no statistically significant differences in the allele and genotype distributions in AD compared with the controls ( p > 0.1), while we found a strong association AD and the APOE e4 allele ( p < 0.0001, data not shown), confirming earlier EOFAD and LOFAD patients were pooled together (FAD group), as no differences found in these categories. The examined samples of 235 AD patients and 192 controls evaluated to have 97.1% power to detect an odds ratio of 2.0 at a 5% significance rate. addition, no correlation was observed between age at onset, sex and any ACE genotype not shown). Stratification of data irrespective of the APOE status did not show an effect of the two genes (Table 1).

4. Discussion

Our data suggest that the ACE genetic variant is not a susceptibility factor to AD, nor does it mitigate the effect of the APOE e4 allele on the risk of developing AD. Several non- mutually exclusive factors can produce conflicting results in association studies of common complex diseases, including the presence of genetic, clinical and population heterogeneity. A possible explanation of the inconsistency between results of different groups may be that the studied ACE I/D polymorphism may have no functional consequences, but may be in linkage disequilibrium with a functional polymorphism linked to the AD risk. Further research is needed to elucidate any role that the ACE polymorphism may play in relation to sporadic and familial AD. With regards to longevity, a recent observation (Kritchevsky et al., 2005) has shown that older adults possessing the ID or DD genotype and who exercised achieved more benefit in preserving mobility function than did those with the II genotype. In our study we confirm this data, since 97 out of 111 (87.4%) of the analyzed centenarians carried the ID or DD genotype and not showing gross functional limitations (i.e., difficulty walking and climbing steps). Centenarians show the highest allele D frequency, although the value is not significant (0.694 versus 0.645 in controls, 0.663 in AD and 0.689 in FAD), thus suggesting that the D allele could belong to a set of epistatic alleles that have pleiotropic age-dependent effects. The comparison between centenarians and controls has a power of 96.61%. However, recent studies on centenarians belonging to different ethnic groups (Choi et al., 2003; Panza et al., 2003) suggested that neither the ACE nor the APOE gene is significantly associated with longevity in the Korean population and in a population from Southern Italy, which do not confirm previous studies (Schachter et al., 1994). In conclusion, our data do not suggest a possible involvement of the D allele in longevity; moreover, they do not support involvement of the ACE gene I/D polymorphism in sporadic and familial AD, nor

Acknowledgements

This study was supported by the Italian Ministry of Instruction, University and Research (grant nos. 2005051707-005 and 2005062887-004) and by the Cassa di Risparmio of Florence (grant no. 2003.1764).

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