Fig. 1: Prospective cohort studies examining the interrelationship of genetics, plasma metabolomics, MedDiet, cognitive function and dementia risk.
a, Prospective follow-up of 4,215 women in the NHS from 1989 to 2023. Genetic and metabolomic profiles were generated from blood samples collected at baseline. Detailed demographic, lifestyle, dietary, medical history and medication use data were collected via questionnaires. Dementia cases were ascertained through the follow-up as a composite endpoint of incident dementia and death due to dementia. In addition, a telephone-based neuropsychological assessment battery was administered longitudinally from 1995 to 2008 to assess cognitive function in a subset of 1,037 participants. A total of 1,490 men from the HPFS were included as a replication cohort (Extended Data Fig. 1a). b, Distribution of plasma metabolites (n = 401). The outer circle represents the variation of each metabolite, with a gradient in gray indicating the coefficient of variation. The inner circle displays the mean relative abundance of each metabolite, shown as a gradient in blue. The innermost circle color codes represent the different HMDB superclasses defined based on chemical structural similarities. c, Overall genetic structure associated with individual metabolites. Each dot represents an individual and is colored by APOE4 genotype, showing no clear pattern between the overall population substructure and APOE4 genotype. The metabolites with the highest Pearson’s correlations with the top two genetic PCs from each metabolite superclass are included on the plot as arrows, colored by their superclass (see legend for b). The arrowhead coordinates represent the correlation coefficients of the metabolites with genetic PC1 and PC2. d, Associations between established genetic risk factors for AD/ADRD and dementia risk. The lines indicate cumulative incidence across APOE4 genotypes and tertiles of the PRS of ADRD (excluding the APOE region) over the follow-up period, with shaded areas representing 95% CIs and P values from the log-rank test annotated. Consistent with the curves, unadjusted hazard ratios (HRs) were estimated using Cox proportional hazards (PH) model; covariate-adjusted HRs with 95% confidence intervals (CIs) are provided in Supplementary Table 4. Person time was accrued from baseline until the earliest occurrence of an incident dementia case, dementia death or the end of follow-up. No adjustment was made for multiple comparisons, because this was a hypothesis-driven analysis. e, A wide range of adherence to the MedDiet, as assessed by a dietary index and intake levels of food and nutrient components of MedDiet. All analyses and distributions were based on data from 4,215 NHS participants. All statistical tests were two sided. MAG, monoacylglycerol; TAG, triacylglycerol. Panel a created using BioRender.com.
