Beyond prion diseases, the M129V polymorphism appears to constitute a part of the genetic background for other neurodegen- erative disorders. The VV genotype has been associated with cog- nitive impairment (MMSE score < 24) and the V allele has been

*Correspondence to: Ewa Golanska; Email: ewa.golanska@umed.lodz.pl Submitted: 11/20/12; Revised: 01/22/13; Accepted: 02/05/13 http://dx.doi.org/10.4161/pri.23903

Table 1. Comparison of PRNP codon 129 polymorphism between analyzed groups

We found that the genotypic frequencies in the control group of younger Poles were expectedly consistent with Hardy-Weinberg equilibrium: MM, 43%; MV, 44%; VV, 13% (HWE p > 0.05). These frequencies are in the range of other reported results. The distribution of the codon 129 genotypes found in different European populations was shown to vary between 35–52% for MM, 39–56% for MV and 9–17% for VV genotypes, placing Poland in the middle of these ranges.7,21-24

Centenarians vs. young controls Centenarians n = 150 Controls n = 165 p Genotype 0.472 MM 69 (46.0) 71 (43.0) MV 56 (37.3) 72 (43.7) VV 25 (16.7) 22 (13.3) allele 0.962 M 194 (64.7) 214 (64.8) V 106 (35.3) 116 (35.2)

Unlike the control subjects, in our centenarian both homozygous genotypes were found more frequently expected (MM, MV and VV): 46, 37 and 17% (expected 46 and 13%), i.e., HWE was rejected (p = 0.025). This is tent with selectively better survival among persons who carry homozygous genotypes to the age of 100 years.

Centenarians with vs. without severe cognitive impairment (s.c.i.)

Centenarians Centenarians with s.c.i. without s.c.i. p n = 82 n = 33 Genotype 0.318 MM 38 (46.3) 15 (45.5) MV 35 (42.7) 11 (33.3) VV 9 (11.0) 7 (21.2) allele 0.420 M 111 (67.7) 41 (62.1) V 53 (32.3) 25 (37.9)

Using the more general hypothesis of unspecified association, directly comparing genotypic 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 recom- mended 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 dif- fered for the two groups. However, it is noteworthy that hetero- zygotes 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.

impairment. The discrepancies may depend on the selection criteria applied for the analyzed groups. This study considered severe cognitive impairment regardless of its origin. These find- ings 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 ε4 allele is most relevant at relatively younger ages.26

Our results suggest selective survival related to the combina- tion 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 find- ing, of course, needs to be verified in other samples. However, it is remarkable that any single common polymorphism demon- strates an effect on longevity. As single factors, APOE ε2 and the absence of APOE ε4 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 if 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 remains 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 the life-span.

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



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