Alpha-2 macroglobulin gene in early- and late-onset Alzheimer disease Galina I. Korovaitseva a , Smita Premkumar d , Anastasia Grigorenko a, b , Yury Molyaka a, c , Vera Galimbet a , Natalya Selezneva a , Svetlana I. Gavrilova a , Lindsay A. Farrer d, e, f , Evgeny I. Rogaev a, * a Mental Health Research Center, Russian Academy of Medical Sciences (RAMS), Moscow, Russia b Institute of Molecular Genetics, Russian Academy of Medical Sciences (RAMS), Moscow, Russia c Center of Medical Genetics, Russian Academy of Medical Sciences (RAMS), Moscow, Russia d Department of Medicine (Genetics Program), Boston University School of Medicine, Boston, MA, USA e Department of Neurology, Boston University School of Medicine, Boston, MA, USA f Epidemiology and Biostatistics, Boston University School of Medicine, Boston, MA, USA Received 10 May 1999; received in revised form 22 June 1999; accepted 24 June 1999 Abstract Alpha-2-macroglobulin (A2M) is a proteinase inhibitor that is present in senile plaques and may play a role in meta- bolism of amyloid beta (Ab ) peptide. Recently it was reported that inheritance of the deletion allele (A2M-2) confers increased risk for late-onset Alzheimer disease (AD) with signi®cance of this effect similar to the e 4 allele of apolipopro- tein E (APOE). We examined the distribution of A2M genotypes and alleles in a cohort of 146 AD patients and 160 age- matched non-demented individuals. There was no evidence for association in the total sample or in subsets strati®ed by age or APOE e 4 status. These results suggest that this polymorphism is not a strong genetic risk factor for either early- or late-onset forms of the disorder. However, they do not exclude the possibility that an AD susceptibility allele is located elsewhere in A2M or a nearby gene. q 1999 Elsevier Science Ireland Ltd. All rights reserved. Keywords: Alpha-2-macroglobulin, Alzheimer disease; Apolipoprotein E; Association; Linkage disequilibrium; Age at onset Lipoprotein receptors, low-density and very low density lipoprotein receptors (LDL-R and VLDL-R, respectively) and lipoprotein receptor-related protein (LRP) and its ligands have been implicated in the pathogenesis of Alzhei- mer disease (AD) in some [6±8,11,15,20] but not all [2,8,12,19] studies. Alpha-2 macroglobulin (A2M) is a component of the b -amyloid plaque that binds LRP. A2M associates with b -amyloid, prevents ®bril formation and is involved in APOE mediated degradation of Ab peptide [5,14]. The A2M gene is located on chromosome 12 and contains a polymorphism de®ned by a 5 base-pair (bp) dele- tion located between 3 and 7 bp upstream from the 5 0 - splice site of the exon which encodes the bait domain region de®n- ing the inhibitory properties of the A2M protein [9]. Recently, a genetic association between this pentanucleo- tide deletion in an intron of A2M (allele 2) and late-onset AD has been reported in a cohort of patients ascertained on the basis of two or more affected siblings [1]. This associa- tion was strongest among a subset of families lacking the APOE e 4 allele. The magnitude and signi®cance of this effect was estimated to be similar to that of the APOE 4/4 genotype, a well-established potent risk factor for AD [20]. To evaluate the effect of the A2M-2 variant in AD more typically encountered in the population, we compared the distribution of A2M alleles and genotypes in a group of rigorously evaluated patients which were not selected with respect to family history or age of onset of dementia with those in a control group of age- and ethnically-matched non- demented individuals. AD cases were ascertained through the Mental Health Research Center (MHRC) in Moscow between 1995 and 1998. All living patients underwent a standard neurological examination, a personal interview, psychometric testing and brain imaging (CT or MRI). These data were supplemented with information contained in the medical records. The diagnosis of AD was established according to ICD10 and NINCDS-ADRDA criteria [10,21]. Neuroscience Letters 271 (1999) 129±131 0304-3940/99/$ - see front matter q 1999 Elsevier Science Ireland Ltd. All rights reserved. PII: S0304-3940(99)00537-6 * Corresponding author. Tel.: 17-095-958-1060; fax: 17-095- 952-8940. E-mail address: rogaev@dol.ru (E.I. Rogaev)