Lifestyle for Brain Health Score, Genetic Risk and Incidence of Dementia

Abstract

AbstractBackgroundAssessing whether modifiable factors are associated with dementia risk regardless of genetic risk for the disease is primordial for precision prevention. So far, studies on gene‐by‐environment interactions (GxE) in dementia have been controversial. We leveraged a large cohort of older persons to investigate the association between numerous modifiable factors, reflected by the lifestyle for brain‐health (LIBRA) score (defined in figure 1), and the incidence of dementia, evaluating effect modification by genetic risk.MethodWe included participants from the Three‐City (3C) study, free of dementia at baseline and followed for up to 17 years. The LIBRA score and a genetic risk score (GRS) based on the latest Alzheimer’s disease GWAS (excluding the apolipoprotein E {APOE} locus) were constructed. Illness‐death models for interval‐censored data were used to assess the relation of LIBRA, GRS and carriership of the e4 allele of the APOE gene (and their interactions) to the incidence of dementia, accounting for potential competing risk by death.ResultThe population included 5170 3C participants aged on average 73.8 years at baseline. Both genetic factors and LIBRA were significantly associated with dementia risk. In multivariable‐adjusted models, each one‐point increase in LIBRA was associated with a 10% higher risk of dementia (95% CI 1.07‐1.13). We found no evidence of GxE interaction (p≥0.2 for two‐order [LIBRA by each genetic variable] and three‐order interaction terms [LIBRA‐by‐GRS‐by‐APOE4]); a higher LIBRA was significantly associated with increased dementia risk in both APOE4 carriers and non‐carriers (figure 1) and in low, medium or high GRS level (figure 2), with similar magnitude of associations in all strata. Although power was limited to examine APOE4 carriers by GRS strata, the trend of association of LIBRA (continuous) to dementia risk was not meaningfully different from what found in other groups (figure 3).ConclusionIn this large cohort of older persons, increasing number of health and lifestyle risk factors for dementia was associated with higher dementia risk in all levels of genetic risk. These findings suggest prevention programs with targeted lifestyle modifications and health management may be efficient even in those with highest risk for dementia based on their genetic susceptibility.