1097/01.jgp.0000310778.20870.ae · Cited by 437 · see citing works
The Mouse Genome Database (MGD): mouse biology and model systems
Bult, C. J., Eppig, J. T., Kadin, J. A., Richardson, J. E., Blake, J. A., & the Mouse Genome Database Group (2007) · Nucleic Acids Research · doi:10.1093/nar/gkm961 · Cited by 415 · see citing works
Pathway and network-based analysis of genome-wide association studies in multiple sclerosis
Baranzini, S. E., Galwey, N. W., Wang, J., Khankhanian, P., Lindberg, R., Pelletier, D., Wu, W., Uitdehaag, B. M. J., Kappos, L., GeneMSA Consortium, et al. (2009) · Human Molecular Genetics · doi:10.1093/hmg/ddp120 · Cited by 383 · see citing works
Gene Ontology Analysis of GWA Study Data Sets Provides Insights into the Biology of Bipolar Disorder
Holmans, P., Green, E. K., Pahwa, J. S., Ferreira, M. A. R., Purcell, S. M., Sklar, P., Owen, M. J., O'Donovan, M. C., & Craddock, N. (2009) · The American Journal of Human Genetics · doi:10.1016/j.ajhg.2009.05.011 · Cited by 378 · see citing works
Self-citationBlasko, I., Stampfer‐Kountchev, M., Robatscher, P., Veerhuis, R., Eikelenboom, P., & Grubeck‐Loebenstein, B. (2004) · Aging Cell · doi:10.1111/j.1474-9728.2004.00101.x · Cited by 374 · see citing works
Vascular risk factors, cognitve decline, and dementia
Hanon, O. (2008) · Vascular Health and Risk Management · doi:10.2147/vhrm.s1839 · Cited by 314 · see citing works
On multiple‐testing correction in genome‐wide association studies
Moskvina, V., & Schmidt, K. M. (2008) · Genetic Epidemiology · doi:10.1002/gepi.20331 · Cited by 266 · see citing works
Self-citationBates, K. A., Verdile, G., Li, Q.-X., Ames, D., Hudson, P., Masters, C. L., & Martins, R. N. (2009) · Molecular Psychiatry · doi:10.1038/mp.2008.96 · Cited by 247 · 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-citationReplication of CLU, CR1, and PICALM Associations With Alzheimer Disease
Carrasquillo, M. M., Belbin, O., Hunter, T. A., Ma, L., Bisceglio, G. D., Zou, F., Crook, J. E., Pankratz, V. S., Dickson, D. W., Graff-Radford, N. R., et al. (2010) · Archives of Neurology · doi:10.1001/archneurol.2010.147 · Cited by 208 · see citing works
Self-citationAn evaluation of GO annotation retrieval for BioCreAtIvE and GOA
Camon, E. B., Barrell, D. G., Dimmer, E. C., Lee, V., Magrane, M., Maslen, J., Binns, D., & Apweiler, R. (2005) · BMC Bioinformatics · doi:10.1186/1471-2105-6-s1-s17 · Cited by 201 · see citing works
Number of dementia sufferers in Europe between the years 2000 and 2050
Wancata, J., Musalek, M., Alexandrowicz, R. W., & Krautgartner, M. (2003) · European Psychiatry · doi:10.1016/j.eurpsy.2003.03.003 · Cited by 166 · see citing works
Implication of the Immune System in Alzheimer's Disease: Evidence from Genome-Wide Pathway Analysis
Lambert, J.-C., Grenier-Boley, B., Chouraki, V., Heath, S., Zelenika, D., Fievet, N., Hannequin, D., Pasquier, F., Hanon, O., Brice, A., et al. (2010) · Journal of Alzheimer's Disease · doi:10.3233/jad-2010-100018 · Cited by 144 · see citing works
Weggen, S., Rogers, M. V., & Eriksen, J. L. (2007) · Trends in Pharmacological Sciences · doi:10.1016/j.tips.2007.09.004 · Cited by 124 · see citing works
Strategies and issues in the detection of pathway enrichment in genome-wide association studies
Hong, M., Yudi Pawitan, Y., Magnusson, P. K. E., & Prince, J. A. (2009) · Human Genetics · doi:10.1007/s00439-009-0676-z · Cited by 118 · see citing works
Koudinov, A. R., Berezov, T. T., Kumar, A. R., & Koudinova, N. V. (1998) · Clinica Chimica Acta · doi:10.1016/s0009-8981(97)00207-6 · Cited by 102 · see citing works
Innate immunity in Alzheimer's disease: a model for local inflammatory reactions.
McGeer, E. G., & McGeer, P. L. (2001) · PubMed · Cited by 75 · see citing works
Chapter 9 Alzheimer's Disease Genetics
Bertram, L. (2009) · International review of neurobiology · doi:10.1016/s0074-7742(09)00409-7 · Cited by 62 · see citing works
Reynolds, C. A., Hong, M.-G., Eriksson, U. K., Blennow, K., Wiklund, F., Johansson, B., Malmberg, B., Berg, S., Alexeyenko, A., Grönberg, H., et al. (2010) · Human Molecular Genetics · doi:10.1093/hmg/ddq079 · Cited by 57 · see citing works
Ritchie, M. D. (2009) · Genome Medicine · doi:10.1186/gm65 · Cited by 26 · see citing works
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The amyloid hypothesis of Alzheimer's disease at 25 years
Selkoe, D. J., & Hardy, J. (2016) · EMBO Molecular Medicine · doi:10.15252/emmm.201606210 · Cited by 6,164 · see citing works
Self-citationMeta-Analysis of 74,046 Individuals Identifies 11 New Susceptibility Loci for Alzheimer’s Disease
(EADI), E. A. D. I., Lambert, J.-C., (GERAD), G. A. E. R. I. A. D., Alzheimer's Disease Genetic Consortium (ADGC), (CHARGE), C. F. H. A. A. R. I. G. E., Ibrahim-Verbaas, C. A., Harold, D., Naj, A. C., Sims, R., Bellenguez, C., et al. (2013) · Nature Genetics · doi:10.1038/ng.2802 · Cited by 4,336 · see citing works
Self-citationKarran, E., Mercken, M., & Strooper, B. D. (2011) · Nature Reviews Drug Discovery · doi:10.1038/nrd3505 · Cited by 2,188 · see citing works
Preclinical Alzheimer’s Disease: Definition, Natural History, and Diagnostic Criteria
Dubois, B., Hampel, H., Feldman, H. H., Scheltens, P., Aisen, P., Andrieu, S., Bakardjian, H., Benali, H., Bertram, L., Blennow, K., et al. (2016) · Alzheimer's & Dementia · doi:10.1016/j.jalz.2016.02.002 · Cited by 1,925 · see citing works
Self-citationGenetic architectures of psychiatric disorders: the emerging picture and its implications
Sullivan, P. F., Daly, M. J., & O'Donovan, M. (2012) · Nature Reviews Genetics · doi:10.1038/nrg3240 · Cited by 1,177 · see citing works
Self-citationMicroglial priming in neurodegenerative disease
Perry, V. H., & Holmes, C. (2014) · Nature Reviews Neurology · doi:10.1038/nrneurol.2014.38 · Cited by 1,127 · see citing works
Self-citationApoE-Directed Therapeutics Rapidly Clear β-Amyloid and Reverse Deficits in AD Mouse Models
Cramer, P. E., Cirrito, J. R., Wesson, D. W., Lee, C. Y. D., Karlo, J. C., Zinn, A. E., Casali, B. T., Restivo, J. L., Goebel, W. D., James, M. J., et al. (2012) · Science · doi:10.1126/science.1217697 · Cited by 1,050 · see citing works
Microglia in Neuroinflammation and Neurodegeneration: From Understanding to Therapy
Muzio, L., Viotti, A., & Martino, G. (2021) · Frontiers in Neuroscience · doi:10.3389/fnins.2021.742065 · Cited by 581 · 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
Alzheimer’s Disease Genetics: From the Bench to the Clinic
Karch, C. M., Cruchaga, C., & Goate, A. M. (2014) · Neuron · doi:10.1016/j.neuron.2014.05.041 · Cited by 473 · see citing works
Self-citationAntibiotics, gut microbiota, and Alzheimer’s disease
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GWAS of Cerebrospinal Fluid Tau Levels Identifies Risk Variants for Alzheimer’s Disease
Cruchaga, C., Kauwe, J. S. K., Harari, O., Jin, S. C., Cai, Y., Karch, C. M., Benitez, B. A., Jeng, A. T., Skorupa, T., Carrell, D., et al. (2013) · Neuron · doi:10.1016/j.neuron.2013.02.026 · Cited by 383 · see citing works
Self-citationApolipoprotein E in Alzheimer's Disease: An Update
Yu, J.-T., Tan, L., & Hardy, J. (2014) · Annual Review of Neuroscience · doi:10.1146/annurev-neuro-071013-014300 · Cited by 394 · see citing works
Self-citationClusterin in Alzheimer’s Disease: Mechanisms, Genetics, and Lessons From Other Pathologies
Foster, E. M., Dangla-Valls, A., Lovestone, S., Ribe, E. M., & Buckley, N. J. (2019) · Frontiers in Neuroscience · doi:10.3389/fnins.2019.00164 · Cited by 381 · see citing works
Self-citationReview: Systemic inflammation and<scp>A</scp>lzheimer's disease
Holmes, C. (2013) · Neuropathology and Applied Neurobiology · doi:10.1111/j.1365-2990.2012.01307.x · Cited by 356 · see citing works
Self-citationEwers, M., Franzmeier, N., Suárez-Calvet, M., Morenas-Rodriguez, E., Caballero, M. A. A., Kleinberger, G., Piccio, L., Cruchaga, C., Deming, Y., Dichgans, M., et al. (2019) · Science Translational Medicine · doi:10.1126/scitranslmed.aav6221 · Cited by 327 · see citing works
Self-citationImmune Signaling in Neurodegeneration
Hammond, T. R., Marsh, S. E., & Stevens, B. (2019) · Immunity · doi:10.1016/j.immuni.2019.03.016 · Cited by 336 · see citing works
Tau and neuroinflammation: what impact for Alzheimer's disease and tauopathies?
Laurent, C., Buée, L., & Blum, D. (2018) · Biomedical Journal · doi:10.1016/j.bj.2018.01.003 · Cited by 348 · see citing works
Microglial genes regulating neuroinflammation in the progression of Alzheimer's disease
Villegas-Llerena, C., Phillips, A., Garcia-Reitboeck, P., Hardy, J., & Pocock, J. M. (2016) · Current Opinion in Neurobiology · doi:10.1016/j.conb.2015.10.004 · Cited by 270 · see citing works
Self-citationInfectious immunity in the central nervous system and brain function
Klein, R. S., Garber, C., & Howard, N. (2017) · Nature Immunology · doi:10.1038/ni.3656 · Cited by 235 · see citing works
Garwood, C. J., Ratcliffe, L. E., Simpson, J. E., Heath, P. R., Ince, P. G., & Wharton, S. B. (2017) · Neuropathology and Applied Neurobiology · doi:10.1111/nan.12338 · Cited by 233 · see citing works
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Zhu, Y., Nwabuisi‐Heath, E., Dumanis, S. B., Tai, L. M., Yu, C., Rebeck, G. W., & Ladu, M. J. (2012) · Glia · doi:10.1002/glia.22289 · Cited by 224 · see citing works
Watson, C. T., Roussos, P., Garg, P., Ho, D. J., Azam, N., Katsel, P. L., Haroutunian, V., & Sharp, A. J. (2016) · Genome Medicine · doi:10.1186/s13073-015-0258-8 · Cited by 201 · see citing works
Complement in the pathogenesis of Alzheimer’s disease
Morgan, B. P. (2018) · Seminars in Immunopathology · doi:10.1007/s00281-017-0662-9 · Cited by 194 · see citing works
Convergent genetic and expression data implicate immunity in Alzheimer's disease
International Genomics of Alzheimer's Disease Consortium (IGAP), Jones, L., Lambert, J., Wang, L., Choi, S., Harold, D., Vedernikov, A., Escott‐Price, V., Stone, T., Richards, A., et al. (2015) · Alzheimer's & Dementia · doi:10.1016/j.jalz.2014.05.1757 · Cited by 199 · see citing works
Self-citationFerrer, I. (2012) · Progress in Neurobiology · doi:10.1016/j.pneurobio.2012.03.005 · Cited by 174 · see citing works
Savage, J. C., Jay, T., Goduni, E., Quigley, C., Mariani, M. M., Malm, T., Ransohoff, R. M., Lamb, B. T., & Landreth, G. E. (2015) · The Journal of Neuroscience · doi:10.1523/jneurosci.4586-14.2015 · Cited by 154 · see citing works
Post-mortem analysis of neuroinflammatory changes in human Alzheimer’s disease
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ATP-binding cassette transporter A1: From metabolism to neurodegeneration
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A unifying hypothesis for Alzheimer's disease: from plaques to neurodegeneration
Edwards, F. A. (2019) · Trends in Neurosciences · doi:10.1016/j.tins.2019.03.003 · Cited by 140 · see citing works
Ramanan, V. K., Risacher, S. L., Nho, K., Kim, S., Shen, L., McDonald, B. C., Yoder, K. K., Hutchins, G. D., West, J. D., Tallman, E. F., et al. (2015) · Brain · doi:10.1093/brain/awv231 · Cited by 133 · see citing works
Jiang, Q., Jin, S., Jiang, Y., Liao, M., Feng, R., Zhang, L., Liu, G., & Hao, J. (2017) · Molecular Neurobiology · doi:10.1007/s12035-015-9670-8 · Cited by 132 · see citing works
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Reduced intrusion development after post-trauma imagery rescripting; an experimental study
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Salih, D. A., Bayram, S., Guelfi, S., Reynolds, R. H., Shoai, M., Ryten, M., Brenton, J. W., Zhang, D., Matarin, M., Botia, J. A., et al. (2019) · Brain Communications · doi:10.1093/braincomms/fcz022 · Cited by 110 · see citing works
Self-citationTansey, K. E., Cameron, D., & Hill, M. J. (2018) · Genome Medicine · doi:10.1186/s13073-018-0523-8 · Cited by 115 · see citing works
Western, D., Timsina, J., Wang, L., Wang, C., Yang, C., Phillips, B., Wang, Y., Liu, M., Ali, M., Beric, A., et al. (2024) · Nature Genetics · doi:10.1038/s41588-024-01972-8 · Cited by 111 · see citing works
Self-citationLeyland, B., Leu, S., & Boussiba, S. (2017) · Fungal Biology · doi:10.1016/j.funbio.2017.07.006 · Cited by 107 · see citing works
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Windham, I. A., & Cohen, S. (2024) · Trends in Cell Biology · doi:10.1016/j.tcb.2023.09.004 · Cited by 103 · see citing works
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Crehan, H., Hardy, J., & Pocock, J. (2013) · Neurobiology of Disease · doi:10.1016/j.nbd.2013.02.003 · Cited by 98 · see citing works
Self-citationLu, Q., Powles, R. L., Abdallah, S., Ou, D., Wang, Q., Hu, Y., Lu, Y., Liu, W., Li, B., Mukherjee, S., et al. (2017) · PLOS Genetics · doi:10.1371/journal.pgen.1006933 · Cited by 97 · see citing works
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Aly, M., & Yonelinas, A. P. (2012) · PLoS ONE · doi:10.1371/journal.pone.0030231 · Cited by 58 · see citing works
Prospects and challenges of imaging neuroinflammation beyond TSPO in Alzheimer’s disease
Faculty, O. B. O. T. M., Boche, D., Gerhard, A., & Rodriguez-Vieitez, E. (2019) · European Journal of Nuclear Medicine and Molecular Imaging · doi:10.1007/s00259-019-04462-w · Cited by 55 · see citing works
Jones, R. E., Andrews, R., Holmans, P., Hill, M., & Taylor, P. R. (2021) · Scientific Reports · doi:10.1038/s41598-021-94324-z · Cited by 39 · see citing works
“Studies investigating AD genetics and pathology have suggested immune gene networks may contribute to an increased risk of developing AD [2,3].”
BackgroundSelf-citationAlzheimer’s disease: rare variants with large effect sizes
Del-Aguila, J. L., Koboldt, D. C., Black, K., Chasse, R., Norton, J., Wilson, R. K., & Cruchaga, C. (2015) · Current Opinion in Genetics & Development · doi:10.1016/j.gde.2015.07.008 · Cited by 41 · see citing works
Genes, pathways and risk prediction in Alzheimer’s disease
Hardy, J., & Escott-Price, V. (2019) · Human Molecular Genetics · doi:10.1093/hmg/ddz163 · Cited by 27 · see citing works
Self-citation
- Authors
- Jones, L., Holmans, P. A., Hamshere, M. L., Harold, D., Moskvina, V., Ivanov, D., Pocklington, A., Abraham, R., Hollingworth, P., Sims, R., Gerrish, A., Pahwa, J. S., Jones, N., Stretton, A., Morgan, A. R., Lovestone, S., Powell, J., Proitsi, P., Lupton, M. K., Brayne, C., Rubinsztein, D. C., Gill, M., Lawlor, B., Lynch, A., Morgan, K., Brown, K. S., Passmore, P. A., Craig, D., McGuinness, B., Todd, S., Holmes, C., Mann, D., Smith, A. D., Love, S., Kehoe, P. G., Mead, S., Fox, N., Rossor, M., Collinge, J., Maier, W., Jessen, F., Schürmann, B., van den Bussche, H., Heuser, I., Peters, O., Kornhuber, J., Wiltfang, J., Dichgans, M., Frölich, L., Hampel, H., Hüll, M., Rujescu, D., Goate, A. M., Kauwe, J. S. K., Cruchaga, C., Nowotny, P., Morris, J. C., Mayo, K., Livingston, G., Bass, N. J., Gurling, H., McQuillin, A., Gwilliam, R., Deloukas, P., Al-Chalabi, A., Shaw, C. E., Singleton, A. B., Guerreiro, R., Mühleisen, T. W., Nöthen, M. M., Moebus, S., Jöckel, K.-H., Klopp, N., Wichmann, H.-E., Rüther, E., Carrasquillo, M. M., Pankratz, V. S., Younkin, S. G., Hardy, J., O'Donovan, M. C., Owen, M. J., & Williams, J.
- Affiliations
- Cardiff University (GB)
- National Health Service (GB)
- King's College London (GB)
- University of Cambridge (GB)
- Trinity College Dublin (IE)
- University of Nottingham (GB)
- Queen's University Belfast (GB)
- University of Southampton (GB)
- University of Manchester (GB)
- John Radcliffe Hospital (GB)
- Frenchay Hospital (GB)
- MRC Prion Unit (GB)
- UCL Queen Square Institute of Neurology (GB)
- University of Bonn (DE)
- University Medical Center Hamburg-Eppendorf (DE)
- Friedrich-Alexander-Universität Erlangen-Nürnberg (DE)
- University of Duisburg-Essen (DE)
- Institut für Schlaganfall- und Demenzforschung (DE)
- Heidelberg University (DE)
- University of Freiburg (DE)
- Ludwig-Maximilians-Universität München (DE)
- Washington University in St. Louis (US)
- Brigham Young University (US)
- University College London (GB)
- Wellcome Sanger Institute (GB)
- National Institutes of Health (US)
- Essen University Hospital (DE)
- Helmholtz Munich (DE)
- University of Göttingen (DE)
- Mayo Clinic (US)
- Corresponding author
- Owen, Michael J.
- Williams, Julie
- ORCID
- Jones, Lesley
- Holmans, Peter A.
- Hamshere, Marian L.
- Harold, Denise
- Ivanov, Dobril
- Pocklington, Andrew
- Sims, Rebecca
- Gerrish, Amy
- Lovestone, Simon
- Powell, John
- Proitsi, Petroula
- Lupton, Michelle K.
- Brayne, Carol
- Rubinsztein, David C.
- Gill, Michael
- Lawlor, Brian
- Morgan, Kevin
- Passmore, Peter A.
- Craig, David
- McGuinness, Bernadette
- Todd, Stephen
- Holmes, Clive
- Mann, David
- Smith, A. David
- Love, Seth
- Kehoe, Patrick G.
- Mead, Simon
- Fox, Nick
- Rossor, Martin
- Collinge, John
- Maier, Wolfgang
- Jessen, Frank
- Heuser, Isabella
- Peters, Oliver
- Kornhuber, Johannes
- Wiltfang, Jens
- Dichgans, Martin
- Hampel, Harald
- Rujescu, Dan
- Goate, Alison M.
- Cruchaga, Carlos
- Morris, John C.
- Livingston, Gill
- Bass, Nicholas J.
- McQuillin, Andrew
- Deloukas, Panos
- Shaw, Christopher E.
- Singleton, Andrew B.
- Guerreiro, Rita
- Mühleisen, Thomas W.
- Nöthen, Markus M.
- Moebus, Susanne
- Jöckel, Karl-Heinz
- Wichmann, H.-Erich
- Carrasquillo, Minerva M.
- Pankratz, V. Shane
- Hardy, John
- Owen, Michael J.
- Williams, Julie
- Venue
- PLoS ONE
- Publisher
- Public Library of Science (PLoS)
- Published
- 2010-11-15
- Volume
- 5
- Issue
- 11
- Pages
- e13950
- ISSN
- 1932-6203 (ISSN-L)
- PMC
- PMC2981526
- OpenAlex
- W2166511841
- Cited by
- 606
- References
- 42
- Citations by year
- 2026: 11 · 2025: 14 · 2024: 22 · 2023: 16 · 2022: 22 · 2021: 59 · 2020: 39 · 2019: 44 · 2018: 48 · 2017: 48 · 2016: 65 · 2015: 33 · 2014: 40 · 2013: 49 · 2012: 49
- FWCI
- 31.40
- Type
- journal article
- Language
- en
- Update notices
- correction (2011-02-11)
- Open access
- gold
- doi.org
- Locations
- PLoS ONE (publishedVersion, cc-by)
- PubMed Central (publishedVersion, cc-by)
- PubMed (publishedVersion)
- Amsterdam UMC (VU Amsterdam) - Institutional Repository (publishedVersion, other-oa)
- Research Portal (Queen's University Belfast) (publishedVersion, cc-by)
- ORCA Online Research @Cardiff (Cardiff University) (acceptedVersion)
- Pure Amsterdam UMC (acceptedVersion, other-oa)
- Digital Commons@Becker (Washington University School of Medicine) (submittedVersion)
- Open access LMU (Ludwid Maxmilian's Universitat Munchen) (submittedVersion)
- Digital Academic REpository of VU University Amsterdam (Vrije Universiteit Amsterdam) (submittedVersion)
- DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
- UCL Discovery (University College London) (submittedVersion)
- Figshare (submittedVersion, cc-by)
- GoeScholar The Publication Server of the Georg-August-Universität Göttingen (Georg-August-Universität Göttingen) (submittedVersion, cc-by)
- ORCA Online Research @Cardiff (Cardiff University) (submittedVersion, cc-by)
- Research Portal (King's College London) (submittedVersion, cc-by)
- Bristol Research (University of Bristol) (submittedVersion)
- UEA Digital Repository (University of East Anglia) (submittedVersion, cc-by)
- Data Archiving and Networked Services (DANS) (submittedVersion, other-oa)
- Universitätsbibliothek der LMU
- Funders
- U.S. Department of Health and Human Services (Z01 AG000950-06)
- Juvenile Diabetes Research Foundation International
- American Health Assistance Foundation
- Abbott Laboratories
- Pfizer
- Wellcome Trust
- Alzheimer's Society
- Translational Genomics Research Institute
- Alzheimer's Research Trust
- Motor Neurone Disease Association
- University College London
- Cardiff University
- Bundesministerium für Bildung und Forschung
- Belgian Federal Science Policy Office
- Alfried Krupp von Bohlen und Halbach-Stiftung
- Universiteit Antwerpen
- Vlaamse regering
- H. Lundbeck A/S
- Instituut Born-Bunge
- Heinz Nixdorf Stiftung
- National Institutes of Health
- Medical Research Council
- Bijzonder Onderzoeksfonds UGent
- National Institute on Aging (Z01AG000950)
- National Institute of Mental Health
- National Institute of Allergy and Infectious Diseases
- National Institute of Diabetes and Digestive and Kidney Diseases
- National Institute of Child Health and Human Development
- 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, cholesterol metabolism, innate immune response, etiology, genetic susceptibility, apolipoprotein E, pathway enrichment, therapeutic target
- MeSH terms
- Alzheimer Disease, Apolipoproteins E, Cholesterol, Chromosome Mapping, Humans, Immune System, Genome, Human, Genetic Predisposition to Disease, Polymorphism, Single Nucleotide, Genome-Wide Association Study
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 ›
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