BACKGROUND: The APOE-gene (ε-2/3/4, combined as six different genotypes: ε-22/23/24/33/34/44) and insulin status modulate dementia risk and play a role in the metabolism of macronutrients.

OBJECTIVE: Our aim was to examine APOE-genotype and fasting insulin as effect-modifiers of the slopes between dietary macronutrients and cognitive performance among older adults at risk for dementia.

METHOD: Panel analyses-with diet and cognition measured at baseline and follow-up at year 1 and 2-were performed in a sub-sample from the FINGER trial (n=676, 60-77 years, 46% females, all non-diabetics). The associations between macronutrients (3-day food records, z-scores) and global cognition (modified Neuropsychological Test Battery, z-score) were analyzed in mixed regression models adjusted for confounders selected a priori. After a gradient was implied by the point estimates in categorical APOE-analyses, we investigated a continuous APOE variable [APOE-gradient, coded -1 (for ε-23), -0.5 (ε-24), 0 (ε-33), 1 (ε-34), 2 (ε-44)] as an effect-modifier.

RESULTS: At increasing levels of the APOE-gradient a relatively more favorable slope between diet and cognition was observed for a lower carbohydrate/fat-ratio (β=-0.040, 95% CI -0.074, -0.006, P=0.020 for interaction diet x APOE-gradient), and higher protein (β=0.075, CI 0.042, 0.109, P=9.4x10^-6). Insulin concentration (log-linear) modulated the association between CFr and cognition by a quadratic interaction (β=-0.016, P=0.039). Coherent findings for exploratory predictors (fiber, fat-subtypes, composite score, metabolic biomarkers) were compatible with published hypotheses of differential dietary adaptation by APOE, with cognition among ε-33 being relatively independent of dietary parameters-implying "metabolic flexibility". Antagonistic slopes to cognition for ε-23 (positive) versus ε-34 and ε-44 (negative) were found for a Higher-carbohydrates-fiber-Lower-fat-protein composite score, even as within-subjects effects.

CONCLUSIONS: APOE-based precision nutrition appears conceptually promising but replications in wider samples are warranted, as well as support from trials. Both relative hyper- and hypo-insulinemia might modulate the effect of diet on cognition.