Polymorphism of the prion protein is associated with cognitive impairment in the elderly

Abstract

Background: Little is known about the role of the prion protein (PrP^sen/gene PRNP). PRNP knockout mice studies suggest that PrP^sen may be involved in CNS degeneration. This observation prompted us to examine the influence of PRNP genetic variability on cognitive abilities in the elderly. Methods: In a community-based sample of 1,163 subjects aged 59 to 71 years, we characterized the valine (Val) and methionine (Met) allele of the PRNP polymorphism at codon 129. The effect of this polymorphism was estimated on the Mini-Mental State Examination (MMSE) and on a global composite score built from a battery of nine different neuropsychological tests. The results were adjusted for age, gender, education, and apolipoprotein E (apoE) polymorphism. Results: Cognitive impairment (MMSE score < 24) was present in 2.5% of the Met-Met individuals, 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 apoEϵ4 allele on cognitive performances. Both apoE ϵ4 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 role of PRNP in the human brain.