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

• Published in: The Journal of nutrition Vol. 153; no. 12; pp. 3506 - 3520
• Main Authors: Norgren, Jakob, Sindi, Shireen, Matton, Anna, Kivipelto, Miia, Kåreholt, Ingemar
• Format: Journal Article
• Language: English
• Published: United States American Institute of Nutrition 01.12.2023
• Subjects: Adults; Alzheimer's disease; Apolipoprotein E; Biomarkers; Carbohydrates; Cognition; Cognitive ability; Confidence intervals; Continuity (mathematics); Dementia; Dementia disorders; Diet; E protein; gene-nutrient interaction; Genotypes; Insulin; insulin resistance; lifestyle medicine; Medicin och hälsovetenskap; Metabolism; Nutrition; Older people; Proteins; Regression analysis; Regression models; Risk; Risk factors; Statistical analysis; apolipoprotein E; gene-nutrient interaction; Alzheimer’s disease; lifestyle medicine; insulin resistance
• ISSN: 0022-3166; 1541-6100; 1541-6100
• DOI: 10.1016/j.tjnut.2023.09.016

The apolipoprotein E gene (APOE 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. 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. 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. 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% 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 ). Insulin concentration (log-linear) modulated the association between the carbohydrate/fat ratio 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. 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.