Interestingly, after stratification of the sample accord- − − ing to gender, we observed that 2578AA and 1190AA − genotypes, as well as 1190A allele show a significant over-representation only among long-lived women. The low number of long-lived men enrolled (n = 45), together with the wide differences in sex ratios between young/elderly and long-lived groups (0.92 versus 0.37 ratio men/women, respectively) might explain these discrepancies; accordingly, Fernandez-Santiago et al. (2006) observed a possible gender- dependent association of VEGF gene variability and ALS; the some authors concluded that the probability to detected an association between VEGF and neurodegenerative disease risk may be greater in populations with higher female/male ratios.

VEGF gene is highly polymorphic, with at least 25 dif- ferent polymorphisms, which are organised into haplotypes, with several common different haplotypes identified in the promoter region alone (Rogers and D’Amato, 2006). Pro- moter variations in the VEGF gene are of particular interest. The association of various diseases with VEGF variability has been reported in over 40 different studies with some- what contradictory results (Del Bo et al., 2006b). The marked variability in the genetic background represents an impor-

Disclosure statement

Recently, the interaction among three VEGF variants − (including 1154G/A polymorphism) has been associated to vascular dementia in Koreans (Kim et al., 2006). It is − − plausible that ( 2578AA) and ( 1190AA) make to live longer and consequently the risk of dementia is increased. − We observed that 2578AA variant, as well as other VEGF genotypes, were differently distributed in long-lived subjects ≤ with a MMSE score 26 compared to long-lived subjects having a MMSE score > 26, even if the differences failed to − reachsignificantresults;onthecontrary,twoalleles( 1190A − and 1154A) show a statistically significant distribution within the two subgroups of long-lived subjects. Neverthe- less, a form of selection pressure might be hypothesized, as suggested by the different distribution of HWE frequen- cies observed among young/elderly subjects and long-lived subjects.

There are no actual or potential conflicts of interest.

Acknowledgements

The financial support of the Italian Ministry of Health to GPC (Research Grant “Malattie Neurodegenerative” “ex Art 56, Legge Finanziaria 2004” entitled “Malattie del motoneu- rone: genomica e proteomica per la definizione di marcatori biologici in cellule e fluidi umani con translazione in modelli murini”) is gratefully acknowledged. This work was sup- ported by grants from Associazione “Amici del Centro Dino Ferrari”, Fondazione Italo Monzino and Ing. Cesare Cusan.

Dementia, for itself, does not drastically curtail an indi- vidual’s life expectancy; the association between cognitive decline and VEGF variability represents so far an impor- tant item of investigation. Recently, it has been reported − that ( 2578AA) genotype was over-represented among patients with mild cognitive impairment (MCI) compared with a control population (Chiappelli et al., 2006). Further- −  more, ( 2578A) allele was higher in APOE 4-positive MCI patients who developed AD than in those who did not. All these findings support the role of VEGF in the deterioration rate of cognitive performances in both preclinical and clinical AD. Due to the low number of long-lived subjects carrying BE4 at least one APOE 4 allele (n = 14), in the present study, we are unable to analyse the interaction between VEGF and APOE genotypes. Longitudinal studies will be required to verify how many subjects included in the present study, will develop cognitive deficits, as well as, MCI or AD. In addition, VEGF variability in subjects with moderate/severe dementia ≤ (having a MMSE score 22) should be investigated.

Appendix A. Supplementary data

Supplementary data associated with this article can be found, in the online version, at doi:10.1016/j. neurobiolaging.2007.05.003.

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