POLYMORPHISM OF THE PRION PROTEIN IS ASSOCIATED WITH COGNITIVE IMPAIRMENT IN THE ELDERLY - THE EVA STUDY

Background: Little is known about the role of the prion protein (PrPse n/gene PRNP). PRNP knockout mice studies suggest that PrPsen may be in volved in CNS degeneration. This observation prompted us to examine th e influence of PRNP genetic variability on cognitive abilities in the elderly. Methods: In a community-based sample of 1,163 subjects aged 5 9 to 71 years, we characterized the valine (Val) and methionine (Met) allele of the PRNP polymorphism at codon 129. The effect of this polym orphism was estimated on the Mini-Mental State Examination (MMSE) and on a global composite score built from a battery of nine different neu ropsychological tests. The results were adjusted for age, gender, educ ation, and apolipoprotein E (apoE) polymorphism. Results: Cognitive im pairment (MMSE score < 24) was present in 2.5% of the Met-Met individu als, 2.9% of the Met-Val individuals, and 7.0% of Val-Val subjects (p = 0.02). Subjects homozygous for the PRNP Val allele had a lower MMSE and global score than the two other genotypes (p < 0.003). This effect was of the same magnitude as that of the apoE epsilon 4 allele on cog nitive performances. Both apoE epsilon 4 and PRNP Val allelic effects were additive. Conclusion: This observation suggests that variability of the PRNP locus may be associated with cognitive performance in the elderly. This result, if confirmed, offers potential clues for the rol e of PRNP in the human brain.