Fig. 3: MedDiet adherence is associated with cognitive health and plasma metabolites in an APOE4-dependent manner.
a, Higher adherence to the MedDiet prospectively associated with a lower risk of dementia and enhanced cognitive performance, as assessed by the telephone-based neuropsychological assessment battery (TICS). For dementia risk analysis, a restricted cubic spline Cox PH model estimated HRs and 95% CIs across varying levels of the MedDiet index, using 0 as the reference. The P value from a likelihood ratio test comparing the model without the MedDiet index and the model with its spline term is annotated. For the TICS score analysis, a generalized linear model estimated the adjusted TICS score and corresponding 95% CI across MedDiet index levels, with P values annotated. The analyses were conducted among NHS participants with cognitive and dietary data (n = 86,740 for dementia analysis and n = 16,244 for cognitive function analysis). b, The protective association between adherence to the MedDiet and risk of dementia most pronounced among APOE4 homozygotes. Stratified HR and 95% CIs for dementia risk per a 1-unit increment in the MedDiet index score, categorized by the APOE4 genotype, were estimated from Cox PH models, with stratified P values annotated (unadjusted for multiple comparisons in the hypothesis-driven analysis). The analyses were conducted among NHS participants with genetic, dietary and dementia outcome data (n = 16,497). c, Strong association between adherence to MedDiet and the overall plasma metabolome from an RF model to classify individuals in the top versus the bottom quartile of the MedDiet index based on plasma metabolites. For the RF classification, the dataset was randomly divided into training (60%) and test (40%) sets. The ROC curve for the test set is shown, with the AUC and 95% CI annotated on the plot. The analyses were conducted among 4,215 NHS participants. d, Associations between MedDiet adherence and plasma metabolite levels differing by APOE4 genotype. The heatmap shows β coefficients representing a 1-s.d. increment in the MedDiet index from a generalized linear model, with plasma metabolite levels as the dependent variable. The analyses were conducted among 4,215 NHS participants. e, Select associations between the MedDiet index and plasma metabolite levels with P < 0.05 from the likelihood ratio test for the interaction between APOE4 genotype and MedDiet index in relation to metabolites, using a generalized linear model stratified by APOE4 genotype. Covariate-adjusted residuals of metabolites are shown along with fitted linear regression lines, 95% CIs and P values for interaction. These results were not adjusted for multiple testing. The analyses were conducted across 4,215 NHS participants. All statistical tests were two sided.
