LONGEVITY KLOTHO GENE POLYMORPHISM AND THE RISK OF DEMENTIA IN OLDER MEN

In mice the Klotho gene encodes a membrane protein that seems to suppress certain physiological aspects associated with the ageing phenotype including reduced lifespan and atherosclerosis. In humans Klotho variants (KL-VS) have been associated with increased longevity and better cognitive function. It is unclear whether they modulate dementia risk. Using an existing cohort of older men, we recruited 527 individuals aged 71–87 years who were free of cognitive impairment. We used data linkage to track the onset of dementia over 10 years. KL-VS genotyping (rs9527025 T/G) followed standard procedures. In these men, 370 (70.2%), 145 (27.5%) and 12 (2.3%) had the TT, TG and GG genotypes of KL-VS polymorphism. The Hardy-Weinberg test showed that this allelic distribution was in equilibrium. Overall the age adjusted annual rate of dementia was 17.2‰ (95%CI=14.0–21.1; total = 5053 person-years). The rates were 14.0‰ (95%CI=10.6–18.4; 3582 person-years), 23.5‰ (95%CI=16.6–33.2; 1363 person-years) and 46.4‰ (95%CI=19.3–111.5; 108 person-years) for men with the TT, TG and GG genotypes. Compared with the TT genotype, the sub-hazard ratios of dementia associated with the TG and GG genotypes were 1.6 (95%CI=1.0, 2.5; p=0.030) and 3.5 (95%CI=1.3, 9.1; p=0.011). The Klotho KL-VS variant is associated with an increase in the incidence of dementia in older men in a dose-dependent fashion (intermediate for heterozygosis and highest for homozygosis). If these findings can be replicated then the risk of dementia may be able to be modulated by exploiting this metabolic pathway.