The genotype 2/2 of the presenilin-1 polymorphism is decreased in Spanish early-onset Alzheimer’s disease Mario Ezquerra a , Rafael Blesa b , Eduardo Tolosa b , Secundı ´ Lopez Pousa c , Miguel Aguilar d , Jordi Pen ˜a e , Christine Van Broeckhoven f , Francisca Ballesta a , Rafael Oliva a, * a Genetics Service, Hospital Clı ´nic i Provincial and Institut August Pi i Sunyer, Villarroel 170, 08036 Barcelona, Spain b Neurology Service, Hospital Clı ´nic i Provincial and Institut August Pi i Sunyer, Barcelona, Spain c Dementia Assessment Unit, Hospital Santa Caterina, Girona, Spain d Hospital Mutua de Terrasa, Terrasa, Spain e Hospital del Mar, Barcelona, Spain f Neurogenetics Laboratory, Flanders Interuniversity Institute for Biotechnology (VIB), Born-Bunge Foundation (BBS), University of Antwerp (UIA), Antwerpen, Belgium Received 7 March 1997; revised version received 30 April 1997; accepted 6 May 1997 Abstract We have found a significantly lower frequency of the presenilin-1 (PS-1) intronic polymorphism 2/2 genotype in early-onset Alzheimer’s disease (AD) patients without APOE e4 alleles (2/2 = 0.054; P = 0.009) as compared to age matched non-e4 controls (2/2 = 0.227). Moreover the average age of onset in AD patients with the PS-1 2/2 genotype is older than that in AD patients with a 1/2 genotype or with a 1/1 genotype. This data suggest a protective effect of the 2/2 genotype which would delay the age of onset in AD. Our results do not support an association between the 1/1 genotype and AD. However, a non-significant increase of the 1/1 genotype is found in non-e4 AD patients (P = 0.20).  1997 Elsevier Science Ireland Ltd. Keywords: Presenilin-1; Alzheimer’s disease; Apolipoprotein E; Polymorphism; Genes Four different genes have been described to be involved in Alzheimer’s disease (AD), the amyloid precursor protein (APP) gene in chromosome 21 [7], the apolipoprotein E (APOE) gene on chromosome 19 [1,2,4,18,19,22,25], the presenilin-1 (PS-1) gene on chromosome 14 [17] and the presenilin-2 (PS-2) gene on chromosome 1 [12]. Several mutations have been detected in the PS-1 gene associated with a severe form of this disease (age of onset 65 years) [3,6,9,10,17,24]. The pathogenic mutations of the PS-1 gene are very heterogeneous [6] and are responsible for most cases of early-onset autosomal dominant AD. Recently, it has been described that an intronic poly- morphism in the PS-1 gene could be involved in late- onset AD (LOAD) [27]. In particular, it has been described that the PS-1 1/1 genotype is associated with a doubling of the risk for LOAD as compared with the 1/2 and 2/2 geno- types. A significant association between the PS-1 1/1 geno- type and AD has also been found in some independent studies [8,11], but not in others [15,20,21]. In some studies the PS-1 1/1 polymorphism was increased mainly in non-e4 AD patients [8,11,20]. We initiated the present work to determine if the PS-1 associations could be replicated in an independent popula- tion with a different genetic background. We have included in the study 174 AD patients (mean age at onset 64.26 years) who all met the NINCDS-ADRDA criteria for probable AD, and 147 controls (spouses and/or accompanying persons; mean age 66.4 years). The patients and controls came from four major hospitals in Catalonia (Spain): the Hospital Clı ´nic Provincial (Barcelona), Hospital Santa Caterina (Gir- ona), Hospital Mutua de Terrasa (Province of Barcelona) and Hospital de Mar (Barcelona). The DNA samples were genotyped as previously described for the intronic poly- morphism of the PS-1 gene [27] and for APOE [26]. Most APOE genotypes in our AD and control groups had Neuroscience Letters 227 (1997) 201–204 0304-3940/97/$17.00  1997 Elsevier Science Ireland Ltd. All rights reserved PII S0304-3940(97)00328-5 * Corresponding author. Tel.: +34 3 4021877; fax: +34 3 4035260; e-mail: oliva@medicina.ub.es