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Rare coding variants in PLCG2, ABI3, and TREM2 implicate microglial-mediated innate immunity in Alzheimer's disease

Nature Genetics volume 49, pages 1373–1384 (2017)Cite this article

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Abstract

We identified rare coding variants associated with Alzheimer's disease in a three-stage case–control study of 85,133 subjects. In stage 1, we genotyped 34,174 samples using a whole-exome microarray. In stage 2, we tested associated variants (P < 1 × 10−4) in 35,962 independent samples using de novo genotyping and imputed genotypes. In stage 3, we used an additional 14,997 samples to test the most significant stage 2 associations (P < 5 × 10−8) using imputed genotypes. We observed three new genome-wide significant nonsynonymous variants associated with Alzheimer's disease: a protective variant in PLCG2 (rs72824905: p.Pro522Arg, P = 5.38 × 10−10, odds ratio (OR) = 0.68, minor allele frequency (MAF)cases = 0.0059, MAFcontrols = 0.0093), a risk variant in ABI3 (rs616338: p.Ser209Phe, P = 4.56 × 10−10, OR = 1.43, MAFcases = 0.011, MAFcontrols = 0.008), and a new genome-wide significant variant in TREM2 (rs143332484: p.Arg62His, P = 1.55 × 10−14, OR = 1.67, MAFcases = 0.0143, MAFcontrols = 0.0089), a known susceptibility gene for Alzheimer's disease. These protein-altering changes are in genes highly expressed in microglia and highlight an immune-related protein–protein interaction network enriched for previously identified risk genes in Alzheimer's disease. These genetic findings provide additional evidence that the microglia-mediated innate immune response contributes directly to the development of Alzheimer's disease.

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Figure 1: Association plots of PLCG2, ABI3, and TREM2.
Figure 2: Protein–protein interaction network (using high-confidence human interactions from the STRING database) of 56 genes enriched for both common and rare variants associated with Alzheimer's disease risk.

References

  1. Gatz, M. et al. Role of genes and environments for explaining Alzheimer disease. Arch. Gen. Psychiatry 63, 168–174 (2006).

    Article  PubMed  Google Scholar 

  2. Lambert, J.-C. et al. Meta-analysis of 74,046 individuals identifies 11 new susceptibility loci for Alzheimer's disease. Nat. Genet. 45, 1452–1458 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  3. Harold, D. et al. Genome-wide association study identifies variants at CLU and PICALM associated with Alzheimer's disease. Nat. Genet. 41, 1088–1093 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  4. Lambert, J.-C. et al. Genome-wide association study identifies variants at CLU and CR1 associated with Alzheimer's disease. Nat. Genet. 41, 1094–1099 (2009).

    Article  CAS  PubMed  Google Scholar 

  5. Escott-Price, V. et al. Gene-wide analysis detects two new susceptibility genes for Alzheimer's disease. PLoS One 9, e94661 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  6. Hollingworth, P. et al. Common variants at ABCA7, MS4A6A/MS4A4E, EPHA1, CD33 and CD2AP are associated with Alzheimer's disease. Nat. Genet. 43, 429–435 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  7. Naj, A.C. et al. Common variants at MS4A4/MS4A6E, CD2AP, CD33 and EPHA1 are associated with late-onset Alzheimer's disease. Nat. Genet. 43, 436–441 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  8. Ruiz, A. et al. Toward fine mapping and functional characterization of genome-wide association study–identified locus rs74615166 (TRIP4) for Alzheimer's disease. Alzheimers Dement. 10, 257–P258 (2014).

    Article  Google Scholar 

  9. Jonsson, T. et al. Variant of TREM2 associated with the risk of Alzheimer's disease. N. Engl. J. Med. 368, 107–116 (2013).

    Article  CAS  PubMed  Google Scholar 

  10. Jonsson, T. et al. A mutation in APP protects against Alzheimer's disease and age-related cognitive decline. Nature 488, 96–99 (2012).

    Article  CAS  PubMed  Google Scholar 

  11. Guerreiro, R. et al. TREM2 variants in Alzheimer's disease. N. Engl. J. Med. 368, 117–127 (2013).

    Article  CAS  PubMed  Google Scholar 

  12. Seshadri, S. et al. Genome-wide analysis of genetic loci associated with Alzheimer disease. J. Am. Med. Assoc. 303, 1832–1840 (2010).

    Article  CAS  Google Scholar 

  13. Escott-Price, V. et al. Common polygenic variation enhances risk prediction for Alzheimer's disease. Brain 138, 3673–3684 (2015).

    Article  PubMed  PubMed Central  Google Scholar 

  14. Bodmer, W. & Bonilla, C. Common and rare variants in multifactorial susceptibility to common diseases. Nat. Genet. 40, 695–701 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  15. Pritchard, J.K. Are rare variants responsible for susceptibility to complex diseases? Am. J. Hum. Genet. 69, 124–137 (2001).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  16. Schork, N.J., Murray, S.S., Frazer, K.A. & Topol, E.J. Common vs. rare allele hypotheses for complex diseases. Curr. Opin. Genet. Dev. 19, 212–219 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  17. Surakka, I. et al. The impact of low-frequency and rare variants on lipid levels. Nat. Genet. 47, 589–597 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  18. Vardarajan, B.N. et al. Coding mutations in SORL1 and Alzheimer disease. Ann. Neurol. 77, 215–227 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  19. Vardarajan, B.N. et al. Rare coding mutations identified by sequencing of Alzheimer disease genome-wide association studies loci. Ann. Neurol. 78, 487–498 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  20. Steinberg, S. et al. Loss-of-function variants in ABCA7 confer risk of Alzheimer's disease. Nat. Genet. 47, 445–447 (2015).

    Article  CAS  PubMed  Google Scholar 

  21. Logue, M.W. et al. Two rare AKAP9 variants are associated with Alzheimer's disease in African Americans. Alzheimers Dement. 10, 609–618 (2014).

    Article  PubMed  PubMed Central  Google Scholar 

  22. Jun, G. et al. PLXNA4 is associated with Alzheimer disease and modulates tau phosphorylation. Ann. Neurol. 76, 379–392 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  23. Hunkapiller, J. et al. A rare coding variant alters UNC5C function and predisposes to Alzheimer's disease. Alzheimers Dement. 9, 853 (2013).

    Article  Google Scholar 

  24. Wetzel-Smith, M.K. et al. A rare mutation in UNC5C predisposes to late-onset Alzheimer's disease and increases neuronal cell death. Nat. Med. 20, 1452–1457 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  25. Richards, A.L. et al. Exome arrays capture polygenic rare variant contributions to schizophrenia. Hum. Mol. Genet. 25, 1001–1007 (2016).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  26. Wessel, J. et al. Low-frequency and rare exome chip variants associate with fasting glucose and type 2 diabetes susceptibility. Nat. Commun. 6, 5897 (2015).

    Article  CAS  PubMed  Google Scholar 

  27. Igartua, C. et al. Ethnic-specific associations of rare and low-frequency DNA sequence variants with asthma. Nat. Commun. 6, 5965 (2015).

    Article  CAS  PubMed  Google Scholar 

  28. Tachmazidou, I. et al. A rare functional cardioprotective APOC3 variant has risen in frequency in distinct population isolates. Nat. Commun. 4, 2872 (2013).

    Article  CAS  PubMed  Google Scholar 

  29. Huyghe, J.R. et al. Exome array analysis identifies new loci and low-frequency variants influencing insulin processing and secretion. Nat. Genet. 45, 197–201 (2013).

    Article  CAS  PubMed  Google Scholar 

  30. Willer, C.J., Li, Y. & Abecasis, G.R. METAL: fast and efficient meta-analysis of genomewide association scans. Bioinformatics 26, 2190–2191 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  31. R Development Core Team. R: A Language and Environment for Statistical Computing (R Foundation for Statistical Computing, 2014).

  32. Das, S. et al. Next-generation genotype imputation service and methods. Nat. Genet. 48, 1284–1287 (2016).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  33. McCarthy, S. et al. A reference panel of 64,976 haplotypes for genotype imputation. Nat. Genet. 48, 1279–1283 (2016).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  34. Jin, S.C. et al. Coding variants in TREM2 increase risk for Alzheimer's disease. Hum. Mol. Genet. 23, 5838–5846 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  35. Lu, Y., Liu, W. & Wang, X. TREM2 variants and risk of Alzheimer's disease: a meta-analysis. Neurol. Sci. 36, 1881–1888 (2015).

    Article  PubMed  Google Scholar 

  36. Cruchaga, C. et al. GWAS of cerebrospinal fluid tau levels identifies risk variants for Alzheimer's disease. Neuron 78, 256–268 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  37. International Genomics of Alzheimer's Disease Consortium (IGAP).. Convergent genetic and expression data implicate immunity in Alzheimer's disease. Alzheimers Dement. 11, 658–671 (2015).

  38. Zhang, Y. et al. Purification and characterization of progenitor and mature human astrocytes reveals transcriptional and functional differences with mouse. Neuron 89, 37–53 (2016).

    Article  CAS  PubMed  Google Scholar 

  39. Milner, J.D. PLAID: a syndrome of complex patterns of disease and unique phenotypes. J. Clin. Immunol. 35, 527–530 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  40. Fairfax, B.P. et al. Innate immune activity conditions the effect of regulatory variants upon monocyte gene expression. Science 343, 1246949 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  41. Sekino, S. et al. The NESH/Abi-3-based WAVE2 complex is functionally distinct from the Abi-1-based WAVE2 complex. Cell Commun. Signal. 13, 41 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  42. Nolz, J.C. et al. The WAVE2 complex regulates actin cytoskeletal reorganization and CRAC-mediated calcium entry during T cell activation. Curr. Biol. 16, 24–34 (2006).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  43. Xing, J., Titus, A.R. & Humphrey, M.B. The TREM2–DAP12 signaling pathway in Nasu–Hakola disease: a molecular genetics perspective. Res. Rep. Biochem. 5, 89–100 (2015).

    PubMed  PubMed Central  Google Scholar 

  44. Neumann, H. & Takahashi, K. Essential role of the microglial triggering receptor expressed on myeloid cells-2 (TREM2) for central nervous tissue immune homeostasis. J. Neuroimmunol. 184, 92–99 (2007).

    Article  CAS  PubMed  Google Scholar 

  45. Painter, M.M. et al. TREM2 in CNS homeostasis and neurodegenerative disease. Mol. Neurodegener. 10, 43 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  46. Ulrich, J.D. et al. In vivo measurement of apolipoprotein E from the brain interstitial fluid using microdialysis. Mol. Neurodegener. 8, 13 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  47. Wang, Y. et al. TREM2 lipid sensing sustains the microglial response in an Alzheimer's disease model. Cell 160, 1061–1071 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  48. Rademakers, R. et al. Mutations in the colony stimulating factor 1 receptor (CSF1R) gene cause hereditary diffuse leukoencephalopathy with spheroids. Nat. Genet. 44, 200–205 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  49. Perlmutter, L.S., Barron, E. & Chui, H.C. Morphologic association between microglia and senile plaque amyloid in Alzheimer's disease. Neurosci. Lett. 119, 32–36 (1990).

    Article  CAS  PubMed  Google Scholar 

  50. Wisniewski, H.M., Wegiel, J., Wang, K.C. & Lach, B. Ultrastructural studies of the cells forming amyloid in the cortical vessel wall in Alzheimer's disease. Acta Neuropathol. 84, 117–127 (1992).

    Article  CAS  PubMed  Google Scholar 

  51. Schwab, C., Klegeris, A. & McGeer, P.L. Inflammation in transgenic mouse models of neurodegenerative disorders. Biochim. Biophys. Acta 1802, 889–902 (2010).

    Article  CAS  PubMed  Google Scholar 

  52. Hong, S. et al. Complement and microglia mediate early synapse loss in Alzheimer mouse models. Science 352, 712–716 (2016).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  53. Olmos-Alonso, A. et al. Pharmacological targeting of CSF1R inhibits microglial proliferation and prevents the progression of Alzheimer's-like pathology. Brain 139, 891–907 (2016).

    Article  PubMed  PubMed Central  Google Scholar 

  54. Paris, D. et al. The spleen tyrosine kinase (Syk) regulates Alzheimer amyloid-β production and tau hyperphosphorylation. J. Biol. Chem. 289, 33927–33944 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  55. Bao, M. et al. CD2AP/SHIP1 complex positively regulates plasmacytoid dendritic cell receptor signaling by inhibiting the E3 ubiquitin ligase Cbl. J. Immunol. 189, 786–792 (2012).

    Article  CAS  PubMed  Google Scholar 

  56. Kurosaki, T. & Tsukada, S. BLNK: connecting Syk and Btk to calcium signals. Immunity 12, 1–5 (2000).

    Article  CAS  PubMed  Google Scholar 

  57. Wang, Y. et al. TREM2-mediated early microglial response limits diffusion and toxicity of amyloid plaques. J. Exp. Med. 213, 667–675 (2016).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  58. Yuan, P. et al. TREM2 haplodeficiency in mice and humans impairs the microglia barrier function leading to decreased amyloid compaction and severe axonal dystrophy. Neuron 90, 724–739 (2016).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  59. Goldstein, J.I. et al. zCall: a rare variant caller for array-based genotyping: genetics and population analysis. Bioinformatics 28, 2543–2545 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  60. Devlin, B. & Roeder, K. Genomic control for association studies. Biometrics 55, 997–1004 (1999).

    CAS  PubMed  Google Scholar 

  61. Grove, M.L. et al. Best practices and joint calling of the HumanExome BeadChip: the CHARGE Consortium. PLoS One 8, e68095 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  62. Patterson, N., Price, A.L. & Reich, D. Population structure and eigenanalysis. PLoS Genet. 2, e190 (2006).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  63. Howie, B., Fuchsberger, C., Stephens, M., Marchini, J. & Abecasis, G.R. Fast and accurate genotype imputation in genome-wide association studies through pre-phasing. Nat. Genet. 44, 955–959 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  64. Fuchsberger, C., Abecasis, G.R. & Hinds, D.A. minimac2: faster genotype imputation. Bioinformatics 31, 782–784 (2015).

    Article  CAS  PubMed  Google Scholar 

  65. Talluri, R. & Shete, S. A linkage disequilibrium–based approach to selecting disease-associated rare variants. PLoS One 8, e69226 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  66. Holmans, P. et al. Gene ontology analysis of GWA study data sets provides insights into the biology of bipolar disorder. Am. J. Hum. Genet. 85, 13–24 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  67. Lim, A.S.P. et al. 24-hour rhythms of DNA methylation and their relation with rhythms of RNA expression in the human dorsolateral prefrontal cortex. PLoS Genet. 10, e1004792 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  68. De Jager, P.L. et al. Alzheimer's disease: early alterations in brain DNA methylation at ANK1, BIN1, RHBDF2 and other loci. Nat. Neurosci. 17, 1156–1163 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  69. Chan, G. et al. CD33 modulates TREM2: convergence of Alzheimer loci. Nat. Neurosci. 18, 1556–1558 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

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Acknowledgements

GERAD/PERADES. We thank all individuals who participated in this study. Cardiff University was supported by the Alzheimer's Society (AS; grant RF014/164) and the Medical Research Council (MRC; grants G0801418/1, MR/K013041/1, MR/L023784/1) (R. Sims is an AS Research Fellow). Cardiff University was also supported by the European Joint Programme for Neurodegenerative Disease (JPND; grant MR/L501517/1), Alzheimer's Research UK (ARUK; grant ARUK-PG2014-1), the Welsh Assembly Government (grant SGR544:CADR), and a donation from the Moondance Charitable Foundation. Cardiff University acknowledges the support of the UK Dementia Research Institute, of which J. Williams is an associate director. Cambridge University acknowledges support from the MRC. Patient recruitment for the MRC Prion Unit/UCL Department of Neurodegenerative Disease collection was supported by the UCLH/UCL Biomedical Centre and NIHR Queen Square Dementia Biomedical Research Unit. The University of Southampton acknowledges support from the AS. King's College London was supported by the NIHR Biomedical Research Centre for Mental Health and the Biomedical Research Unit for Dementia at the South London and Maudsley NHS Foundation Trust and by King's College London and the MRC. ARUK and the Big Lottery Fund provided support to Nottingham University. Ulster Garden Villages, AS, ARUK, the American Federation for Aging Research, and the Northern Ireland R&D Office provided support for Queen's University, Belfast. The Centro de Biología Molecular Severo Ochoa (CSIS-UAM), CIBERNED, Instituto de Investigación Sanitaria la Paz, University Hospital La Paz, and the Universidad Autónoma de Madrid were supported by grants from the Ministerio de Educación y Ciencia and the Ministerio de Sanidad y Consumo (Instituto de Salud Carlos III) and by an institutional grant of the Fundación Ramón Areces to the CMBSO. We thank I. Sastre and A. Martinez-Garcia for DNA preparation, and P. Gil and P. Coria for their recruitment efforts. The Department of Neurology, University Hospital Mútua de Terrassa, was supported by CIBERNED, Instituto de Salud Carlos III, Madrid, Spain, and acknowledges M.A. Pastor (University of Navarra Medical School and Center for Applied Medical Research), M. Seijo-Martinez (Hospital do Salnes), and R. Rene, J. Gascon, and J. Campdelacreu (Hospital de Bellvitage) for providing DNA samples. The Hospital de la Sant Pau, Universitat Autònoma de Barcelona, acknowledges support from the Spanish Ministry of Economy and Competitiveness (grant PI12/01311) and from the Generalitat de Catalunya (2014SGR-235). The Santa Lucia Foundation and the Fondazione Ca' Granda IRCCS Ospedale Policlinico, Italy, acknowledge the Italian Ministry of Health (grant RC 10.11.12.13/A). The Bonn samples are part of the German Dementia Competence Network (DCN) and the German Research Network on Degenerative Dementia (KNDD), which are funded by the German Federal Ministry of Education and Research (grants KND: 01G10102, 01GI0420, 01GI0422, 01GI0423, 01GI0429, 01GI0431, 01GI0433, 04GI0434; grants KNDD: 01GI1007A, 01GI0710, 01GI0711, 01GI0712, 01GI0713, 01GI0714, 01GI0715, 01GI0716, 01ET1006B). M.M.N. is a member of the German Research Foundation (DFG) cluster of excellence ImmunoSensation. Funding for Saarland University was provided by the German Federal Ministry of Education and Research (BMBF), grant 01GS08125, to M. Riemenschneider. The University of Washington was supported by grants from the US National Institutes of Health (R01-NS085419 and R01-AG044546), the Alzheimer's Association (NIRG-11-200110), and the American Federation for Aging Research (C. Cruchaga was recipient of a New Investigator Award in Alzheimer's disease). Brigham Young University was supported by the Alzheimer's Association (MNIRG-11-205368), the BYU Gerontology Program, and the US National Institutes of Health (R01-AG11380, R01-AG021136, P30-S069329-01, R01-AG042611). We also acknowledge funding from the Institute of Neurology, UCL, London, who was supported in part by ARUK via an anonymous donor, and by a fellowship to R.G. The participation of D.S., M.U., and C. Masullo in the study was completely supported by Ministero della Salute, IRCCS Research Program, Ricerca Corrente 2015–2017, Linea 2 'Malattiecomplesse e Terapie Innovative' and by the '5 × 1000' voluntary contribution. AddNeuromed is supported by InnoMed, an Integrated Project funded by the European Union's Sixth Framework Programme priority FP6-2004-LIFESCIHEALTH-5, Life Sciences, Genomics, and Biotechnology for Health. We are grateful to the Wellcome Trust for awarding a Principal Research Fellowship to D.C.R. (095317/Z/11/Z). M. Riemenschneider was funded by BMBF NGFN grant 01GS08125. B.N. was supported by the Fondazione Cassa di Risparmio di Pistoia e Pescia (grants 2014.0365, 2011.0264, 2013.0347). H. Hampel is supported by the AXA Research Fund, the Fondation Universite Pierre et Marie Curie, and the 'Fondation pour la Recherche sur Alzheimer', Paris, France. The research leading to these results has received funding from the program 'Investissements d'Avenir', ANR-10-IAIHU-06 (Agence Nationale de la Recherche-10-IA Agence Institut Hospitalo-Universitaire-6.

CHARGE. Infrastructure for the CHARGE Consortium is supported in part by National Heart, Lung, and Blood Institute grant HL105756 and for the neurology working group by AG033193 and AG049505.

Rotterdam (RS). The Rotterdam Study is funded by Erasmus Medical Center and Erasmus University, Rotterdam, the Netherlands Organization for Health Research and Development (ZonMw), the Research Institute for Diseases in the Elderly (RIDE), the Ministry of Education, Culture and Science, the Ministry for Health, Welfare and Sports, the European Commission (DG XII), and the municipality of Rotterdam. The authors are grateful to the study participants, the staff from the Rotterdam Study, and the participating general practitioners and pharmacists. Generation and management of the Illumina exome chip v1.0 array data for the Rotterdam Study (RS-I) was executed by the Human Genotyping Facility of the Genetic Laboratory of the Department of Internal Medicine (http://www.glimdna.org/), Erasmus MC, Rotterdam, the Netherlands. The Exome chip array data set was funded by the Genetic Laboratory of the Department of Internal Medicine, Erasmus MC, from the Netherlands Genomics Initiative (NGI)/Netherlands Organization for Scientific Research (NWO)-sponsored Netherlands Consortium for Healthy Aging (NCHA; project 050-060-810); the Netherlands Organization for Scientific Research (NWO; project 184021007); and by the Rainbow Project (RP10; Netherlands Exome Chip Project) of Biobanking and Biomolecular Research Infrastructure Netherlands (BBMRI-NL; http://www.bbmri.nl). Generation and management of GWAS genotype data for the Rotterdam Study (RS-I, RS-II, RS-III) was executed by the Human Genotyping Facility of the Genetic Laboratory of the Department of Internal Medicine, Erasmus MC, Rotterdam, the Netherlands. The GWAS data sets are supported by the Netherlands Organization of Scientific Research NWO Investments (175.010.2005.011, 911-03-012), the Genetic Laboratory of the Department of Internal Medicine, Erasmus MC, the Research Institute for Diseases in the Elderly (014-93-015; RIDE2), and the Netherlands Genomics Initiative (NGI)/Netherlands Organization for Scientific Research (NWO) Netherlands Consortium for Healthy Aging (NCHA), project 050-060-810. This study makes use of an extended data set of RS-II and RS-III samples based on Illumina Omni 2.5 and 5.0 GWAS genotype data. This data set was funded by the Genetic Laboratory of the Department of Internal Medicine, the Department of Forensic Molecular Biology, and the Department of Dermatology, Erasmus MC, Rotterdam, the Netherlands. We thank M. Jhamai, S. Higgins, and M. Verkerk for their help in creating the exome chip database; C. Medina-Gomez, L. Karsten, and L. Broer for quality control and variant calling; M. Jhamai, M. Verkerk, L. Herrera, M. Peters, and C. Medina-Gomez for their help in creating the GWAS database; and L. Broer for the creation of the HRC-imputed data. Variants were called using the best practice protocol developed by M.L. Grove and colleagues as part of the CHARGE Consortium Exome Chip central calling effort. The work for this manuscript was further supported by ADAPTED: Alzheimer's Disease Apolipoprotein Pathology for Treatment Elucidation and Development (115975); the CoSTREAM project (http://www.costream.eu/); and funding from the European Union's Horizon 2020 research and innovation programme under grant agreement 667375.

AGES. The AGES study has been funded by NIA contracts N01-AG-12100 and HHSN271201200022C with contributions from NEI, NIDCD, and NHLBI, the NIA Intramural Research Program, Hjartavernd (the Icelandic Heart Association), and the Althingi (the Icelandic Parliament).

Cardiovascular Health Study (CHS). This research was supported by contracts HHSN268201200036C, HHSN268200800007C, N01HC55222, N01HC85079, N01HC85080, N01HC85081, N01HC85082, N01HC85083, and N01HC85086 and grant U01HL080295 from the National Heart, Lung, and Blood Institute (NHLBI), with additional contribution from the National Institute of Neurological Disorders and Stroke (NINDS). Additional support was provided by R01AG033193, R01AG023629, R01AG15928, and R01AG20098 and by U01AG049505 from the National Institute on Aging (NIA). The provision of genotyping data was supported in part by the National Center for Advancing Translational Sciences, CTSI grant UL1TR000124, and National Institute of Diabetes and Digestive and Kidney Disease Diabetes Research Center (DRC) grant DK063491 to the Southern California Diabetes Endocrinology Research Center. A full list of CHS principal investigators and institutions can be found at https://chs-nhlbi.org/. The content is solely the responsibility of the authors and does not necessarily represent the official views of the US National Institutes of Health.

Framingham Heart Study. This work was supported by the National Heart, Lung, and Blood Institute's Framingham Heart Study (contracts N01-HC-25195 and HHSN268201500001I). This study was also supported by grants from the National Institute on Aging: AG033193, U01-AG049505, and AG008122 (S. Seshadri). S. Seshadri and A.L.D. were also supported by additional grants from the National Institute on Aging (R01AG049607) and the National Institute of Neurological Disorders and Stroke (R01-NS017950).

Fundació ACE. We sincerely acknowledge the collaboration of S. Ruiz, M. Rosende-Roca, A. Mauleon, L. Vargas, O. Rodriguez-Gomez, M. Alegret, A. Espinosa, G. Ortega, M. Tarragona, C. Abdelnour, and D. Sanchez. We thank all patients for their participation in this project. We are obliged to T. Port-Carbo and her family for their support of the Fundació ACE research programs. Fundació ACE collaborates with CIBERNED and is one of the participating centers of Dementia Genetics Spanish Consortium 430 (DEGESCO). CIBERNED is an Instituto de Salud Carlos III Project. A. Ruiz is supported by grant PI13/02434 (Acción Estratégica en Salud, Instituto de Salud Carlos III, Ministerio de Economía y Competitividad, Spain) and Obra Social 'La Caixa' (Barcelona, Spain).

ADGC. The US National Institutes of Health, National Institute on Aging (NIH-NIA) supported this work through the following grants: ADGC, U01 AG032984, and RC2 AG036528. Samples from the National Cell Repository for Alzheimer's Disease (NCRAD), which receives government support under a cooperative agreement grant (U24 AG21886) awarded by the National Institute on Aging (NIA), were used in this study. We thank the contributors who collected samples used in this study, as well as the patients and their families, whose help and participation made this work possible. Data for this study were prepared, archived, and distributed by the National Institute on Aging Alzheimer's Disease Data Storage Site (NIAGADS) at the University of Pennsylvania (U24-AG041689-01), NACC (U01 AG016976), NIA LOAD (Columbia University) (U24 AG026395, R01AG041797), Banner Sun Health Research Institute (P30 AG019610), Boston University (P30 AG013846, U01 AG10483, R01 CA129769, R01 MH080295, R01 AG017173, R01 AG025259, R01 AG048927, R01AG33193), Columbia University (P50 AG008702, R37 AG015473), Duke University (P30 AG028377, AG05128), Emory University (AG025688), Group Health Research Institute (UO1 AG006781, UO1 HG004610, UO1 HG006375), Indiana University (P30 AG10133), Johns Hopkins University (P50 AG005146, R01 AG020688), Massachusetts General Hospital (P50 AG005134), Mayo Clinic (P50 AG016574), Mount Sinai School of Medicine (P50 AG005138, P01 AG002219), New York University (P30 AG08051, UL1 RR029893, 5R01AG012101, 5R01AG022374, 5R01AG013616, 1RC2AG036502, 1R01AG035137), Northwestern University (P30 AG013854), Oregon Health & Science University (P30 AG008017, R01 AG026916), Rush University (P30 AG010161, R01 AG019085, R01 AG15819, R01 AG17917, R01 AG30146), TGen (R01 NS059873), University of Alabama at Birmingham (P50 AG016582), University of Arizona (R01 AG031581), University of California, Davis (P30 AG010129), University of California, Irvine (P50 AG016573), University of California, Los Angeles (P50 AG016570), University of California, San Diego (P50 AG005131), University of California, San Francisco (P50 AG023501, P01 AG019724), University of Kentucky (P30 AG028383, AG05144), University of Michigan (P50 AG008671), University of Pennsylvania (P30 AG010124), University of Pittsburgh (P50 AG005133, AG030653, AG041718, AG07562, AG02365), University of Southern California (P50 AG005142), University of Texas Southwestern (P30 AG012300), University of Miami (R01 AG027944, AG010491, AG027944, AG021547, AG019757), University of Washington (P50 AG005136), University of Wisconsin (P50 AG033514), Vanderbilt University (R01 AG019085), and Washington University (P50 AG005681, P01 AG03991). The Kathleen Price Bryan Brain Bank at Duke University Medical Center is funded by NINDS grant NS39764, NIMH MH60451, and by GlaxoSmithKline. Support was also provided by the Alzheimer's Association (L.A.F., IIRG-08-89720; M.P.-V., IIRG-05-14147), the US Department of Veterans Affairs Administration, the Office of Research and Development, the Biomedical Laboratory Research Program, and the BrightFocus Foundation (M.P.-V., A2111048). P.S.G.-H. is supported by the Wellcome Trust, the Howard Hughes Medical Institute, and the Canadian Institutes of Health Research. Genotyping of the TGEN2 cohort was supported by Kronos Science. The TGen series was also funded by NIA grant AG041232 to A.J.M. and M.J.H., the Banner Alzheimer's Foundation, the Johnnie B. Byrd Sr. Alzheimer's Institute, the Medical Research Council, and the state of Arizona and also includes samples from the following sites: the Newcastle Brain Tissue Resource (funding via the Medical Research Council, local NHS trusts, and Newcastle University), the MRC London Brain Bank for Neurodegenerative Diseases (funding via the Medical Research Council), the South West Dementia Brain Bank (funding via numerous sources including the Higher Education Funding Council for England (HEFCE), Alzheimer's Research UK (ARUK), and BRACE as well as the North Bristol NHS Trust Research and Innovation Department and DeNDRoN), the Netherlands Brain Bank (funding via numerous sources including Stichting MS Research, Brain Net Europe, Hersenstichting Nederland Breinbrekend Werk, International Parkinson Fonds, Internationale Stiching Alzheimer Onderzoek), and the Institut de Neuropatologia, Servei Anatomia Patologica, Universitat de Barcelona. ADNI data collection and sharing were funded by US National Institutes of Health grant U01 AG024904 and Department of Defense award W81XWH-12-2-0012. ADNI is funded by the National Institute on Aging, the National Institute of Biomedical Imaging and Bioengineering, and through generous contributions from the following: AbbVie, Alzheimer's Association; the Alzheimer's Drug Discovery Foundation; Araclon Biotech; BioClinica, Inc.; Biogen; Bristol-Myers Squibb Company; CereSpir, Inc.; Eisai, Inc.; Elan Pharmaceuticals, Inc.; Eli Lilly and Company; EuroImmun; F. Hoffmann-La Roche, Ltd., and its affiliated company Genentech, Inc.; Fujirebio; GE Healthcare; IXICO, Ltd.; Janssen Alzheimer Immunotherapy Research & Development, LLC.; Johnson & Johnson Pharmaceutical Research & Development, LLC.; Lumosity; Lundbeck; Merck & Co., Inc.; Meso Scale Diagnostics, LLC.; NeuroRx Research; Neurotrack Technologies; Novartis Pharmaceuticals Corporation; Pfizer, Inc.; Piramal Imaging; Servier; Takeda Pharmaceutical Company; and Transition Therapeutics. The Canadian Institutes of Health Research provide funds to support ADNI clinical sites in Canada. Private sector contributions are facilitated by the Foundation for the National Institutes of Health (http://www.fnih.org/). The grantee organization is the Northern California Institute for Research and Education, and the study is coordinated by the Alzheimer's Disease Cooperative Study at the University of California, San Diego. ADNI data are disseminated by the Laboratory for Neuro Imaging at the University of Southern California. We thank D.S. Snyder and M. Miller from the NIA who are ex-officio ADGC members.

EADI. This work was supported by INSERM, the National Foundation for Alzheimer's Disease and Related Disorders, the Institut Pasteur de Lille, and the Centre National de Génotypage. This work has been developed and supported by the LABEX (Laboratory of Excellence Program Investment for the Future) DISTALZ grant (Development of Innovative Strategies for a Transdisciplinary Approach to Alzheimer's Disease) including funding from MEL (Métropole Européenne de Lille), ERDF (European Regional Development Fund), and the Conseil Régional du Nord-Pas-de-Calais. The Three-City Study was performed as part of collaboration between INSERM, Victor Segalen Bordeaux II University, and Sanofi-Synthelabo. The Fondation pour la Recherche Médicale funded the preparation and initiation of the study. The 3C Study was also funded by the Caisse Nationale Maladie des Travailleurs Salaries, Direction Générale de la Santé, MGEN, Institut de la Longévité, Agence Française de Sécurité Sanitaire des Produits de Santé, the Aquitaine and Bourgogne regional councils, Agence Nationale de la Recherche (ANR supported the COGINUT and COVADIS projects), Fondation de France, and the joint French Ministry of Research/INSERM 'Cohortes et Collections de Données Biologiques' program. The Lille Genopole received an unconditional grant from Eisai and was supported by the European Joint Programme for Neurodegenerative Disease (JPND: grant MR/L501517/1). The Three-City Biological Bank was developed and maintained by the Laboratory for Genomic Analysis LAG-BRC, Institut Pasteur de Lille.

Belgium sample collection. Research at the Antwerp site is funded in part by the Interuniversity Attraction Poles program of the Belgian Science Policy Office, the Foundation for Alzheimer Research (SAO-FRA), a Methusalem Excellence Grant of the Flemish Government, the Research Foundation Flanders (FWO), and the Special Research Fund of the University of Antwerp, Belgium. Authors from the Antwerp site thank the personnel of the VIB Genetic Service Facility, the Biobank of the Institute Born-Bunge, and the Departments of Neurology and Memory Clinics at the Hospital Network Antwerp and University Hospitals Leuven.

Finnish sample collection. Financial support for this project was provided by the Health Research Council of the Academy of Finland, EVO grant 5772708 of Kuopio University Hospital, and the Nordic Center of Excellence in Neurodegeneration.

Swedish sample collection. Sample collection was financially supported in part by the Swedish Brain Power network, the Marianne and Marcus Wallenberg Foundation, the Swedish Research Council (521-2010-3134), King Gustaf V and Queen Victoria's Foundation of Freemasons, the Regional Agreement on Medical Training and Clinical Research (ALF) between the Stockholm County Council and the Karolinska Institutet, the Swedish Brain Foundation, and the Swedish Alzheimer Foundation.

AMP AD University of Florida/Mayo Clinic/Institutes of Systems Biology. For human brain donations, we thank all patients and their families, without whom this work would not have been possible. This work was supported by NIH/NIA AG046139-01 (T.E.G., N.E.-T., N.P., S.G.Y.). We thank T.G. Beach (Banner Sun Health Institute) for sharing human tissue.

The Mayo Clinic Brain Bank. Data collection was supported through funding by NIA grants P50 AG016574, R01 AG032990, U01 AG046139, R01 AG018023, U01 AG006576, U01 AG006786, R01 AG025711, R01 AG017216, and R01 AG003949, NINDS grant R01 NS080820, the CurePSP Foundation, and support from the Mayo Foundation.

Sun Health Research Institute Brain and Body Donation Program of Sun City, Arizona. The Brain and Body Donation Program is supported by the National Institute of Neurological Disorders and Stroke (U24 NS072026 National Brain and Tissue Resource for Parkinson's Disease and Related Disorders), the National Institute on Aging (P30 AG19610 Arizona Alzheimer's Disease Core Center), the Arizona Department of Health Services (contract 211002, Arizona Alzheimer's Research Center), the Arizona Biomedical Research Commission (contracts 4001, 0011, 05-901, and 1001 to the Arizona Parkinson's Disease Consortium), and the Michael J. Fox Foundation for Parkinson's Research.

Author information

Author notes

  1. Rebecca Sims, Sven J van der Lee, Adam C Naj and Céline Bellenguez: These authors contributed equally to this work.

  2. Philippe Amouyel, Cornelia M van Duijn, Alfredo Ramirez, Li-San Wang, Jean-Charles Lambert, Sudha Seshadri, Julie Williams and Gerard D Schellenberg: These authors jointly directed this work.

Authors and Affiliations

  1. Institute of Psychological Medicine and Clinical Neurosciences, MRC Centre for Neuropsychiatric Genetics and Genomics, Cardiff University, Cardiff, UK

    Rebecca Sims, Nandini Badarinarayan, Rachel Raybould, Maria Vronskaya, Rhodri Thomas, Taniesha Morgan, Nicola Denning, Elisa Majounie, Melanie Dunstan, Amy Braddel, Charlene Thomas, Alun Meggy, Rachel Marshall, Amy Gerrish, Jade Chapman, Sarah Taylor, Matt Hill, Michael C O'Donovan, Michael J Owen, Lesley Jones, Valentina Escott-Price, Peter A Holmans & Julie Williams

  2. Department of Epidemiology, Erasmus Medical Center, Rotterdam, The Netherlands

    Sven J van der Lee, Shahzad Ahmad, Frank J Wolters, Hieab H Adams, Albert Hofman, Fernando Rivadeneira, Andre G Uitterlinden, M Arfan Ikram, Najaf Amin & Cornelia M van Duijn

  3. Department of Biostatistics and Epidemiology/Center for Clinical Epidemiology and Biostatistics, University of Pennsylvania Perelman School of Medicine, Philadelphia, Pennsylvania, USA

    Adam C Naj

  4. INSERM, U1167, RID-AGE–Risk Factors and Molecular Determinants of Aging-Related Diseases, Lille, France

    Céline Bellenguez, Benjamin Grenier-Boley, Nathalie Fievet, Philippe Amouyel & Jean-Charles Lambert

  5. Institut Pasteur de Lille, Lille, France

    Céline Bellenguez, Benjamin Grenier-Boley, Nathalie Fievet, Philippe Amouyel & Jean-Charles Lambert

  6. University Lille, U1167–Excellence Laboratory LabEx DISTALZ, Lille, France

    Céline Bellenguez, Benjamin Grenier-Boley, Nathalie Fievet, Philippe Amouyel & Jean-Charles Lambert

  7. Icelandic Heart Association, Kopavogur, Iceland

    Johanna Jakobsdottir, Albert V Smith, Gudny Eiriksdottir, Valur Emilsson, Thor Aspelund & Vilmundur Gudnason

  8. John P. Hussman Institute for Human Genomics, University of Miami, Miami, Florida, USA

    Brian W Kunkle, Eden R Martin, Kara L Hamilton-Nelson, Gary W Beecham, Patrice Whitehead, John R Gilbert, William Perry & Margaret A Pericak-Vance

  9. CEA/Institut de Génomique, Centre National de Génotypage, Evry, France

    Anne Boland, Robert Olaso, Cécile Dulary, Céline Derbois, Delphine Bacq, Fabienne Garzia, Feroze Golamaully, Gislain Septier & Jean-François Deleuze

  10. Department of Medicine, Cardiovascular Health Research Unit, University of Washington, Seattle, Washington, USA

    Joshua C Bis, Jennifer A Brody & Bruce M Psaty

  11. Department of Human Genetics, Dr. John T. Macdonald Foundation, University of Miami, Miami, Florida, USA

    Eden R Martin, Gary W Beecham, John R Gilbert & Margaret A Pericak-Vance

  12. Institute of Human Genetics, University of Bonn, Bonn, Germany

    Stefanie Heilmann-Heimbach, Per Hoffmann, Markus M Nöthen, Stefan Herms, Andreas J Forstner & Alfredo Ramirez

  13. Department of Genomics, Life & Brain Center, University of Bonn, Bonn, Germany

    Stefanie Heilmann-Heimbach, Per Hoffmann, Markus M Nöthen, Stefan Herms & Andreas J Forstner

  14. Boston University School of Medicine, Boston, Massachusetts, USA

    Vincent Chouraki, Seung-Hoan Choi, Claudia L Satizabal, Daniel Levy, Jayanadra J Himali, Lindsay A Farrer & Sudha Seshadri

  15. Framingham Heart Study, Framingham, Massachusetts, USA

    Vincent Chouraki, Claudia L Satizabal, L Adrienne Cupples, Daniel Levy, Alexa S Beiser, Christopher J O'Donnell, Anita L DeStefano & Sudha Seshadri

  16. Department of Pathology and Laboratory Medicine, Penn Neurodegeneration Genomics Center, University of Pennsylvania Perelman School of Medicine, Philadelphia, Pennsylvania, USA

    Amanda B Kuzma, Otto Valladares, Liming Qu, Yi Zhao, John Malamon, Beth Dombroski, Laura B Cantwell, Li-San Wang & Gerard D Schellenberg

  17. Department of Molecular Genetics, Neurodegenerative Brain Diseases Group, VIB, Antwerp, Belgium

    Kristel Sleegers & Christine Van Broeckhoven

  18. Institute Born-Bunge, University of Antwerp, Antwerp, Belgium

    Kristel Sleegers, Sebastien Engelborghs, Peter P De Deyn & Christine Van Broeckhoven

  19. Research Center and Memory Clinic of Fundació ACE, Institut Català de Neurociències Aplicades, Barcelona, Spain

    Agustin Ruiz, Sonia Moreno-Grau, Isabel Henández, Lluis Tarraga, Oscar Sotolongo-Grau & Merce Boada

  20. Immunology Biomarkers Group, Genentech, South San Francisco, California, USA

    Robert R Graham & Timothy W Behrens

  21. Division of Medical Genetics, University Hospital and Department of Biomedicine, University of Basel, Basel, Switzerland

    Per Hoffmann & Stefan Herms

  22. School of Public Health, Human Genetics Center, University of Texas Health Science Center at Houston, Houston, Texas, USA

    Megan L Grove & Eric Boerwinkle

  23. Department of Neurology, Taub Institute on Alzheimer's Disease and the Aging Brain, Columbia University, New York, New York, USA

    Badri N Vardarajan, Sandra Barral, Lawrence S Honig, Jennifer Williamson & Richard Mayeux

  24. Gertrude H. Sergievsky Center, Columbia University, New York, New York, USA

    Badri N Vardarajan, Sandra Barral, Christiane Reitz & Richard Mayeux

  25. Department of Neurology, Columbia University, New York, New York, USA

    Badri N Vardarajan, Sandra Barral, Christiane Reitz & Richard Mayeux

  26. Institute of Biomedicine, University of Eastern Finland, Kuopio, Finland

    Mikko Hiltunen

  27. Department of Neurology, Kuopio University Hospital, Kuopio, Finland

    Mikko Hiltunen, Hilkka Soininen, Seppo Helisalmi, Anne Maria Koivisto & Annakaisa Haapasalo

  28. Departments of Neurology and Psychiatry, Program in Translational NeuroPsychiatric Genomics, Institute for the Neurosciences, Brigham and Women's Hospital, Boston, Massachusetts, USA

    Charles C White

  29. UMR 894, Center for Psychiatry and Neuroscience, INSERM, Université Paris Descartes, Paris, France

    Jacques Epelbaum

  30. German Center for Neurodegenerative Diseases (DZNE), Bonn, Germany

    Wolfgang Maier & Frank Jessen

  31. Department of Psychiatry and Psychotherapy, University of Bonn, Bonn, Germany

    Wolfgang Maier, Frank Jessen, Reinhard Heun & Alfredo Ramirez

  32. Department of Biostatistics, Boston University School of Public Health, Boston, Massachusetts, USA

    Seung-Hoan Choi, Josée Dupuis, L Adrienne Cupples, Alexa S Beiser, Yuning Chen, Qiong Yang, Shuo Li & Anita L DeStefano

  33. Faculty of Medicine, University of Iceland, Reykjavik, Iceland

    Albert V Smith & Vilmundur Gudnason

  34. Institute for Systems Biology, Seattle, Washington, USA

    Cory C Funk, Hongdong Li & Nathan D Price

  35. School of Biotechnology, Dublin City University, Dublin, Ireland

    Denise Harold

  36. Department of Biomedical Sciences, Section of Neuroscience and Clinical Pharmacology, University of Cagliari, Cagliari, Italy

    Alessio Squassina

  37. Neurology Service and CIBERNED, 'Marqués de Valdecilla' University Hospital (University of Cantabria and IFIMAV), Santander, Spain

    Pascual Sánchez-Juan & Onofre Combarros

  38. Department of Immunology, Hospital Universitario Doctor Negrín, Las Palmas de Gran Canaria, Spain

    Florentino Sanchez Garcia, Maria Candida Deniz Naranjo, Carmen Muñoz Fernadez & Yoland Aladro Benito

  39. Brown Foundation Institute of Molecular Medicine, University of Texas Health Sciences Center at Houston, Houston, Texas, USA

    Myriam Fornage & Xueqiu Jian

  40. Departments of Medicine, Geriatrics, Gerontology and Neurology, University of Mississippi Medical Center, Jackson, Mississippi, USA

    Thomas H Mosley

  41. Centre Hospitalier du Rouvray, Sotteville les, Rouen, France

    David Wallon & Dominique Campion

  42. INSERM U1079, Rouen University, IRIB, Normandy University, Rouen, France

    David Wallon, Didier Hannequin & Dominique Campion

  43. Department of Basic and Clinical Neuroscience, Institute of Psychiatry, Psychology and Neuroscience, King's College London, London, UK

    Michelle K Lupton, Petra Proitsi, Yogen Patel, Joseph T Hughes & John Powell

  44. Genetic Epidemiology, QIMR Berghofer Medical Research Institute, Herston, Queensland, Australia

    Michelle K Lupton

  45. Department of Geriatric Medicine, Karolinska University Hospital Huddinge, Stockholm, Sweden

    Laura Fratiglioni & Caroline Graff

  46. Department of Neurobiology, Aging Research Center, Care Sciences and Society, Karolinska Institutet and Stockholm University, Stockholm, Sweden

    Laura Fratiglioni & Lina Keller

  47. Institute of Genetics, Queen's Medical Centre, University of Nottingham, Nottingham, UK

    Christopher Medway, Kristelle Brown, Jenny Lord, James Turton & Kevin Morgan

  48. Department of Medicine, University of Washington, Seattle, Washington, USA

    Shubhabrata Mukherjee, Paul K Crane, Wayne C McCormick, Chang-En Yu & Eric B Larson

  49. Department of Medicine, Section of Computational Biomedicine, Boston University School of Medicine, Boston, Massachusetts, USA

    Honghuang Lin

  50. Department of Basic Medicine, Neurodegenerative Disease Unit, Neuroscience, and Sense Organs, University of Bari Aldo Moro, Bari, Italy

    Francesco Panza

  51. Centre for Public Health, School of Medicine, Dentistry and Biomedical Sciences, Queen's University, Belfast, UK

    Bernadette McGuinness, Stephen Todd, David Craig, Janet Johnston & Peter Passmore

  52. Department of Neuroscience, Mayo Clinic, Jacksonville, Florida, USA

    Jeremy D Burgess, Mariet Allen, Xue Wang, Minerva M Carrasquillo, Neill R Graff-Radford, Nilufer Ertekin-Taner, Steven G Younkin & Dennis W Dickson

  53. Geriatric Medicine–Memory Unit and Rare Disease Centre, University of Bari Aldo Moro, Bari, Italy

    Vincenzo Solfrizzi

  54. Department of Medical Sciences, Geriatric Unit and Gerontology–Geriatrics Research Laboratory, IRCCS Casa Sollievo della Sofferenza, San Giovanni Rotondo, Italy

    Davide Seripa, Maria Urbano & Alberto Pilotto

  55. Department of Medicine, Section of Gerontology and Geriatrics, University of Perugia, Perugia, Italy

    Pau Pastor, Patrizia Mecocci, Virginia Boccardi & Roberta Cecchetti

  56. Department of Neurology, Rouen University Hospital, Rouen, France

    Didier Hannequin

  57. Department of Neurology, University Hospital La Paz, Universidad Autónoma de Madrid, Madrid, Spain

    Ana Frank-García

  58. Instituto de Investigación Sanitaria Hospital la Paz (IdiPAZ), Madrid, Spain

    Ana Frank-García & María J Bullido

  59. Centro de Investigación Biomédica en Red de Enfermedades Neurodegenerativas (CIBERNED), Instituto de Salud Carlos III, Madrid, Spain

    Ana Frank-García, Mònica Díez Fairén, Alberto Lleó, Juan Fortea, Rafael Blesa, María J Bullido, Jordi Clarimón, Bruce M Psaty & Sara Ortega-Cubero

  60. National Heart, Lung, and Blood Institute, Bethesda, Maryland, USA

    Daniel Levy

  61. Department of Neuroscience, Center for Translational Research in Neurodegenerative Disease, University of Florida, Gainesville, Florida, USA

    Paramita Chakrabarty, Carolina Ceballos Diaz & Todd E Golde

  62. Department of Neuroscience, University of Parma, Parma, Italy

    Paolo Caffarra & Letizia Concari

  63. Center for Cognitive Disorders AUSL, Parma, Italy

    Paolo Caffarra & Letizia Concari

  64. Department of Psychiatry, Martin Luther University Halle-Wittenberg, Halle, Germany

    Ina Giegling, Annette M Hartmann & Dan Rujescu

  65. Department of Public Health/Geriatrics, Uppsala University, Uppsala, Sweden

    Vilmantas Giedraitis, Lars Lannfelt, Lena Kilander, RoseMarie Brundin & Martin Ingelsson

  66. AXA Research Fund and UPMC Chair, Paris, France

    Harald Hampel

  67. Sorbonne Universités, Université Pierre et Marie Curie, Paris, France

    Harald Hampel

  68. Département de Neurologie, Institut de la Mémoire et de la Maladie d'Alzheimer (IM2A) and Institut du Cerveau et de la Moelle Épinière (ICM), Hôpital de la Pitié-Salpêtrière, Paris, France

    Harald Hampel

  69. Laboratory of Epidemiology and Population Sciences, National Institute on Aging, Bethesda, Maryland, USA

    Melissa E Garcia & Lenore J Launer

  70. Epidemiology and Public Health Department, Centre Hospitalier Universitaire de Lille, Lille, France

    Florence Pasquier & Philippe Amouyel

  71. INSERM UMRS 1171, CNR-Maj, Lille, France

    Florence Pasquier

  72. Department of Pharmacology and Neuroscience, University of North Texas Health Science Center, Fort Worth, Texas, USA

    Robert C Barber

  73. Department of Primary Medical Care, University Medical Centre Hamburg-Eppendorf, Hamburg, Germany

    Martin Scherer

  74. Department of Psychiatry, University of Texas Southwestern Medical Center, Dallas, Texas, USA

    Perrie M Adams

  75. Department of Psychiatry and Psychotherapy, University of Cologne, Cologne, Germany

    Markus Leber, Frank Jessen & Alfredo Ramirez

  76. Department of Neurology, Johns Hopkins University, Baltimore, Maryland, USA

    Marilyn S Albert

  77. Institute of Social Medicine, Occupational Health and Public Health, University of Leipzig, Leipzig, Germany

    Steffi Riedel-Heller

  78. Faculty of Pharmaceutical Sciences, University of Iceland, Reykjavik, Iceland

    Valur Emilsson

  79. National Alzheimer's Coordinating Center, University of Washington, Seattle, Washington, USA

    Duane Beekly

  80. Schools of Life Sciences and Medicine, University of Nottingham, Nottingham, UK

    Anne Braae, Imelda S Barber & Keeley Brookes

  81. Department of Neurology, Clinical Division of Neurogeriatrics, Medical University Graz, Graz, Austria

    Reinhold Schmidt

  82. Department of Epidemiology, Harvard School of Public Health, Boston, Massachusetts, USA

    Deborah Blacker

  83. Department of Psychiatry, Massachusetts General Hospital/Harvard Medical School, Boston, Massachusetts, USA

    Deborah Blacker

  84. Department of Neurology, Catholic University of Rome, Rome, Italy

    Carlo Masullo

  85. Institute of Molecular Biology and Biochemistry, Medical University Graz, Graz, Austria

    Helena Schmidt

  86. Alzheimer's Disease and Memory Disorders Center, Baylor College of Medicine, Houston, Texas, USA

    Rachelle S Doody

  87. Department of Clinical and Behavioural Neurology, Experimental Neuropsychiatry Laboratory, IRCCS Santa Lucia Foundation, Rome, Italy

    Gianfranco Spalletta, Paola Bossù, Eleonora Sacchinelli, Carlo Caltagirone, Maria Donata Orfei & Antonio Ciaramella

  88. Department of Neurology, University of Washington, Seattle, Washington, USA

    W T Longstreth Jr & Thomas D Bird

  89. Department of Epidemiology, University of Washington, Seattle, Washington, USA

    W T Longstreth Jr, Annette L Fitzpatrick, Walter A Kukull & Bruce M Psaty

  90. Office of Strategy and Measurement, University of North Texas Health Science Center, Fort Worth, Texas, USA

    Thomas J Fairchild

  91. Department of Psychiatry, University of Pittsburgh, Pittsburgh, Pennsylvania, USA

    Oscar L Lopez

  92. Department of Neurology, University of Pittsburgh, Pittsburgh, Pennsylvania, USA

    Oscar L Lopez

  93. C.S. Kubik Laboratory for Neuropathology, Massachusetts General Hospital, Charlestown, Massachusetts, USA

    Matthew P Frosch

  94. Department of Pathology and Laboratory Medicine, Indiana University, Indianapolis, Indiana, USA

    Bernardino Ghetti, Jill R Murrell & Salvatore Spina

  95. Department of Surgery, University of Texas Southwestern Medical Center, Dallas, Texas, USA

    Ryan M Huebinger

  96. Alzheimer's Disease Research Center, University of Pittsburgh, Pittsburgh, Pennsylvania, USA

    M Ilyas Kamboh

  97. Department of Human Genetics, University of Pittsburgh, Pittsburgh, Pennsylvania, USA

    M Ilyas Kamboh

  98. Department of Psychiatry, Washington University School of Medicine, St. Louis, Missouri, USA

    John Morris & Carlos Cruchaga

  99. Hope Center Program on Protein Aggregation and Neurodegeneration, Washington University School of Medicine, St. Louis, Missouri, USA

    John Morris & Carlos Cruchaga

  100. Department of Neurology, Albert Einstein College of Medicine, Bronx, New York, USA

    Mindy J Katz & Richard B Lipton

  101. Department of Mathematics and Statistics, Utah State University, Logan, Utah, USA

    Chris Corcoran, JoAnn Tschanz, Maria Norton & Ron Munger

  102. Fundació per la Recerca Biomèdica i Social Mútua Terrassa, Terrassa, Barcelona, Spain

    Miquel Aguilar & Mònica Díez Fairén

  103. Department of Neurology, Memory Unit, Hospital Universitario Mútua Terrassa, Terrassa, Barcelona, Spain

    Miquel Aguilar

  104. Department of Old Age Psychiatry, Institute of Psychiatry, Psychology and Neuroscience, King's College London, London, UK

    Angela Hodges

  105. INSERM U558, University of Toulouse, Toulouse, France

    Bruno Vellas

  106. Elderly and Psychiatric Disorders Department, Medical University of Lodz, Lodz, Poland

    Iwona Kloszewska

  107. Department of Health Sciences, Psychiatry for the Elderly, University of Leicester, Leicester, UK

    Makrina Daniilidou

  108. Department of Neurodegenerative Disease, MRC Prion Unit, UCL Institute of Neurology, London, UK

    James Uphill, John Collinge, Simon Mead & Andre G Uitterlinden

  109. Department of Pathophysiology and Transplantation, University of Milan, Fondazione Ca' Granda, IRCCS Ospedale Policlinico, Milan, Italy

    Chiara Fenoglio, Maria Serpente, Marina Arcaro, Daniela Galimberti, Elio Scarpini & Andre G Uitterlinden

  110. Department of Psychiatry and Psychotherapy, University Hospital, Saarland, Germany

    Sabrina Pichler, Manuel Mayhaus, Wei Gu & Matthias Riemenschneider

  111. Neurology Department and Sant Pau Biomedical Research Institute, Memory Unit, Hospital de la Santa Creu i Sant Pau, Autonomous University of Barcelona, Barcelona, Spain

    Alberto Lleó, Juan Fortea, Rafael Blesa & Jordi Clarimón

  112. Regional Neurogenetic Centre (CRN), ASP Catanzaro, Lamezia Terme, Italy

    Chiara Cupidi, Raffaele Giovanni Maletta, Maura Gallo & Amalia Cecilia Bruni

  113. Department of Psychiatry and Behavioral Sciences, University of Washington School of Medicine, Seattle, Washington, USA

    David Carrell, Ge Li, Elaine Peskind, Murray Raskind & Debby W Tsuang

  114. NEUROFARBA (Department of Neuroscience, Psychology, Drug Research and Child Health), University of Florence, Florence, Italy

    Sandro Sorbi & Benedetta Nacmias

  115. IRCCS 'Don Carlo Gnocchi', Florence, Italy

    Sandro Sorbi & Benedetta Nacmias

  116. Institute for Medical Informatics, Biometry and Epidemiology, University Hospital of Essen, University Duisburg-Essen, Essen, Germany

    Susanne Moebus

  117. Department of Psychiatry and Psychotherapy, University of Erlangen-Nuremberg, Erlangen, Germany

    Johannes Kornhuber

  118. Istituto di Ricovero e Cura a Carattere Scientifico (IRCCS) Associazione Oasi Maria Santissima Srl, Troina, Italy

    Paolo Bosco

  119. Mercers Institute for Research on Aging, St. James Hospital and Trinity College, Dublin, Ireland

    Michael Gill, Brian Lawlor & Aoibhinn Lynch

  120. Department of Molecular Neuroscience, UCL, Institute of Neurology, London, UK

    Nick C Fox, John Hardy, Jose Bras & Rita Guerreiro

  121. Department of Neurology, University of Michigan, Ann Arbor, Michigan, USA

    Roger L Albin & Henry L Paulson

  122. Geriatric Research, Education and Clinical Center (GRECC), VA Ann Arbor Healthcare System (VAAAHS), Ann Arbor, Michigan, USA

    Roger L Albin

  123. Michigan Alzheimer Disease Center, Ann Arbor, Michigan, USA

    Roger L Albin & Henry L Paulson

  124. Indiana Alzheimer's Disease Center, Indiana University School of Medicine, Indianapolis, Indiana, USA

    Liana G Apostolova

  125. Department of Medical and Molecular Genetics, Indiana University, Indianapolis, Indiana, USA

    Liana G Apostolova, Kelley M Faber, Tatiana M Foroud, Jill R Murrell & Andrew J Saykin

  126. Department of Neurology, Indiana University, Indianapolis, Indiana, USA

    Liana G Apostolova & Martin R Farlow

  127. Department of Radiology and Imaging Sciences, Indiana University, Indianapolis, Indiana, USA

    Liana G Apostolova & Andrew J Saykin

  128. Department of Psychiatry, University of Pennsylvania Perelman School of Medicine, Philadelphia, Pennsylvania, USA

    Steven E Arnold

  129. Geriatric Research, Education and Clinical Center (GRECC), University of Wisconsin, Madison, Wisconsin, USA

    Sanjay Asthana & Craig S Atwood

  130. Department of Medicine, University of Wisconsin, Madison, Wisconsin, USA

    Sanjay Asthana, Craig S Atwood, Cynthia M Carlsson & Mark A Sager

  131. Wisconsin Alzheimer's Disease Research Center, Madison, Wisconsin, USA

    Sanjay Asthana, Craig S Atwood & Cynthia M Carlsson

  132. Department of Medicine (Genetics Program), Boston University, Boston, Massachusetts, USA

    Clinton T Baldwin, Gyungah Jun & Lindsay A Farrer

  133. Department of Neurological Sciences, Rush University Medical Center, Chicago, Illinois, USA

    Lisa L Barnes, Julie A Schneider, Lei Yu & David A Bennett

  134. Department of Behavioral Sciences, Rush University Medical Center, Chicago, Illinois, USA

    Lisa L Barnes

  135. Rush Alzheimer's Disease Center, Rush University Medical Center, Chicago, Illinois, USA

    Lisa L Barnes, Julie A Schneider, Lei Yu & David A Bennett

  136. Civin Laboratory for Neuropathology, Banner Sun Health Research Institute, Phoenix, Arizona, USA

    Thomas G Beach

  137. Departments of Psychiatry, Neurology, and Psychology, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania, USA

    James T Becker

  138. Department of Pathology, Northwestern University Feinberg School of Medicine, Chicago, Illinois, USA

    Eileen H Bigio

  139. Cognitive Neurology and Alzheimer's Disease Center, Northwestern University Feinberg School of Medicine, Chicago, Illinois, USA

    Eileen H Bigio, Marsel Mesulam & Sandra Weintraub

  140. VA Puget Sound Health Care System/GRECC, Seattle, Washington, USA

    Thomas D Bird, Ge Li, Debby W Tsuang & Clive Holmes

  141. Department of Neurology, Mayo Clinic, Rochester, Minnesota, USA

    Bradley F Boeve & Ronald C Petersen

  142. Swedish Medical Center, Seattle, Washington, USA

    James D Bowen

  143. Department of Neurology, University of California, San Francisco, San Francisco, California, USA

    Adam Boxer, Anna Karydas, Bruce L Miller, Howard J Rosen & William W Seeley

  144. Department of Medicine, Duke University, Durham, North Carolina, USA

    James R Burke & Kathleen A Welsh-Bohmer

  145. University of Kansas Alzheimer's Disease Center, University of Kansas Medical Center, Kansas City, Kansas, USA

    Jeffrey M Burns & Russell H Swerdlow

  146. Department of Genetics and Genomic Sciences, Mount Sinai School of Medicine, New York, New York, USA

    Joseph D Buxbaum

  147. Department of Neuroscience, Mount Sinai School of Medicine, New York, New York, USA

    Joseph D Buxbaum & Alison M Goate

  148. Department of Psychiatry, Mount Sinai School of Medicine, New York, New York, USA

    Joseph D Buxbaum & Mary Sano

  149. Department of Pathology and Immunology, Washington University, St. Louis, Missouri, USA

    Nigel J Cairns & John C Morris

  150. USF Health Byrd Alzheimer's Institute, University of South Florida, Tampa, Florida, USA

    Chuanhai Cao, Ashok Raj & Amanda G Smith

  151. Fred Hutchinson Cancer Research Center, Seattle, Washington, USA

    Chris S Carlson & Andrew N McDavid

  152. Department of Psychiatry and Behavioral Sciences, Miller School of Medicine, University of Miami, Miami, Florida, USA

    Regina M Carney, Elizabeth A Crocco & Amanda J Myers

  153. Department of Pathology and Laboratory Medicine, Medical University of South Carolina, Charleston, South Carolina, USA

    Steven L Carroll

  154. Department of Neurology, University of Southern California, Los Angeles, California, USA

    Helena C Chui & Lon S Schneider

  155. Department of Neurology, Medical University of South Carolina, Charleston, South Carolina, USA

    David G Clark

  156. Department of Neurology, Ralph H. Johnson VA Medical Center, Charleston, South Carolina, USA

    David G Clark

  157. Department of Neurology, University of California, Irvine, Irvine, California, USA

    David H Cribbs & Aimee Pierce

  158. Department of Neurology, University of California, Davis, Sacramento, California, USA

    Charles DeCarli & John M Olichney

  159. Institute for Memory Impairments and Neurological Disorders, University of California, Irvine, Irvine, California, USA

    Malcolm Dick & Wayne W Poon

  160. Wien Center for Alzheimer's Disease and Memory Disorders, Mount Sinai Medical Center, Miami Beach, Florida, USA

    Ranjan Duara

  161. Department of Internal Medicine, Rush Institute for Healthy Aging, Rush University Medical Center, Chicago, Illinois, USA

    Denis A Evans

  162. Department of Pathology, University of Alabama at Birmingham, Birmingham, Alabama, USA

    Kenneth B Fallon

  163. Department of Biostatistics, Sanders-Brown Center on Aging, University of Kentucky, Lexington, Kentucky, USA

    David W Fardo

  164. Department of Psychiatry, New York University, New York, New York, USA

    Steven Ferris & Barry Reisberg

  165. Department of Neurosciences, University of California, San Diego, La Jolla, California, USA

    Douglas R Galasko & Eliezer Masliah

  166. Department of Pathology and Laboratory Medicine, Emory University, Atlanta, Georgia, USA

    Marla Gearing

  167. Emory Alzheimer's Disease Center, Emory University, Atlanta, Georgia, USA

    Marla Gearing

  168. Neurogenetics Program, University of California, Los Angeles, Los Angeles, California, USA

    Daniel H Geschwind

  169. Department of Neurology, Mayo Clinic, Jacksonville, Florida, USA

    Neill R Graff-Radford, Nilufer Ertekin-Taner & Steven G Younkin

  170. Division of Genetics, Department of Medicine and Partners Center for Personalized Genetic Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, Massachusetts, USA

    Robert C Green

  171. Department of Neurology, Massachusetts General Hospital/Harvard Medical School, Boston, Massachusetts, USA

    John H Growdon, Bradley T Hyman & Rudolph E Tanzi

  172. Department of Pathology (Neuropathology), University of Pittsburgh, Pittsburgh, Pennsylvania, USA

    Ronald L Hamilton

  173. Department of Neurology, University of Alabama at Birmingham, Birmingham, Alabama, USA

    Lindy E Harrell, Daniel C Marson & Erik D Roberson

  174. Neurogenomics Division, Translational Genomics Research Institute, Phoenix, Arizona, USA

    Matthew J Huentelman & Eric M Reiman

  175. Department of Pathology, Duke University, Durham, North Carolina, USA

    Christine M Hulette

  176. Department of Genome Sciences, University of Washington, Seattle, Washington, USA

    Gail P Jarvik

  177. Department of Medicine (Medical Genetics), University of Washington, Seattle, Washington, USA

    Gail P Jarvik

  178. Department of Epidemiology, Sanders-Brown Center on Aging, College of Public Health, University of Kentucky, Lexington, Kentucky, USA

    Erin Abner

  179. Department of Pathology and Laboratory Medicine, University of California, Davis, Sacramento, California, USA

    Lee-Way Jin & Joshua W Miller

  180. Department of Biostatistics, Boston University, Boston, Massachusetts, USA

    Gyungah Jun, Kathryn L Lunetta & Lindsay A Farrer

  181. Department of Ophthalmology, Boston University, Boston, Massachusetts, USA

    Gyungah Jun & Lindsay A Farrer

  182. Department of Neurology, Oregon Health & Science University, Portland, Oregon, USA

    Jeffrey A Kaye & Joseph F Quinn

  183. Department of Neurology, Portland Veterans Affairs Medical Center, Portland, Oregon, USA

    Jeffrey A Kaye & Joseph F Quinn

  184. Department of Pathology and Laboratory Medicine, University of California, Irvine, Irvine, California, USA

    Ronald Kim

  185. Department of Neurology, Boston University, Boston, Massachusetts, USA

    Neil W Kowall, Ann C McKee, Robert A Stern & Lindsay A Farrer

  186. Department of Pathology, Boston University, Boston, Massachusetts, USA

    Neil W Kowall & Ann C McKee

  187. Department of Neuropsychology, University of California, San Francisco, San Francisco, California, USA

    Joel H Kramer

  188. Department of Neurobiology and Behavior, University of California, Irvine, Irvine, California, USA

    Frank M LaFerla

  189. Department of Neurology, Emory University, Atlanta, Georgia, USA

    James J Lah, Allan I Levey & Thomas S Wingo

  190. Cleveland Clinic Lou Ruvo Center for Brain Health, Cleveland Clinic, Cleveland, Ohio, USA

    James B Leverenz

  191. Department of Pathology, University of Michigan, Ann Arbor, Michigan, USA

    Andrew P Lieberman

  192. Department of Psychiatry, Johns Hopkins University, Baltimore, Maryland, USA

    Constantine G Lyketsos

  193. Department of Medicine–Pulmonary, New York University, New York, New York, USA

    Frank Martiniuk

  194. Department of Neurology, University of Miami, Miami, Florida, USA

    Deborah C Mash

  195. Department of Pathology, University of California, San Diego, La Jolla, California, USA

    Eliezer Masliah

  196. School of Nursing Northwest Research Group on Aging, University of Washington, Seattle, Washington, USA

    Susan M McCurry

  197. Department of Neurology, Northwestern University Feinberg School of Medicine, Chicago, Illinois, USA

    Marsel Mesulam

  198. Department of Pathology, University of Southern California, Los Angeles, California, USA

    Carol A Miller

  199. Department of Neurology, Washington University, St. Louis, Missouri, USA

    John C Morris

  200. Division of Geriatrics, Internal Medicine, University of North Texas Health Science Center, Fort Worth, Texas, USA

    Sid O'Bryant

  201. Department of Internal Medicine, University of New Mexico Health Sciences Center, Albuquerque, New Mexico, USA

    Vernon S Pankratz

  202. Department of Laboratory Medicine and Pathology, Mayo Clinic, Rochester, Minnesota, USA

    Joseph E Parisi

  203. Department of Neurology, University of Colorado School of Medicine, Aurora, Colorado, USA

    Huntington Potter

  204. Alzheimer's Disease Center, New York University, New York, New York, USA

    Barry Reisberg

  205. Department of Epidemiology, Columbia University, New York, New York, USA

    Christiane Reitz

  206. Department of Neurology, University of California, Los Angeles, Los Angeles, California, USA

    John M Ringman & Harry V Vinters

  207. Tanz Centre for Research in Neurodegenerative Disease, University of Toronto, Toronto, Ontario, Canada

    Ekaterina Rogaeva & Peter St George-Hyslop

  208. Department of Neurology, University of Texas Southwestern Medical Center, Dallas, Texas, USA

    Roger N Rosenberg

  209. Department of Pathology (Neuropathology), Rush University Medical Center, Chicago, Illinois, USA

    Julie A Schneider

  210. Department of Psychiatry, University of Southern California, Los Angeles, California, USA

    Lon S Schneider

  211. Department of Pathology, University of Washington, Seattle, Washington, USA

    Joshua A Sonnen, C Dirk Keene & Thomas J Montine

  212. Translational Medicine, Novartis Institutes for Biomedical Research, Cambridge, Massachusetts, USA

    Tricia A Thornton-Wells

  213. Department of Pathology and Laboratory Medicine, University of Pennsylvania Perelman School of Medicine, Philadelphia, Pennsylvania, USA

    John Q Trojanowski & Vivianna M Van Deerlin

  214. Department of Pathology, Johns Hopkins University, Baltimore, Maryland, USA

    Juan C Troncoso

  215. Department of Anatomy and Neurobiology, Sanders-Brown Center on Aging, University of Kentucky, Lexington, Kentucky, USA

    Linda J Van Eldik

  216. Department of Pathology and Laboratory Medicine, University of California, Los Angeles, Los Angeles, California, USA

    Harry V Vinters

  217. Department of Pathology, Taub Institute on Alzheimer's Disease and the Aging Brain, Columbia University, New York, New York, USA

    Jean Paul Vonsattel

  218. Department of Psychiatry, Northwestern University Feinberg School of Medicine, Chicago, Illinois, USA

    Sandra Weintraub

  219. Department of Psychiatry and Behavioral Sciences, Duke University, Durham, North Carolina, USA

    Kathleen A Welsh-Bohmer

  220. Department of Genetics, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, USA

    Kirk C Wilhelmsen

  221. Department of Pathology, Oregon Health & Science University, Portland, Oregon, USA

    Randall L Woltjer

  222. Department of Neurology, Evelyn F. McKnight Brain Institute, Miller School of Medicine, University of Miami, Miami, Florida, USA

    Clinton B Wright

  223. Department of Neurology and Memory Clinic, Hospital Network Antwerp, Antwerp, Belgium

    Sebastien Engelborghs, Rik Vandenberghe & Peter P De Deyn

  224. Department of Neurology, Laboratory for Cognitive Neurology, University of Leuven, Leuven, Belgium

    Rik Vandenberghe

  225. Department of Geriatric Medicine, Genetics Unit, Karolinska University Hospital Huddinge, Stockholm, Sweden

    Hakan Thonberg, Charlotte Forsell, Lena Lilius & Anne Kinhult-Stählbom

  226. Department of Neurobiology, Care Sciences and Society, KIADRC, Karolinska Institutet, Stockholm, Sweden

    Hakan Thonberg, Charlotte Forsell, Lena Lilius, Anne Kinhult-Stählbom & Caroline Graff

  227. Institute of Clinical Medicine/Neurology, University of Eastern Finland, Kuopio, Finland

    Seppo Helisalmi, Anne Maria Koivisto & Annakaisa Haapasalo

  228. CHU Lille, Memory Center of Lille (Centre Mémoire de Ressources et de Recherche), Lille, France

    Vincent Dermecourt

  229. Geriatrics Department, University Paris Descartes, EA 4468, AP–HP, Hôpital Broca, Paris, France

    Nathalie Fievet & Olivier Hanon

  230. University of Bordeaux, Neuroepidemiology, Bordeaux, France

    Carole Dufouil

  231. INSERM, Neuroepidemiology, UMR 897, Bordeaux, France

    Carole Dufouil

  232. INSERM U1127, CNRS UMR 7225, Sorbonne Universités, UPMC Université Paris 06, UMRS 1127, Institut du Cerveau et de la Moelle Épinière, Paris, France

    Alexis Brice & Christophe Tzourio

  233. Department of Genetics, AP–HP, Pitié-Salpêtrière Hospital, Paris, France

    Alexis Brice

  234. INSERM U1061, La Colombière Hospital, Montpellier, France

    Karen Ritchie

  235. Département de Neurologie, Institut de la Mémoire et de la Maladie d'Alzheimer (IM2A), Hôpital de la Pitié-Salpêtrière, AP–HP, Paris, France

    Bruno Dubois & Claudine Berr

  236. Institut des Neurosciences Translationnelles de Paris (IHU-A-ICM), Institut du Cerveau et de la Moelle Épinière (ICM), Paris, France

    Bruno Dubois

  237. INSERM, CNRS, UMRS 975, Institut du Cerveau et de la Moelle Épinière (ICM), Paris, France

    Bruno Dubois

  238. Sorbonne Universités, Université Pierre et Marie Curie, Hôpital de la Pitié-Salpêtrière, AP–HP, Paris, France

    Bruno Dubois

  239. Department of Family Medicine, University of Washington, Seattle, Washington, USA

    Annette L Fitzpatrick

  240. Centre for Public Health, University of Iceland, Reykjavik, Iceland

    Thor Aspelund

  241. Group Health Research Institute, Group Health, Seattle, Washington, USA

    Eric B Larson

  242. Institute for Translational Genomics and Population Sciences, Los Angeles BioMedical Research Institute at Harbor-UCLA Medical Center, Torrance, California, USA

    Jerome I Rotter

  243. Centro de Biología Molecular Severo Ochoa (CSIC-UAM), Madrid, Spain

    María J Bullido

  244. Molecular Genetics Laboratory-Hospital, University of Central Asturias, Oviedo, Spain

    Eliecer Coto & Victoria Alvarez

  245. Human Genome Sequencing Center, Baylor College of Medicine, Houston, Texas, USA

    Eric Boerwinkle

  246. Department of Internal Medicine, Erasmus University Medical Center, Rotterdam, The Netherlands

    Fernando Rivadeneira

  247. Netherlands Consortium on Health Aging and National Genomics Initiative, Leiden, The Netherlands

    Fernando Rivadeneira

  248. Arizona Alzheimer's Consortium, Phoenix, Arizona, USA

    Eric M Reiman

  249. Banner Alzheimer's Institute, Phoenix, Arizona, USA

    Eric M Reiman

  250. Department of Psychiatry, University of Arizona, Phoenix, Arizona, USA

    Eric M Reiman

  251. Department of Clinical Sciences, University of Texas Southwestern Medical Center, Dallas, Texas, USA

    Joan S Reisch

  252. Departments of Psychiatry, Medicine, and Family and Community Medicine and South Texas Veterans Health Administration Geriatric Research Education and Clinical Center (GRECC), University of Texas Health Science Center at San Antonio, San Antonio, Texas, USA

    Donald R Royall

  253. Institute for Stroke and Dementia Research, Klinikum der Universität München, Munich, Germany

    Martin Dichgans

  254. German Center for Neurodegenerative Diseases (DZNE), Munich, Germany

    Martin Dichgans

  255. Cambridge Institute for Medical Research, University of Cambridge, Cambridge, UK

    Peter St George-Hyslop & David C Rubinsztein

  256. Department of Experimental and Clinical Medicine, Neurological Institute, University of Pisa, Pisa, Italy

    Michelangelo Mancuso & Ubaldo Bonuccelli

  257. PharmaTherapeutics Clinical Research, Pfizer Worldwide Research and Development, Cambridge, Massachusetts, USA

    Ashley R Winslow

  258. Institute of Neurology, Catholic University of Sacred Hearth, Rome, Italy

    Antonio Daniele

  259. Departments of Neurology, Pharmacology, and Neuroscience, Texas Tech University Health Science Center, Lubbock, Texas, USA

    Chuang-Kuo Wu

  260. Department of Psychiatry, Charité University Medicine, Berlin, Germany

    Oliver Peters

  261. Institute of Public Health, University of Cambridge, Cambridge, UK

    Carol Brayne

  262. Department of Medical Sciences, Institute of Biomedicine (iBiMED), University of Aveiro, Aveiro, Portugal

    Jose Bras & Rita Guerreiro

  263. Institute of Psychiatry, Psychology and Neuroscience, King's College London, London, UK

    Ammar Al-Chalabi & Christopher E Shaw

  264. Institute of Brain, Behaviour and Mental Health, Clinical and Cognitive Neuroscience Research Group, University of Manchester, Manchester, UK

    David Mann

  265. 3rd Department of Neurology, Medical School, Aristotle University of Thessaloniki, Thessaloniki, Greece

    Magda Tsolaki

  266. Division of Clinical Neurosciences, School of Medicine, University of Southampton, Southampton, UK

    Rebecca Sussams

  267. Department of Psychiatry, University of Oxford, Oxford, UK

    Simon Lovestone

  268. Florida Alzheimer's Disease Research Center, Gainesville, Florida, USA

    Todd E Golde

  269. Department of Neurology, Center for Translational and Systems Neuroimmunology, Columbia University Medical Center, New York, New York, USA

    Philip L De Jager

  270. Department of Health Services, University of Washington, Seattle, Washington, USA

    Bruce M Psaty

  271. Department of Neurology, Memory Research and Resources Center, CMRR of Montpellier, Hospital Gui de Chauliac, Montpellier, France

    Claudine Berr

  272. Department of Neurology, Montpellier University, Montpellier, France

    Claudine Berr

  273. Memory Research and Resources Center, CMRR de Bordeaux, Bordeaux, France

    Jean-François Dartigues

  274. Division of Neurosciences, Neurogenetics Laboratory, Centre for Applied Medical Research, University of Navarra School of Medicine, Pamplona, Spain

    Sara Ortega-Cubero

  275. Department of Neurology, Complejo Asistencial Universitario de Palencia, Palencia, Spain

    Sara Ortega-Cubero

  276. Center for Applied Genomics, Children's Hospital of Philadelphia, Philadelphia, Pennsylvania, USA

    Hakon Hakonarson

  277. Departments of Biology and Neuroscience, Brigham Young University, Provo, Utah, USA

    John Keoni Kauwe

  278. Department of Neurology, Erasmus MC University Medical Center, Rotterdam, The Netherlands

    M Arfan Ikram

  279. Department of Epidemiology and Biostatistics, Case Western Reserve University, Cleveland, Ohio, USA

    Jonathan L Haines

  280. University of Bordeaux, Neuroepidemiology, UMR 897, Bordeaux, France

    Christophe Tzourio

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