APOE-Genotype and Insulin Modulate Estimated Effect of Dietary Macronutrients on Cognitive Performance: Panel Analyses in Nondiabetic Older Adults at Risk of Dementia

Abstract

Background: The apolipoprotein E (gene) (APOE gene; ε-2/3/4, combined as 6 different genotypes: ε-22/23/24/33/34/44) and insulin status modulate dementia risk and play a role in the metabolism of macronutrients.

Objectives: We aimed to examine APOE-genotype and fasting insulin as effect modifiers of the slopes between dietary macronutrients and cognitive performance among older adults at risk of dementia.

Methods: Panel analyses-with diet and cognition measured at baseline and follow-up at years 1 and 2-were performed in a sub-sample from the FINGER (Finnish Geriatric Intervention Study to Prevent Cognitive Impairment and Disability) trial (n = 676, 60-77 y, 46% females, all nondiabetics). The associations between macronutrients (3-d 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 concentrations 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% confidence interval (CI): -0.074, -0.006; P = 0.020 for interaction diet × APOE-gradient), and higher protein (β = 0.075, 95% CI: 0.042, 0.109; P = 9.4 × 10-6). Insulin concentration (log-linear) modulated the association between log-ratio carbohydrates/fat 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) compared with 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 hypoinsulinemia might modulate the effect of diet on cognition.

Keywords: Alzheimer’s disease; apolipoprotein E; gene-nutrient interaction; insulin resistance; target trial.

Conflict of interest statement

Conflict of interest MK reports the following relations: Advisory board membership for BioArctic, Biogen, Combinostics, and Nestlé. Speaking and lecture fees for Biogen, Nestlé, Nutricia, and Roche. All other authors report no conflicts of interest.

Copyright © 2023 The Author(s). Published by Elsevier Inc. All rights reserved.