Objective:Early studies suggested that angiotensin I converting enzyme (peptidyl-dipeptidase A) 1 (ACE) gene polymorphism has been associated with an increased risk for coronary artery disease and, more recently, with sporadic late-onset Alzheimer’s disease (AD). Studies conducted in northern European populations have considered ACE*I allele to be a risk factor for various types of cognitive decline, while other studies in southern European populations found either a slight but significantly increased frequency of ACE*I in AD patients or did not detect any effect of ACE polymorphism.We investigated whether there was evidence in southern Italy of an association between the ACE polymorphism and increased risk of AD. Secondly, we compared our results with the findings from published studies on other European populations. Design:Case-control study. We consecutively examined in our centre 141 patients with AD (age at onset, 71 years), and 268 unrelated caregivers, spouses, friends, neighbors, or volunteers (age at collection, 72 years). Materials and Methods:APOE genotypes were determined as detailed elsewhere (Neurosci Lett 1999;277: 53-56). ACE genotypes were produced using established methods followed by a quality control amplification step necessary in detecting under-amplified ACE*I alleles. The statistical analysis was performed by Pearson c2 test (Hardy-Weinberg equilibrium), and Mann-Whitney test. The Cochran-Armitage trend test was carried out to evaluate the geographical trend among ACE allele and genotype frequencies in AD patients and controls of three European countries (Italy, Spain, and United Kingdom), from published studies. The data were analyzed by SAS FREQ procedure (version 8.2). Results:No statistically significant differences were found in ACE genotype frequencies between AD patients and controls. AD patients with ACE*I/*I genotype were on average 3.6 years younger at onset than those with ACE*D/*D genotype, without statistical significance. The ACE*I allele frequency in AD patients and controls showed a statistically significant decreasing trend from Northern to Southern regions of Europe, while there was a concomitant increase in ACE*D allele frequency. Conclusion:The present study does not support previous findings that increased AD risk is associated with ACE*I genotype and allele frequencies. The age at onset of AD patients with the ACE*I/*I genotype appeared to be lower than those with the ACE*D/*D genotype. Though this was not statistically significant, it suggests that the presence of an ACE*I allele might bring forward the onset of the disease without being linked to an increased overall risk of it occurring. It is becoming apparent that the possible association between the ACE polymorphism and increased AD risk is complex. A possible explanation may be the direct result of geographical genetic variation which we have hypothesized. Indeed, as with our previous findings with APOE, we report here that the putative associations between ACE gene variants and increased risk of AD may be influenced by geographical genetic variations.
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