Implication of the Immune System in Alzheimer's Disease: Evidence from Genome-Wide Pathway Analysis
Open accessAbstract
The results of several genome-wide association studies (GWASs) in the field of Alzheimer's disease (AD) have recently been published. Although these studies reported in detail on single-nucleotide polymorphisms (SNPs) and the neighboring genes with the strongest evidence of association with AD, little attention was paid to the rest of the genome. However, complementary statistical and bio-informatics approaches now enable the extraction of pertinent information from other SNPs and/or genes which are only nominally associated with the disease risk. Two different tools (the ALIGATOR and GenGen/KEGG software packages) were used to analyze a large GWAS dataset containing 2,032 AD cases and 5,328 controls. Convergent outputs from the two gene set enrichment approaches suggested an immune system dysfunction in AD. Furthermore, although these statistical approaches did not adopt a priori hypotheses concerning a biological function's putative role in the disease process, genes associated with AD risk were overrepresented in the "Alzheimer's disease" KEGG pathway. In conclusion, a systematic search for biological pathways using GWAS data set seems to comfort the primary causes already suspected but may specifically highlight the importance of the immune system in AD.
The claims and statistics of this paper haven’t been checked yet.
Run the check — free, no account needed. It reads the open-access text and checks the sources it cites.
Integrity signals
Registry
Cites
Statistics
Claims the paper makes
The claims and statistics of this paper haven’t been checked yet.
Run the check — free, no account needed. It reads the open-access text and checks the sources it cites.
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?
GWAS have identified several single-nucleotide polymorphisms in immune genes as independent risk factors for late-onset AD, directly implicating microglia-mediated mechanisms in sporadic AD progression.
“Likewise, genome-wide association studies (GWAS) have identified several single-nucleotide polymorphisms (SNPs) in immune genes as independent risk factors for LOAD [52–55], directly implicating microglia-mediated mechanisms in sporadic AD progression.”
From Systems-based proteomics to resolve the biology of Alzheimer’s disease beyond amyloid and tau (2021) · cites this paper as [53]
Self-check
Percentages, sums and reported differences re-computed from the paper’s own numbers.
The self-check needs the paper’s full text.
Cites
Subramanian, A., Tamayo, P., Mootha, V. K., Mukherjee, S., Ebert, B. L., Gillette, M. A., Paulovich, A., Pomeroy, S. L., Golub, T. R., Lander, E. S., et al. (2005) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.0506580102 · Cited by 53,625 · 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
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
The Wellcome Trust Case Control Consortium, U.K.
Mossman, K. (2008) · Scientific American · doi:10.1038/scientificamerican0108-42a · Cited by 2,714 · 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
Self-citationGenome-wide association study identifies eight loci associated with blood pressure
Wellcome Trust Case Control Consortium, Newton-Cheh, C., Johnson, T., Gateva, V., Tobin, M. D., Bochud, M., Coin, L., Najjar, S. S., Zhao, J. H., Heath, S. C., et al. (2009) · Nature Genetics · doi:10.1038/ng.361 · Cited by 1,215 · see citing works
Self-citationCommon genetic variants on 5p14.1 associate with autism spectrum disorders
Wang, K., Zhang, H., Ma, D., Bucan, M., Glessner, J. T., Abrahams, B. S., Salyakina, D., Imielinski, M., Bradfield, J. P., Sleiman, P. M. A., et al. (2009) · Nature · doi:10.1038/nature07999 · Cited by 989 · see citing works
Macroautophagy—a novel β-amyloid peptide-generating pathway activated in Alzheimer's disease
Yu, W. H., Cuervo, A. M., Kumar, A., Peterhoff, C. M., Schmidt, S. D., Lee, J.-H., Mohan, P. S., Mercken, M., Farmery, M. R., Tjernberg, L. O., et al. (2005) · The Journal of Cell Biology · doi:10.1083/jcb.200505082 · Cited by 967 · 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
Autophagy, amyloidogenesis and Alzheimer disease
Nixon, R. A. (2007) · Journal of Cell Science · doi:10.1242/jcs.019265 · Cited by 749 · see citing works
Hunter, D. J., Peltonen, L., Guiducci, C., Crawford, G., Hirschhorn, J. N., Lyon, H. N., & Speliotes, E. K. (2009) · DSpace@MIT (Massachusetts Institute of Technology) · Cited by 687 · see citing works
(2003) · Neuroepidemiology · doi:10.1159/000072920 · Cited by 672 · see citing works
Vassar, R., Kovacs, D. M., Yan, R., & Wong, P. C. (2009) · The Journal of Neuroscience · doi:10.1523/jneurosci.3657-09.2009 · Cited by 577 · see citing works
Use and misuse of the gene ontology annotations
Rhee, S. Y., Wood, V., Dolinski, K. J., & Drăghici, S. (2008) · Nature Reviews Genetics · doi:10.1038/nrg2363 · Cited by 506 · 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
Choroid plexus: biology and pathology
Wolburg, H., & Paulus, W. (2009) · Acta Neuropathologica · doi:10.1007/s00401-009-0627-8 · Cited by 376 · see citing works
A Polymorphism in CALHM1 Influences Ca2+ Homeostasis, Aβ Levels, and Alzheimer's Disease Risk
Dreses‐Werringloer, U., Lambert, J., Vingtdeux, V., Zhao, H., Vais, H., Siebert, A. P., Jain, A., Koppel, J. L., Rovelet‐Lecrux, A., Hannequin, D., et al. (2008) · Cell · doi:10.1016/j.cell.2008.05.048 · Cited by 319 · see citing works
Self-citationDiverse Genome-wide Association Studies Associate the IL12/IL23 Pathway with Crohn Disease
Wang, K., Zhang, H., Kugathasan, S., Annese, V., Bradfield, J. P., Russell, R. K., Sleiman, P. M. A., Imielinski, M., Glessner, J., Hou, C., et al. (2009) · The American Journal of Human Genetics · doi:10.1016/j.ajhg.2009.01.026 · Cited by 291 · see citing works
Aβ Species Removal After Aβ <sub>42</sub> Immunization
Nicoll, J. A. R., Barton, E., Boche, D., Neal, J. W., Ferrer, I., Thompson, P., Vlachouli, C., Wilkinson, D., Bayer, A., Games, D., et al. (2006) · Journal of Neuropathology & Experimental Neurology · doi:10.1097/01.jnen.0000240466.10758.ce · Cited by 265 · see citing works
Transcriptomic and genetic studies identify IL-33 as a candidate gene for Alzheimer's disease
Chapuis, J., Hot, D., Hansmannel, F., Kerdraon, O., Ferreira, S., Hubans, C., Maurage, C. A., Huot, L., Bensemain, F., Laumet, G., et al. (2009) · Molecular Psychiatry · doi:10.1038/mp.2009.10 · Cited by 201 · see citing works
Self-citationMolecular diagnosis of autosomal dominant early onset Alzheimer’s disease: an update: Table 1
Raux, G., Guyant‐Maréchal, L., Martin, C., Bou, J., Penet, C., Brice, A., Hannequin, D., Frébourg, T., & Campion, D. (2005) · Journal of Medical Genetics · doi:10.1136/jmg.2005.033456 · Cited by 199 · see citing works
Self-citationUsing genome‐wide pathway analysis to unravel the etiology of complex diseases
Elbers, C. C., van Eijk, K. R., Franke, L., Mulder, F., van der Schouw, Y. T., Wijmenga, C., & Onland‐Moret, N. C. (2009) · Genetic Epidemiology · doi:10.1002/gepi.20395 · Cited by 190 · see citing works
The ADAMs family: Coordinators of nervous system development, plasticity and repair
Yang, P., Baker, K. A., & Hagg, T. (2006) · Progress in Neurobiology · doi:10.1016/j.pneurobio.2006.05.001 · Cited by 134 · 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
Self-citationFarrer, L. A. (1997) · JAMA · doi:10.1001/jama.1997.03550160069041 · Cited by 124 · see citing works
Autoantibodies against β‐amyloid are common in Alzheimer's disease and help control plaque burden
Kellner, A., Matschke, J., Bernreuther, C., Moch, H., Ferrer, I., & Glatzel, M. (2009) · Annals of Neurology · doi:10.1002/ana.21475 · Cited by 113 · see citing works
Review: Autophagy in neurodegeneration: firefighter and/or incendiarist?
Rami, A. (2009) · Neuropathology and Applied Neurobiology · doi:10.1111/j.1365-2990.2009.01034.x · Cited by 107 · see citing works
Differential expression of individual complement regulators in the brain and choroid plexus.
Singhrao, S. K., Neal, J. W., Rushmere, N. K., Morgan, B. P., & Gasque, P. (1999) · PubMed · Cited by 95 · see citing works
Dysregulation of Calcium Homeostasis in Alzheimer’s Disease
Small, D. H. (2009) · Neurochemical Research · doi:10.1007/s11064-009-9960-5 · Cited by 94 · see citing works
Resende, R., Pereira, C., Agostinho, P. M., Vieira, A. P., Malva, J. O., & Oliveira, C. R. (2007) · Brain Research · doi:10.1016/j.brainres.2007.01.071 · Cited by 92 · see citing works
Trends in meta-analysis of genetic association studies
Zintzaras, E., & Lau, J. (2007) · Journal of Human Genetics · doi:10.1007/s10038-007-0223-5 · Cited by 86 · see citing works
Erdei, A., Isaák, A., Török, K., Sándor, N., Kremlitzka, M., Prechl, J., & Bajtay, Z. (2009) · Molecular Immunology · doi:10.1016/j.molimm.2009.05.181 · Cited by 84 · see citing works
Enriching the Analysis of Genomewide Association Studies with Hierarchical Modeling
Chen, G. K., & Witte, J. S. (2007) · The American Journal of Human Genetics · doi:10.1086/519794 · Cited by 79 · see citing works
Common genetic variants on 5p14.1 associate with autism spectrum disorders
Sweeney, J. A., Klin, A., Chiavacci, R. M., et al. (2020) · Carolina Digital Repository (University of North Carolina at Chapel Hill) · doi:10.17615/g04w-kk07 · Cited by 63 · see citing works
Human monoclonal antibodies against amyloid-beta from healthy adults
Geylis, V., Kourilov, V., Meiner, Z., Nennesmo, I., Bogdanović, N., & Steinitz, M. O. (2004) · Neurobiology of Aging · doi:10.1016/j.neurobiolaging.2004.06.008 · Cited by 51 · see citing works
Major histocompatibility complex and sporadic Alzheimer's disease: a critical reappraisal
Candore, G., Balistreri, C. R., Colonna‐Romano, G., Lio, D., & Caruso, C. (2004) · Experimental Gerontology · doi:10.1016/j.exger.2003.10.027 · Cited by 36 · see citing works
A TAP2 genotype associated with Alzheimer's disease in APOE4 carriers
Bullido, M. J., Martı́nez-Garcı́a, A., Artiga, M. J., Aldudo, J., Sastre, I., Gil, P., Coria, F., Muñoz, D. G., Hachinski, V., Frank, A., et al. (2006) · Neurobiology of Aging · doi:10.1016/j.neurobiolaging.2006.02.011 · Cited by 30 · see citing works
Complex Diseases, Complex Genes
Kraft, P., & Raychaudhuri, S. (2009) · Epidemiology · doi:10.1097/ede.0b013e3181a93b98 · Cited by 29 · see citing works
Cheung, Y.-T., Zhang, N. Q., Hung, C. H.-L., Lai, C. S.-W., Yu, M.-S., So, K., & Chang, R. C. (2010) · Journal of Cellular and Molecular Medicine · doi:10.1111/j.1582-4934.2009.00990.x · Cited by 25 · see citing works
Antigens and Autophagy: The Path Less Travelled?
Taylor, G. S., & Rickinson, A. B. (2007) · Autophagy · doi:10.4161/auto.3425 · Cited by 5 · see citing works
Flagged first, then by citations
Cited by
Sorted by citations
Meta-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-citationJones, L., Holmans, P. A., Hamshere, M. L., Harold, D., Moskvina, V., Ivanov, D., Pocklington, A., Abraham, R., Hollingworth, P., Sims, R., et al. (2010) · PLoS ONE · doi:10.1371/journal.pone.0013950 · Cited by 606 · 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
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
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-citationGene set analysis of genome-wide association studies: Methodological issues and perspectives
Wang, L., Jia, P., Wolfinger, R. D., Chen, X., & Zhao, Z. (2011) · Genomics · doi:10.1016/j.ygeno.2011.04.006 · Cited by 207 · see citing works
Dourlen, P., Kilinc, D., Malmanche, N., Chapuis, J., & Lambert, J.-C. (2019) · Acta Neuropathologica · doi:10.1007/s00401-019-02004-0 · Cited by 168 · see citing works
Self-citationMartin, E., Boucher, C., Fontaine, B., & Delarasse, C. (2017) · Aging Cell · doi:10.1111/acel.12522 · Cited by 156 · see citing works
Liu, X., Hao, W., Qin, Y., Decker, Y., Wang, X., Burkart, M., Schötz, K., Menger, M. D., Fassbender, K., & Liu, Y. (2015) · Brain Behavior and Immunity · doi:10.1016/j.bbi.2015.01.011 · Cited by 149 · 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
Systems-based proteomics to resolve the biology of Alzheimer’s disease beyond amyloid and tau
Rayaprolu, S., Higginbotham, L., Bagchi, P., Watson, C. M., Zhang, T., Levey, A. I., Rangaraju, S., & Seyfried, N. T. (2021) · Neuropsychopharmacology · doi:10.1038/s41386-020-00840-3 · Cited by 118 · see citing works
- Authors
- Lambert, J.-C., Grenier-Boley, B., Chouraki, V., Heath, S., Zelenika, D., Fievet, N., Hannequin, D., Pasquier, F., Hanon, O., Brice, A., Epelbaum, J., Berr, C., Dartigues, J.-F., Tzourio, C., Campion, D., Lathrop, M., & Amouyel, P.
- Affiliations
- Inserm (FR)
- INSERM U744, Lille, France
- Commissariat à l'Énergie Atomique et aux Énergies Alternatives (FR)
- Centre National de Génotypage, Institut Génomique, Commissariat à l'Energie Atomique, Evry, France
- Centre Hospitalier Universitaire de Lille (FR)
- INSERM U897, Victor Segalen University, Bordeaux, France
- ORCID
- Venue
- Journal of Alzheimer's Disease
- Publisher
- SAGE Publications
- Published
- 2010-06-13
- Volume
- 20
- Issue
- 4
- Pages
- 1107-1118
- ISSN
- 1387-2877 (ISSN-L)
- 1875-8908
- OpenAlex
- W1515176900
- Cited by
- 144
- References
- 40
- Citations by year
- 2026: 2 · 2025: 3 · 2024: 7 · 2023: 6 · 2022: 7 · 2021: 6 · 2020: 6 · 2019: 13 · 2018: 9 · 2017: 5 · 2016: 14 · 2015: 9 · 2014: 18 · 2013: 8 · 2012: 6
- FWCI
- 8.45
- Type
- journal article
- Language
- en
- Open access
- hybrid
- doi.org
- Licence
- Locations
- Journal of Alzheimer s Disease (publishedVersion, cc-by-nc)
- PubMed (publishedVersion)
- Funders
- Sanofi
- Institut National de la Santé et de la Recherche Médicale
- Fondation pour la Recherche Médicale
- Eisai
- Fondation de France
- Mutuelle Générale de l'Education Nationale
- 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 › Neuroscience › Neurology › Neuroinflammation and Neurodegeneration Mechanisms
- Keywords
- Alzheimer's disease, immune dysfunction
- MeSH terms
- Aged, Alzheimer Disease, Data Interpretation, Statistical, DNA, France, Humans, Immune System, Immunity, Risk, Software, Databases, Factual, Computational Biology, 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 ›
Are you an author, or do you see a problem with this page? Request a review
