Genetic influences on oxidative stress and their association with normal cognitive ageing.

Oxidative stress is hypothesised to play a major role in ageing processes. Reactive oxygen species produced during normal aerobic metabolism damage cellular macromolecules. The brain is particularly susceptible to oxidative stress due to its high rate of aerobic metabolism. We hypothesised that polymorphisms in genes contributing to antioxidant defences are associated with variation in normal cognitive ageing in the absence of dementia. We examined associations between two SNPs (rs2073495 and rs743658) in Lactotransferrin (LTF), a gene involved in iron absorption, and the common M129V SNP in the prion protein gene, PRNP (rs1799990), with cognitive ability and cognitive ageing in a cohort of non-demented individuals born in 1921. All had cognitive ability measured at age 11 in the Scottish Mental Survey of 1932, and again at age 79. No association was identified with LTF. PRNP M129V was significantly related to Moray House Test (MHT) IQ scores at age 79, adjusted for sex and age 11 IQ (p=0.006). Individuals homozygous for the methionine allele performed significantly better than heterozygotes. This study supports the hypothesis that genetic variations in antioxidant defence genes, specifically PRNP, are important influences on the trajectory of normal cognitive ageing. An interaction between PRNP and klotho (KL) genotypes was also identified (p=0.015), highlighting the importance of analysing gene interactions when investigating associations with quantitative traits.