Abstract
<p>INTRODUCTIONLittle is understood about the extent to which lifestyle factors can advance or delay the risk of developing dementia, and whether that is dependent on non-modifiable factors, e.g. sex and genetic susceptibility.METHODSAmong 224,516 UK Biobank participants aged ≥50 years at baseline, Cox regression examined the relations of apolipoprotein E gene (APOE) genotypes, and lifestyle with incident dementia. Rate advancement periods were used to quantify the association between these factors and advancing or delaying incidence rate relative to age.RESULTSOver median follow-up of 13.6 years, versus neutral APOE ε3ε3, ε4 presence advanced dementia risk by 5.58 years whereas ε2 presence delayed by 1.08 year (q&lt;0.001). Overall unfavourable lifestyle advanced dementia risk by 1.90 years - specifically, smoking, heavy drinking, and prolonged sedentariness, by 0.64 to 1.52 years (q&lt;0.001). Interactions showed that overall unfavourable lifestyle advanced more dementia risk more among ε2 carriers than ε4 carriers, and ε4 presence advanced more in females than males.DISCUSSIONOverall unfavourable lifestyle and APOE ε4 genotype advanced dementia risk independently by almost 2 and 6 years respectively, with significant gene-lifestyle and gene-sex interactions. Lifestyle’s benefit on cognitive preservation is to some extent sex and genotype-specific, which targeted intervention does not currently consider.</p>