1. Small, S.A. & Duff, K. Linking Abeta and tau in late-onset Alzheimer's disease: a dual pathway hypothesis. Neuron 60, 534–542 (2008).

   Article  CAS  Google Scholar 

2. Hardy, J. & Selkoe, D.J. The amyloid hypothesis of Alzheimer's disease: progress and problems on the road to therapeutics. Science 297, 353–356 (2002).

   Article  CAS  Google Scholar 

3. Campion, D. et al. Early-onset autosomal dominant Alzheimer disease: prevalence, genetic heterogeneity, and mutation spectrum. Am. J. Hum. Genet. 65, 664–670 (1999).

   Article  CAS  Google Scholar 

4. Farrer, L.A. et al. Effects of age, sex, and ethnicity on the association between apolipoprotein E genotype and Alzheimer disease. A meta-analysis. APOE and Alzheimer Disease Meta Analysis Consortium. J. Am. Med. Assoc. 278, 1349–1356 (1997).

   Article  CAS  Google Scholar 

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

   Article  Google Scholar 

6. Ashford, J.W. & Mortimer, J.A. Non-familial Alzheimer's disease is mainly due to genetic factors. J. Alzheimers Dis. 4, 169–177 (2002).

   Article  Google Scholar 

7. Bertram, L., McQueen, M.B., Mullin, K., Blacker, D. & Tanzi, R.E. Systematic meta-analyses of Alzheimer disease genetic association studies: the AlzGene database. Nat. Genet. 39, 17–23 (2007).

   Article  CAS  Google Scholar 

8. Reiman, E.M. et al. GAB2 alleles modify Alzheimer's risk in APOE epsilon4 carriers. Neuron 54, 713–720 (2007).

   Article  CAS  Google Scholar 

9. Li, H. et al. Candidate single-nucleotide polymorphisms from a genomewide association study of alzheimer disease. Arch. Neurol. 65, 45–53 (2008).

   Article  Google Scholar 

10. Bertram, L. et al. Genome-wide association analysis reveals putative Alzheimer's disease susceptibility loci in addition to APOE. Am. J. Hum. Genet. 83, 623–632 (2008).

    Article  CAS  Google Scholar 

11. Beecham, G.W. et al. Genome-wide association study implicates a chromosome 12 risk locus for late-onset Alzheimer disease. Am. J. Hum. Genet. 84, 35–43 (2009).

    Article  CAS  Google Scholar 

12. Carrasquillo, M.M. et al. Genetic variation in PCDH11X is associated with susceptibility to late-onset Alzheimer's disease. Nat. Genet. 41, 192–198 (2009).

    Article  CAS  Google Scholar 

13. Butler, A.W. et al. Meta-analysis of linkage studies for Alzheimer's disease-A web resource. Neurobiol. Aging 30, 1037–1047 (2009).

    Article  Google Scholar 

14. Roheim, P.S., Carey, M., Forte, T. & Vega, G.L. Apolipoproteins in human cerebrospinal fluid. Proc. Natl. Acad. Sci. USA 76, 4646–4649 (1979).

    Article  CAS  Google Scholar 

15. May, P.C. & Finch, C.E. Sulfated glycoprotein 2: new relationships of this multifunctional protein to neurodegeneration. Trends Neurosci. 15, 391–396 (1992).

    Article  CAS  Google Scholar 

16. May, P.C. et al. Dynamics of gene expression for a hippocampal glycoprotein elevated in Alzheimer's disease and in response to experimental lesions in rat. Neuron 5, 831–839 (1990).

    Article  CAS  Google Scholar 

17. Calero, M. et al. Apolipoprotein J (clusterin) and Alzheimer's disease. Microsc. Res. Tech. 50, 305–315 (2000).

    Article  CAS  Google Scholar 

18. Ghiso, J. et al. The cerebrospinal-fluid soluble form of Alzheimer's amyloid beta is complexed to SP-40,40 (apolipoprotein J), an inhibitor of the complement membrane-attack complex. Biochem. J. 293, 27–30 (1993).

    Article  CAS  Google Scholar 

19. Zlokovic, B.V. et al. Glycoprotein 330/megalin: probable role in receptor-mediated transport of apolipoprotein J alone and in a complex with Alzheimer disease amyloid beta at the blood-brain and blood-cerebrospinal fluid barriers. Proc. Natl. Acad. Sci. USA 93, 4229–4234 (1996).

    Article  CAS  Google Scholar 

20. DeMattos, R.B. et al. Clusterin promotes amyloid plaque formation and is critical for neuritic toxicity in a mouse model of Alzheimer's disease. Proc. Natl. Acad. Sci. USA 99, 10843–10848 (2002).

    Article  CAS  Google Scholar 

21. DeMattos, R.B. et al. ApoE and clusterin cooperatively suppress Abeta levels and deposition: evidence that ApoE regulates extracellular Abeta metabolism in vivo. Neuron 41, 193–202 (2004).

    Article  CAS  Google Scholar 

22. Bell, R.D. et al. Transport pathways for clearance of human Alzheimer's amyloid beta-peptide and apolipoproteins E and J in the mouse central nervous system. J. Cereb. Blood Flow Metab. 27, 909–918 (2007).

    Article  CAS  Google Scholar 

23. Holtzman, D.M. In vivo effects of ApoE and clusterin on amyloid-beta metabolism and neuropathology. J. Mol. Neurosci. 23, 247–254 (2004).

    Article  CAS  Google Scholar 

24. Lambert, J.C. & Amouyel, P. Genetic heterogeneity of Alzheimer's disease: complexity and advances. Psychoneuroendocrinology 32, S62–S70 (2007).

    Article  CAS  Google Scholar 

25. Holtzman, D.M. et al. Expression of human apolipoprotein E reduces amyloid-beta deposition in a mouse model of Alzheimer's disease. J. Clin. Invest. 103, R15–R21 (1999).

    Article  CAS  Google Scholar 

26. Iida, K., Mornaghi, R. & Nussenzweig, V. Complement receptor (CR1) deficiency in erythrocytes from patients with systemic lupus erythematosus. J. Exp. Med. 155, 1427–1438 (1982).

    Article  CAS  Google Scholar 

27. Song, W.C., Sarrias, M.R. & Lambris, J.D. Complement and innate immunity. Immunopharmacology 49, 187–198 (2000).

    Article  CAS  Google Scholar 

28. Khera, R. & Das, N. Complement receptor 1: disease associations and therapeutic implications. Mol. Immunol. 46, 761–772 (2009).

    Article  CAS  Google Scholar 

29. Webster, S., Bradt, B., Rogers, J. & Cooper, N. Aggregation state-dependent activation of the classical complement pathway by the amyloid beta peptide. J. Neurochem. 69, 388–398 (1997).

    Article  CAS  Google Scholar 

30. Rogers, J. et al. Peripheral clearance of amyloid beta peptide by complement C3-dependent adherence to erythrocytes. Neurobiol. Aging 27, 1733–1739 (2006).

    Article  CAS  Google Scholar 

31. Kuo, Y.M. et al. Amyloid-beta peptides interact with plasma proteins and erythrocytes: implications for their quantitation in plasma. Biochem. Biophys. Res. Commun. 268, 750–756 (2000).

    Article  CAS  Google Scholar 

32. Zhou, J., Fonseca, M.I., Pisalyaput, K. & Tenner, A.J. Complement C3 and C4 expression in C1q sufficient and deficient mouse models of Alzheimer's disease. J. Neurochem. 106, 2080–2092 (2008).

    Article  CAS  Google Scholar 

33. Wyss-Coray, T. et al. Prominent neurodegeneration and increased plaque formation in complement-inhibited Alzheimer's mice. Proc. Natl. Acad. Sci. USA 99, 10837–10842 (2002).

    Article  CAS  Google Scholar 

34. Donnelly, P. Progress and challenges in genome-wide association studies in humans. Nature 456, 728–731 (2008).

    Article  CAS  Google Scholar 

35. Maher, B. Personal genomes: The case of the missing heritability. Nature 456, 18–21 (2008).

    Article  CAS  Google Scholar 

36. Harold, D. et al. Genome-wide association study identifies variants at CLU and PICALM associated with Alzheimer's disease. Nat. Genet. advance online publication, doi:10.1038/ng.440 (6 September 2009).

37. Heath, S.C. et al. Investigation of the fine structure of European populations with applications to disease association studies. Eur. J. Hum. Genet. 16, 1413–1429 (2008).

    Article  CAS  Google Scholar 

38. Price, A.L. et al. Principal components analysis corrects for stratification in genome-wide association studies. Nat. Genet. 38, 904–909 (2006).

    Article  CAS  Google Scholar 

39. Breslow, N.E., Day, N.E., Halvorsen, K.T., Prentice, R.L. & Sabai, C. Estimation of multiple relative risk functions in matched case-control studies. Am. J. Epidemiol. 108, 299–307 (1978).

    Article  CAS  Google Scholar 

40. Barrett, J.C., Fry, B., Maller, J. & Daly, M.J. Haploview: analysis and visualization of LD and haplotype maps. Bioinformatics 21, 263–265 (2005).

    Article  CAS  Google Scholar 

41. Tregouet, D.A. & Tiret, L. Cox proportional Hazards survival regression in haplotype-based association analysis using the stochastic-EM algorithm. Eur. J. Hum. Genet. 12, 971–974 (2004).

    Article  CAS  Google Scholar 

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The work was made possible by the generous participation of the control subjects, the subjects with Alzheimer's disease, and their families. We thank A. Boland (Centre National de Génotypage) for her technical help in preparing the DNA samples for analyses. This work was supported by the National Foundation for Alzheimer's Disease and Related Disorders, the Institut Pasteur de Lille and the Centre National de Génotypage.

The Three-City Study was performed as part of a collaboration between the Institut National de la Santé et de la Recherche Médicale (Inserm), the Victor Segalen Bordeaux II University and Sanofi-Synthélabo. The Fondation pour la Recherche Médicale funded the preparation and initiation of the study. The 3C Study was also funded by the Caisse Nationale d'Assurance Maladie des Travailleurs Salariés, Direction Générale de la Santé, Mutuelle Générale de l'Education Nationale, Institut de la Longévité, Agence Française de Sécurité Sanitaire des Produits de Santé, the Aquitaine and Bourgogne Regional Councils, Fondation de France and the joint French Ministry of Research/Inserm 'Cohortes et collections de données biologiques' programme. Lille Génopôle received an unconditional grant from Eisai.

Belgium sample collection: the Antwerp site (CVB) was in part supported by the VIB Genetic Service Facility (http://www.vibgeneticservicefacility.be/) and the Biobank of the Institute Born-Bunge; the Special Research Fund of the University of Antwerp; the Fund for Scientific Research-Flanders (FWO-V); the Foundation for Alzheimer Research (SAO-FRMA); and the Interuniversity Attraction Poles (IAP) program P6/43 of the Belgian Federal Science Policy Office, Belgium; K.S. is a postdoctoral fellow and K.B. a PhD fellow of the FWO-V.

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 Centre of Excellence in Neurodegeneration.

Italian sample collection: the Bologna site (FL) obtained funds from the Italian Ministry of research and University as well as Carimonte Foundation. The Florence site was supported by a grant from the Italian ministry of Health (RFPS-2006-7-334858). The Milan site was supported by a grant from the 'fondazione Monzino'. We appreciate the expert contribution of C. Romano.

Spanish sample collection: the Madrid site (MB) was supported by grants of the Ministerio de Educación y Ciencia and the Ministerio de Sanidad y Consumo (Instituto de Salud Carlos III) and an institutional grant of the Fundación Ramón Areces to the Centro de Biología Molecular Severo Ochoa. We thank I. Sastre and A. Martínez-García for the preparation and control of the DNA collection and P. Gil and P. Coria for their cooperation in the recruitment of cases and controls. We are grateful to the Asociación de Familiares de Alzheimer de Madrid (AFAL) for continuous encouragement and help.

Authors and Affiliations

1. Inserm U744, Lille, France

   Jean-Charles Lambert, Gael Even, Nathalie Fiévet & Philippe Amouyel

2. Institut Pasteur de Lille, Lille, France

   Jean-Charles Lambert, Gael Even, Nathalie Fiévet & Philippe Amouyel

3. Université de Lille Nord de France, Lille, France

   Jean-Charles Lambert, Florence Pasquier & Philippe Amouyel

4. Centre National de Génotypage, Institut Genomique, Commissariat à l'énergie Atomique, Evry, France

   Simon Heath, Diana Zelenika, Ivo Gut & Mark Lathrop

5. Inserm U614, Faculté de Médecine-Pharmacie de Rouen, Rouen, France

   Dominique Campion & Didier Hannequin

6. Department of Molecular Genetics, Neurodegenerative Brain Diseases group, VIB, Antwerpen, Belgium

   Kristel Sleegers, Karolien Bettens & Christine Van Broeckhoven

7. Institute Born-Bunge and University of Antwerp, Antwerpen, Belgium

   Kristel Sleegers, Karolien Bettens, Sebastiaan Engelborghs, Peter De Deyn & Christine Van Broeckhoven

8. Department of Neurology, Kuopio University and University Hospital, Finland

   Mikko Hiltunen, Seppo Helisalmi & Hilkka Soininen

9. Neurology Service and Centro Investigación Biomédica en Red para Enfermedades Neurodegenerativas (CIBERNED), 'Marqués de Valdecilla' University Hospital, University of Cantabria, Santander, Spain

   Onofre Combarros & Ignacio Mateo

10. Centro de Biologia Molecular Severo Ochoa, Universidad Autónoma de Madrid–Consejo Superior de Investigaciones Científicas and CIBERNED, Universidad Autonoma, Cantoblanco, Madrid, Spain

    Maria J Bullido

11. Departement de Geriatrie, Centre Hospitalier Universitaire de Dijon, Dijon, France

    Béatrice Tavernier

12. Inserm U897, Victor Segalen University, Bordeaux, France

    Luc Letenneur, Pascale Barberger-Gateau & Jean-François Dartigues

13. Inserm U888, Hôpital La Colombière, Montpellier, France

    Claudine Berr & Karen Ritchie

14. Centre Hospitalier Régional Universitaire de Lille, Lille, France

    Florence Pasquier & Philippe Amouyel

15. Memory Clinic and Department of Neurology, Ziekenhuisnetwerk Antwerpen Middelheim, Antwerpen, Belgium

    Sebastiaan Engelborghs & Peter De Deyn

16. Servicio de Neurologia, Hospital Universitario La Paz, Universidad Autónoma de Madrid and CIBERNED, Madrid, Spain

    Ana Franck

17. Department of Experimental Pathology, School of Medicine, University of Bologna, Italy

    Elisa Porcellini & Federico Licastro

18. Inserm U894 Faculté de Médecine, Université Paris Descartes, Paris, France

    Olivier Hanon

19. Banco de ADN, Universidad del Pais Vasco(UPV/EHU), Facultad de Farmacia, Vitoria-Gasteiz, Spain

    Marian M de Pancorbo

20. Molecular Psychiatry Laboratory, Queensland Institute of Medical Research, Royal Brisbane Hospital, Queensland, Australia

    Corinne Lendon

21. Inserm U708, Paris, France

    Carole Dufouil, Christophe Tzourio & Annick Alpérovitch

22. Université Pierre et Marie Curie Paris 6, Paris, France

    Carole Dufouil, Christophe Tzourio & Annick Alpérovitch

23. Department of genetics, Institut de la vision, Inserm, Université Pierre et Marie Curie Paris 6, Paris, France

    Céline Jaillard & Thierry Leveillard

24. Genetic Molecular Unit, Hospital Universitario Central de Asturias, Oviedo, Spain

    Victoria Alvarez

25. Istituto Di Ricovero e Cura a Carattere Scientifico (IRCCS) Associazione Oasi Maria Santissima, Institute for Research on Mental Retardation and Brain Aging, Troina, Italy

    Paolo Bosco

26. Department of Neuroscience, Neurological Clinic, University of Pisa, Italy

    Michelangelo Mancuso

27. Department of Geriatrics, Center for Aging Brain, Memory Unit, University of Bari, Bari, Italy

    Francesco Panza

28. Department of Neurological and Psychiatric Sciences, Florence, Italy

    Benedetta Nacmias

29. Department of Clinical and Behavioral Neurology, IRCCS Santa Lucia Foundation, Roma, Italy

    Paola Bossù

30. Department of Neuroscience, Laboratory of Molecular Genetics, Section of Clinical Pharmacology, University of Cagliari, Italy

    Paola Piccardi

31. Department of Clinical Medicine and Prevention, University of Milano-Bicocca, Monza, Italy

    Giorgio Annoni

32. Department of Medical Science, Geriatric Unit & Gerontology-Geriatric Research Laboratory, IRCCS Casa Sollievo della Sofferenza, San Giovanni Rotondo, Italy

    Davide Seripa

33. Department of Neurological Sciences, Dino Ferrari Center, University of Milan, IRCCS Ospedale Maggiore Policlinico, Milan, Italy

    Daniela Galimberti

34. Fondation Jean Dausset–Centre d'Etudes du Polymorphisme Humain, Paris, France

    Hélène Blanché & Mark Lathrop

Consortia

the European Alzheimer's Disease Initiative Investigators

Contributions

Project conception, design, management. J.-C.L., M.L., P.A. Phenotype collection, data management. France: D.C., B.T., L.L., C.B., F.Pasquier, N.F., P.B.-G., O.H., C.L., C.D., C.J., T.L., D.H., K.R., H.B., J.-F.D., C.T., A.A. Belgium: K.S., K.B., S.E., P.D.D., C.V.B. Finland: M.H., S.Helisalmi, H.S. Italy: E.P., P.Bosco, M.M., F.Panza, B.N., P.Bossù, P.P., G.A., D.S., D.G., F.L. Spain: O.C., M.J.B., I.M., A.F., M.M.d.P., V.A. Genome-wide, validation genotyping. S.Heath., D.Z., I.G. Data analysis: J.-C.L., S.Heath., G.E., M.L., P.A. Writing group: J.-C.L., S.Heath., M.L., P.A.

Corresponding author

Correspondence to Philippe Amouyel.

Competing interests

The authors have a patent under consideration based on the findings of this work.

A full list of members is provided in the Supplementary Note.

Cite this article

Lambert, JC., Heath, S., Even, G. et al. Genome-wide association study identifies variants at CLU and CR1 associated with Alzheimer's disease. Nat Genet 41, 1094–1099 (2009). https://doi.org/10.1038/ng.439

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• Received: 12 May 2009

• Accepted: 31 July 2009

• Published: 06 September 2009

• Issue date: October 2009

• DOI: https://doi.org/10.1038/ng.439