Insulin degrading enzyme and alpha-3 catenin polymorphisms in Italian patients with Alzheimer disease.

To the Editor: Among the several attractive candidate genes for late-onset Alzheimer disease (LOAD), located on chromosome 10q, recent observations provided evidence of an association for insulin degrading enzyme (IDE) and alpha-3 catenin (CTNNA3) genes. Insulin degrading enzyme protein degrade both extracellular b-amyloid constituent of amyloid plaques and the intracellular domain of the amyloid precursor protein, whereas the CTNNA3 gene encodes a novel a catenin, which interacts closely with the b cateninPresenilin1 complex. Because IDE and CTNNA3 are considered positionally and functionally promising candidate genes for AD, and both regulate Ab production through different mechanisms, we can hypothesize that their genetic variants could have a synergic effect on the disease dependently or independently of Apolipoprotein E (ApoE) e4 status. Several but different single nucleotide polymorphisms (SNPs) and haplotypes in these genes have been reported related to AD with inconsistent results. To investigate the role of IDE and CTNNA3 as AD-modifying genes, we performed a case-control study on four SNPs (IDE1: rs3758505, IDE8: rs4646958; CTNNA3 rs7070570 or 4360; and rs12357560 or 4783) previously singularly associated, in the Caucasian population, with the disease in relation to quantitative traits (plasma Ab levels) and ApoE genotype. We analyzed a sample of 302 Italian patients with sporadic AD (210 LOAD, mean age at onset 72.3 6 4.9; 92 early-onset AD, EOAD, mean age at onset 58.3 6 5.5) collected at the Department of Neurology of the University of Florence and 164 sexand age-matched healthy controls. Clinical AD diagnoses fulfilled published guidelines. The local ethical committee approved the study protocol and an informed written consent was obtained from all subjects or, when appropriate, their caregivers. The distributions of each SNP analyzed followed the Hardy-Weinberg equilibrium in all groups. The genotype frequencies (Table 1) were similar in the two AD subgroups and they did not differ comparing LOAD with EOAD or with respect to controls, except for a statistically significant difference (P = 0.04) observed in CTNNA3-rs12357560 for the GG genotype. A significant overexpression of the ApoE e4 allele in the LOAD group was confirmed (data not shown). The examination of the SNPs in the current sample failed to detect any influence upon sex, age at onset, and ApoE e4 allele status (Table 2). Statistical analysis was performed using SPSS software (SPSS, Inc., Evanston, IL). Genotype and allele frequencies were analyzed using the x test. To test the effects of ApoE e4 allele status and the 4 SNPs genotypes alone or in combination, logistic regression analysis was used. Comparisons of the age at onset between the genotype groups were made using the ANOVA test. Haplotype distributions of the two markers for each gene, estimated using the PHASE version 2.0 software, were not statistically different between the AD and control groups. Our data suggest that IDE and CTNNA3 do not represent strong independent susceptibility factors for sporadic AD, confirming that they do not contribute directly to the disease, as previously reported. The slight association we detected between rs12357560 and AD was found to not correlate to the ApoE e4 allele; therefore, IDE and CTNNA3 genes do not show a synergic interaction with ApoE for the disease. However, we could not exclude that they may affect other primary traits of AD pathology and severity, as reported for plasma Ab levels. The discordance of our results with respect to previous data may be explained in terms of heterogeneity among different populations, or due to the interactions between genetic components and other environmental factors. Other possible candidate genes, spanning the genomic region responsible for the linkage on chromosome 10, should be evaluated as potential risk factors for AD.