In conclusion, our study provides novel insights into the distribution of the M129V polymorphism among Polish centenarians. Our findings suggest that homozygosity for either the M or V allele may confer a survival advantage to the age of 100 years. However, further studies are needed to confirm these results and to investigate the potential role of this polymorphism in other age-related diseases.Frequencies for the two groups of subjects did not provide evidence that centenarians differed from younger Poles in terms of codon 129 polymorphism (Table 1). No trends were demonstrated for the number of M as opposed to V alleles (0, 1, 2) comparing the two groups (Cochran-Armitage test for trend, p = 0.999). This test has been recommended as useful in samples not consistent with HWE.25 We then considered whether codon 129 polymorphism formed part of the genetic background of severe cognitive impairment among centenarians (Table 1). At this sample size (82 subjects with and 33 without severe cognitive impairment), there was no statistically significant evidence that genotypic frequencies differed for the two groups. However, it is noteworthy that heterozygotes tended to be more common among the severely impaired (43% vs. 33%). No statistically significant trends in the number of M and V alleles were identified (data not shown). Figures in parentheses are percentages. The discrepancies may depend on the selection criteria applied for the analyzed groups. This study considered severe cognitive impairment regardless of its origin. These findings indicate that prevalence-incidence bias may operate for codon 129 variation and account for differing implications of reported studies. Given the findings of this study, larger studies might demonstrate that codon 129 variation continues to be a determinant of neurodegeneration and cognitive impairment at very advanced ages. This is in contrast to the situation for APOE where the 4 allele is most relevant at relatively younger ages.26 Our results suggest selective survival related to the combination of PRNP codon 129 alleles that have been inherited: the observed deviation from HWE in the centenarian group may result from a higher mortality rate among heterozygotes. The centenarians were not related, so inbreeding as a potential source of the observed deviation from HWE can be excluded. Our finding, of course, needs to be verified in other samples. However, it is remarkable that any single common polymorphism demonstrates an effect on longevity. As single factors, APOE 2 and the absence of APOE 4 have previously been shown to influence average longevity, explaining perhaps 1% of lifespan.26,27 It was proposed that the oldest individuals may be divided into three groups: the escapers who reached the age of 100 free from typical age-related diseases, the survivors who live long despite suffering from age-associated diseases and the delayers, affected by age-related diseases with an unusually late age of onset.30 The centenarians with cognitive impairment may belong to the two latter groups. Irrespective of whether they represent the delayers or the survivors, their molecular background of cognitive impairment may be different than in populations analyzed in average AD studies, i.e., usually 20-30 years younger than centenarians. A healthy survival past the age of 100 years may be influenced by a pattern of genetic as well as environmental factors which still remain to be unraveled. Frequencies do not differ significantly between the oldest-old and the young controls (general association). This suggests that the influence of M129V polymorphism on susceptibility for a spectrum of disorders is too weak or the diseases are too rare as it is in the case of prion diseases to result in elimination of particular genotype carriers from long-living individuals. Further studies in large groups are necessary to finally elucidate the influence of the PRNP polymorphism on lifespan. Concerning neurodegeneration, the relevance of M versus V allele needs to be considered more carefully in terms of age, age at onset, duration of disease and method of case acquisition. The results published thus far have been divergent, pointing at VV6,28,29 as well as MM genotype8 as a risk factor for cognitive impairment. We investigated 150 centenarians (130 women and 20 men) aged 100-107, mean age 101.1 ± 1.1 years, who participated in the multicenter scientific project Genetic and Environmental Factors of Longevity of Polish Centenarians (PolStu), coordinated by the International Institute of Molecular and Cellular Biology in Warsaw. The individuals were not related. The recruitment of the participants and their general clinical evaluation are described by Mossakowska et al.31 Refusal to participate in testing or the participant being otherwise uncooperative were reasons for exclusion. As controls, we tested DNA samples from 165 blood donors aged 18-56, mean age 27.8 ± 9.1 years; 91 women and 74 men, obtained from the Department of Paediatrics, Oncology, Haematology and Diabetology, Medical University of Lodz. These subjects are assumed to represent the same source population as the centenarians, but with little selection for mortality. In the present study, we used data on cognitive performance extracted from the existing databaseThe protein gene M allele is a risk factor for Alzheimer's disease. J Neural Transm;  :   -   ; PMID:   ; http://dx.doi.org/./s---. Riemenschneider M, Klopp N, Xiang W, Wagenpfeil S, Vollmert C, Müller U, et al. Prion protein codon 129 polymorphism and risk of Alzheimer's disease. Neurology;  :   -   ; PMID:   ; http://dx.doi.org/./WNL. Labate A, Manna I, Gambardella A, Le Piane E, La Russa A, Condino F, et al. Association between the MV variant allele of PRNP gene and mild temporal lobe epilepsy in women. Neurosci Lett;  :   -   ; PMID:   ; http://dx.doi.org/./j.neu-let. Li X, Rowland LP, Mitsumoto H, Przedborski S, Bird TD, Schellenberg GD, et al. Prion