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Archives of Gerontology and Geriatrics 45 (2007) 201–206

converting enzyme polymorphism in sporadic and familial Alzheimer’s disease and longevity

Benedetta Nacmias , Silvia Bagnoli , Andrea Tedde , a a b Elena Cellini , Valentina Bessi , Biancamaria Guarnieri , b a a Luigi Ortensi , Silvia Piacentini , Laura Bracco , Sandro Sorbi

aDepartment of Neurological and Psychiatric Sciences, University of Florence, Florence and Centro di Ricerca, Trasferimento e Alta Formazione DENOTHE,

Received 26 May 2006; received in revised form 16 October 2006; accepted 20 October 2006 Available online 19 December 2006

Abstract

A recent, large meta-analysis has reproposed the role of the angiotensin converting enzyme (ACE) insertion/deletion (I/D) polymorphism as a risk factor for Alzheimer’s disease (AD). To further investigate the proposed association and to better clarify the role of ACE as a risk factor for AD, we analyzed the genotype and allele frequency distribution of ACE I/D and apolipoprotein E (APOE) genepolymorphismsin235ItalianpatientswithsporadicAD,153withfamilialAD(FAD),192healthy controls and 111 centenarians. Patients with AD were consecutively gathered from among the outpatients from the Neurology Department at the University of Florence. All 691 subjects were genotypedforACEandAPOEpolymorphisms.TherewerenosignificantdifferencesinACEgenotypes or allele frequencies in all the studied groups, even after stratification for APOE e4 carrier status. CentenariansshowthehighestalleleDfrequency,althoughthevalueisnotsignificant,thussuggestinga possible implication of the D allele as an epistatic allele that has pleiotropic age-dependent effects. In conclusion, our data suggest that the ACE allelic variant is not a susceptibility factor in sporadic and familial AD (FAD), nor does it mitigate the effect of the APOE e4 allele in the risk of developing AD. Moreover, our data do not suggest a possible involvement of the D allele in longevity. # 2006 Elsevier Ireland Ltd. All rights reserved.

Keywords: Alzheimer’s disease; ACE; Apolipoprotein E; Gene-polymorphism; Longevity and ACE

1. Introduction

AD is an insidious and progressive neurodegenerative disorder that accounts for the vast majority of age-related dementia. Rare, fully penetrant autosomal dominant mutations in three genes (i.e., amyloid precursor protein = APP; presenilin 1 = PS1 and presenilin 2 = PS2) have been shown to cause 50% of the familial form of the disease, while a common, incompletely penetrant susceptibility variant, the APOE e4 allele, significantly increases the risk of developing sporadic AD (Strittmatter and Roses, 1995). The search for other genetic factors have shown polymorphisms in an increasing number of genes, all possibly involved in the AD pathogenesis interfering with b- amyloid deposition (Tanzi and Bertram, 2005). ACE (17q23) is a dipeptidyl carboxypeptidase that plays an important role in blood pressure regulation and electrolyte balance by hydrolyzing angiotensin I into angiotensin II, a potent vasopressor. ACE is one of the several risk factors for AD shared with vascular dementia (VaD) (Kolsch et al., 2005). According to recent studies, ACE may modulate the susceptibility to and progression of AD via degradation of amyloid b-protein (Ab) whose progressive accumulation and deposition is an early and pathogenically important feature of Alzheimer disease (Hemming and Selkoe, 2005). Despite biological support of ACE playing a role in AD, studies assessing the ACE insertion/ deletion (I/D) polymorphism in AD are conflicting (Lehmann et al., 2005). A 287-bp Alu I/D polymorphism in intron 16 of the ACE gene has been associated with athletic performance, aging and disease, and recently with physical decline, with contrasting results (Kritchevsky et al., 2005).

A collaborative study from 1999 provides evidence of a possible association between ACE gene I alleles and an increased risk of AD, independent of APOE status et al., 1999). Since then there have been a considerable number of papers and published on attempts to replicate these findings and there certainly has been a of results, some of which support, some of which found evidence indicating the allele and some of which that found no evidence one way or the other. A meta- provided evidence that the I allele of the ACE I/D polymorphism is associated an increased risk of late-onset AD (Elkins et al., 2004). Another more recent, large has reproposed the role of the ACE I/D polymorphism as a risk factor for (Lehmann et al., 2005) confirming the association of the ACE I/D polymorphism as a for AD. Moreover, further association studies were published showing a increase in the risk of AD in patients who were either homozygous for the ACE allele, as seen in a sample of subjects of German origin (Kolsch et al., 2005) and in of Dutch origin, independent of vascular factors (Sleegers et al., 2005), or who homozygous for the ACE D allele, as seen in a sample of subjects of Chinese origin

In light of these contrasting findings, we investigated the segregation of ACE I/D polymorphism and APOE gene polymorphisms in a case-control study in Italian patients with sporadic and FAD in order to analyze a possible implication for ACE as a risk factor and whether or not such effects are dependent on the APOE e4 allele. Moreover, we analyzed the I/D genotype distribution in a sample of 111 Italian centenarians in order to study a possible implication for ACE in longevity.

2. Methods