Alzheimer’s disease (AD) is marked by the buildup of amyloid plaques, the spread of abnormal tau protein and the progressive loss of brain cells. Of these changes, tau accumulation and neuronal death are most closely tied to memory decline and dementia symptoms. While recent therapies that target amyloid slow progression, they do not stop the disease, underscoring the urgent need for new strategies. One promising avenue looks beyond the brain itself to the gut microbiome, the diverse community of bacteria and other microbes in the digestive tract. People with AD and those at risk often have changes in their gut microbiome, and animal studies show that altering gut bacteria can reduce both amyloid and tau pathology. This raises the possibility that diet, which strongly influences the microbiome, could affect Alzheimer’s progression. A particular focus is on soluble dietary fiber (SDF), found in foods like oats, beans and fruits. Humans cannot digest this fiber, but gut bacteria ferment it into small molecules, including short-chain fatty acids (SCFAs). SCFAs regulate immune activity and inflammation, which in turn may affect brain health and disease. While high-fiber diets are often considered universally beneficial, recent evidence suggests the picture may be more complex.
Dr. Seo and colleagues have provided compelling preliminary evidence for this complexity. In tau mice (P301S) expressing human APOE variants, they found that SCFAs can worsen tau-related brain damage, suggesting that excessive fermentable fiber might accelerate neurodegeneration rather than prevent it. These effects were strongly influenced by genetics: mice carrying APOE4, the major genetic risk factor for AD, were especially vulnerable. Further experiments with SCFAs revealed that the absence or disruption of gut microbes, either in germ-free mice (mice born without a gut microbiome) or through early-life antibiotic treatment, protected against brain shrinkage and reduced tau buildup, but only in certain APOE backgrounds. The team also found that gut changes altered the behavior of astrocytes and microglia, the brain’s support and immune cells. With fewer microbial signals, these cells maintained a more balanced, homeostatic state instead of becoming reactive and inflammatory, which in turn protected neurons. Finally, by manipulating SCFAs directly, the team demonstrated that these microbial byproducts serve as key messengers: lowering SCFA levels reduced inflammation and tau pathology, while reintroducing them triggered greater tau accumulation, immune activation and neurodegeneration. Together, these findings reveal a powerful link between diet, the microbiome and AD risk—highlighting that soluble dietary fiber may not always be protective and could even worsen tau-driven damage in individuals carrying APOE4. The team hypothesizes that a high intake of soluble dietary fiber can promote tau-driven neurodegeneration by altering microbiome metabolism and immune responses in the brain, in ways that depend on the APOE genotype.
To test this, they will use two experimental aims. In aim one, they will examine how a high-fiber diet affects brain health in tau mice (P301S) carrying human versions of APOE3, which does not affect AD risk, or APOE4, which increases risk. Some mice will receive a diet rich in fermentable fiber, while others will receive a fermentable fiber-free control diet. The researchers will track changes in brain volume, tau buildup, and glial cell activity as well as memory-related behaviors. This will determine whether soluble fiber intake exacerbates tau pathology and whether APOE4 mice are particularly susceptible to its effects. In aim two, they will investigate the “fingerprints” of gut–brain communication. These fingerprints represent the unique patterns of bacteria, metabolites such as SCFAs, and immune molecules that may signal how changes in the gut influence the brain. The team will examine gut bacteria, metabolites like SCFAs and immune molecules in blood samples to see how they connect to brain changes. This will reveal how dietary fiber shapes the microbiome–immune–brain axis, and whether specific microbial or metabolic signatures predict disease progression. Together, these studies will move the field forward by testing whether a commonly recommended dietary component, soluble fiber, could have safe and beneficial effects in improving outcomes, or unexpected harmful effects in AD, especially for people with APOE4. If successful, this research could identify new strategies to personalize dietary advice, clarify when and how microbiome-targeted therapies may be safe and ultimately open new avenues for slowing neurodegeneration.
