Neurogenetics (1999) 2 : 109–113 Q Springer-Verlag 1999 DOI 10.007/s100489900061 Original article Is the LDL receptor-related protein involved in Alzheimer’s disease? Jean C. Lambert 7 Marie C. Chartier-Harlin 7 Dominique Cottel 7 Florence Richard Eric Neuman 7 David Guez 7 Sylvie Legrain 7 Claudine Berr 7 Philippe Amouyel Nicole Helbecque Received: October 29, 1998 / Accepted: December 30, 1998 / Published online: March 11, 1999 J.C. Lambert 7 M.C. Chartier-Harlin 7 D. Cottel 7 F. Richard P. Amouyel (Y) 7 N. Helbecque Service d’Epidémiologie et de Santé Publique – INSERM U.508, Institut Pasteur de Lille, 1 rue Calmette, F-59019 Lille Cedex, France Tel.: (33)-3-20 87 77 10; Fax: (33)-3-20 87 78 94; email: philippe.amouyel6pasteur-lille-fr E. Neuman 7 D. Guez IRIServier, 6 place des Pléiades, F-92415 Courbevoie Cedex, France S. Legrain Hôpital P. Brousse, 12 avenue Paul Vaillant Couturier, F-94807 Villejuif Cedex, France C. Berr INSERM U.360, Hôpital de la Salpétrière, F-75651 Paris Cedex, France ABSTRACT LDL-related protein receptor (LRP) is the main recep- tor in the brain for apolipoprotein E. Moreover, the LRP gene is located on chromosome 12, the site of a potential Alzheimer’s disease (AD) locus. We explored the association between the LRP gene and AD in 600 French Caucasian patients (37.8% men, mean age 72.0B8.0 years, mean age at onset 68.7B8.1 years) and age-matched controls (np646, 37.0% men, mean age 72.5B8.2 years) and observed an association between a (TTTC) repeat at the 3’ end of an Alu sequence in the LRP gene and the risk of developing AD. Three alleles were detected in this population [corresponding to 83, 87, and 91 base pairs (bp)], the 91-bp allele being asso- ciated with an increased risk of developing AD [all pa- tients: odds ratio (OR) 1.6, P~0.01; late-onset AD: OR 1.8, P~0.01]. This suggests an association between the LRP locus and AD. However, in the light of studies related to the exon 3 LRP polymorphism and given the low strength of the association reported here, a biologi- cally active variant may exist on chromosome 12, either in the LRP gene itself or in another gene in the vicini- ty. Key words Alzheimer disease 7 LDL-related protein receptor 7 Polymorphism 7 Population study INTRODUCTION Alzheimer’s disease (AD) is the most common type of dementia among the elderly. The age at onset allows classification of patients into early (before 65 years) and late-onset (after 65 years) AD. Previous studies have shown an influence of genetic factors (amyloid-b precursor protein [1], presenilin-1 [2], and presenilin-2 [3, 4] genes) on the age at onset of the disease. In par- ticular, the ε4 allele of the apolipoprotein E (APOE) gene acts in a dose-related manner [5] to decrease age at onset of AD. At present, the APOE ε4 allele is the most frequently identified genetic risk factor for AD, accounting for about 40%–50% of late-onset cases. The mechanism of this association is not fully under- stood. In the brain, apoE is proposed to function as a ligand stimulating cholesterol and/or lipid utilization in neurons [6]. Its main receptor in the brain is the LDL receptor-related protein (LRP) [7], which is also a pos- sible amyloid precursor protein receptor [8]. The LRP gene is located on chromosome 12, a susceptibility lo- cus implicated in AD [9, 10]. Hence we investigated the association between a previously described tetranucleo- tide polymorphism and AD in a European population. The reported polymorphism involves a (TTTC) n re- peat, and four different alleles have been described to date [11, 12] corresponding to 83, 87, 91, and 95 base pairs (bp) (the 87- and 91-bp being the most frequent). An association between the 87-bp allele and late-onset AD has been reported in an American population [13], but other studies were not able to find any association [14–17]. A preliminary study from our laboratory on a small number of Caucasians [18] showed a tendency for the 87-bp allele to be protective. In order to clarify this controversy, we undertook this study of a large Euro- pean population.