Forkhead Box O 3 (FOXO3) genotype is strongly associated with human longevity and may be protective against neurodegeneration. Air pollution is a risk factor for cognitive decline and dementia. We aimed to study the individual and combined effects of FOXO3 and air pollution on cognitive function in a large prospective cohort with up to 14 years of follow-up. We measured cognitive function and impairment using the Mini-Mental State Examination (MMSE). We used tagging SNPs rs2253310, rs2802292, and rs4946936 to identify the FOXO3 gene, of which roughly half of the population had the longevity-associated polymorphism. We matched annual average fine particulate matter (PM2.5) concentrations within a 1 km2 grid. We conducted cross-sectional and longitudinal analyses using multivariable linear and logistic regression models and generalized estimating equations. At baseline, carriers of the longevity-associated homozygous minor alleles of FOXO3 SNPs had a higher MMSE score than the carriers of homozygous major alleles. In the longitudinal follow-up, carriers of FOXO3 homozygous minor alleles had lower odds of cognitive impairment compared with noncarriers. Higher PM2.5 was associated with a lower MMSE score and higher odds of cognitive impairment. The positive effects of FOXO3 were the strongest in females, older people, and residents in areas with lower air pollution.
Keywords: FOXO3; Air pollution; Cognitive function; Gene–environment interaction.
© The Author(s) 2022. Published by Oxford University Press on behalf of The Gerontological Society of America.