α-2 macroglobulin gene and Alzheimer disease

Blacker et al.1 reported an association between a deletion in exon 18 of the α-2 macroglobulin (A2M) gene and Alzheimer disease (AD) in a sample of affected and unaffected siblings from

families segregating AD. They observed that the degree of conferred risk for AD in A2M allele 2 (A2M*2) carriers was similar in magnitude to that for carriers of the apolipoprotein (APOE) ɛ4

allele (APOE*E4). We set out to test for a similar association in a powerful, case-control sample composed of 2,616 individuals taken from populations from Europe and the United States. In

addition, we extended our analysis of the National Institute of Mental Health (NIMH) family samples studied by Blacker et al.1 using linkage and association approaches. We pooled this NIMH

series (270 sibpairs) with a similar series of 125 sibpairs collected through the auspices of the National Institution of Aging (NIA) at the Indiana Alzheimer cell repository to increase the

power of our analysis.

We studied four independent association samples of unrelated AD patients with onset over 50 years and relevant controls (Table 1) and diagnosed AD patients according to NINCDS-ADRDA (ref. 2)

criteria with either probable or definite AD. We calculated that this sample had over 99% power to detect an effect of equivalent size to that reported by Blacker et al.1 in their familial

sample (odds ratio (OR)=3.56), assuming a stringent α level of 0.001. Furthermore, we calculated that our sample was sufficiently powerful (80%) to detect an extremely small effect (OR≥1.2)

assuming an α level of 0.05.

We thank the clinicians and staff of the Mayo Institute and Washington University School of Medicine, NIMH and NIA. This work was supported by the Medical Research Council (UK), the Institut

National pour la Santé Et la Recherche Médicale (INSERM), the Institut Pasteur de Lille, the Conseil Régional du Nord-Pas de Calais axe régional de recherche sur les maladies

neurodégénératives et le vieillissement cérébral and the Fondation pour la Recherche Médicale, The Mayo Foundation, National Institute of Health, the Alzheimer's Disease Association and the

Nettie and Rebecca Brown Foundation.

Varuni Rudrasingham, Fabienne Wavrant-De Vrièze, Jean-Charles Lambert and Sumi Chakraverty: These authors contributed equally to this work

Department of Psycological Medicine, University of Wales College of Medicine, Heath Park, Cardiff, CF14 4XN

Varuni Rudrasingham, Patrick Kehoe, Frances Rice, Stephanie Carty, Peter Holmans, Michael J. Owen & Julie Williams

Birdsallh Building, Mayo Clinic Jacksonville, 4500 San Pablo Road, Jacksonville, 32084, Florida, USA

Fabienne Wavrant-De Vrièze, Richard Crook, Jordi Pérez-Tur & John Hardy

CJF 95-05 INSERM, Institut Pasteur de Lille, 1 Rue du Pr Calmette, Lille, 59019, Cedex, France

Jean-Charles Lambert, Philippe Amouyel, Bernard Frigard, Dominique Cottel & Marie-Christine Chartier-Harlin

Departments of Neurology, Psychiatry and Genetics, Washington University School of Medicine, 4940 Children's Place, St. Louis, 63110, Missouri, USA

Sumi Chakraverty, William Wu, John C. Morris, Peter Holmans & Alison Goate

Department of Neurology, Mayo Clinic Rochester, Rochester, 55905, Minnesota, USA

Section of Old Age Psychiatry, Institute of Psychiatry, De Crespigny Park, London, SE5 8AF, UK

Anyone you share the following link with will be able to read this content: