APOE4 genotype shapes the role of dietary fibers in cognitive health through gut microbiota changes.

APOE4, a key risk factor for Alzheimer's disease, influences gut microbiota and microbial metabolites (e.g. amino acids and dietary fiber (DF) derived short-chain fatty acids (SCFAs)). However, its role in modulating microbiota-driven DF metabolism and its effect on cognitive status remains unclear. This cross-sectional study (n = 170) investigates the association between APOE4 genotype, DF consumption, and metabolism in individuals with subjective cognitive impairment (SCI) and mild cognitive impairment (MCI) compared to healthy controls (HC). Liquid Chromatography Tandem Mass Spectrometry (LC-MS/MS) and 1H NMR metabolomic techniques were used to quantify SCFAs in serum and fecal samples, respectively. Gut microbiota speciation was carried out by 16S rRNA amplicon sequencing. We found that DF intake was significantly associated with APOE4 genotype and cognitive status, with lower consumption in APOE4 carriers (p < 0.05) and those with cognitive impairment (SCI and MCI) (p = 0.03). Differences (p < 0.05) in gut microbiota (both α- and β-diversity) and SCFAs were evident between APOE4 and non-APOE4 carriers, with stronger associations with DF consumption and cognitive status evident in non-APOE4 carriers. These findings suggest that targeting DF-induced changes in gut microbiota and serum SCFAs may be an effective strategy for mitigating cognitive impairment, but primarily in non-APOE4 carriers.