Fecal short-chain fatty acids vary by sex and amyloid status

Short-chain fatty acids (SCFAs), produced by gut microbes, influence Alzheimer's disease (AD) pathology in animals. Less is known about SCFAs and AD in humans. We profiled feces of adults along the AD continuum to investigate gut microbiome and SCFA associations with AD pathology and cognition.

We measured SCFAs and bacterial abundances in fecal samples from 287 participants in the Wisconsin Alzheimer's Disease Research Center and Wisconsin Registry for Alzheimer's Prevention. We performed regressions examining associations between SCFAs or gut microbes and AD pathology and cognition.

Fecal propionate, isovalerate, and propionate-producing bacteria are inversely associated with amyloid status. Mediation analysis found that propionate mediates sex-specific associations between SCFAs and cerebrospinal fluid biomarkers. SCFA levels are associated with slower cognitive decline.

These results link SCFAs and propionate-producing bacteria with AD. This may inform efforts to leverage diet and specific bacteria to boost SCFA production and potentially ameliorate AD progression.

Fecal SCFAs link to lower amyloid burden and microglial activation, notably in females. SCFA-producing gut microbes have reduced abundance in amyloid-positive participants. Fecal propionate mediates relationships between gut microbes and amyloid status. SCFAs are associated with slower plasma pTau₂₁₇ accumulation in females. SCFAs are associated with slower cognitive decline.