Barbara B. Bendlin

The gut microbiome modulates metabolic and neurovascular processes implicated in Alzheimer’s disease and related dementias (ADRD), but the underlying mechanisms remain unclear. Here, we identify the bacterial metabolite imidazole propionate (ImP) as a modifier of ADRD pathology. In a cohort of 1196 cognitively unimpaired adults, higher plasma ImP levels were associated with lower preclinical cognitive scores and biomarkers of ADRD, both cross-sectionally and longitudinally. Fecal metagenomic analysis linked putative ImP producers to ADRD phenotypes. Genome-wide integrative analysis revealed a locus on chromosome 12 associated with both plasma ImP levels and AD risk in humans, supporting a host genetic contribution to ImP regulation and a causal role of this metabolite in AD. In mice, chronic ImP administration exacerbated AD-like pathology. ImP impaired brain endothelial barrier and promoted tau hyperphosphorylation in primary neurons, an effect blocked by glycogen synthase kinase-3β inhibition. Together, this study links ImP to hallmarks of neurodegeneration and suggests that targeting ImP may represent a potential strategy to modify ADRD risk.

Cognitive impairment is increasing with global aging, yet mechanisms linking diet, the gut microbiome, and metabolism to cognitive function remain unclear. To investigate a diet-microbiome-metabolome axis associated with cognition, we integrated fecal metagenomics, diet, and multi-platform plasma metabolomics in 505 older adults from four ADRCs. Several microbes broadly associated with circulating metabolites were also linked to multiple measures of cognitive performance. These taxa exhibited coordinated metabolic signatures, with cognition-positive microbes associated with antioxidant, lipid, and microbial–host co-metabolites, and microbes negatively associated with cognition were linked to inflammatory and aromatic amino acid–derived metabolites. Dietary patterns, particularly the Healthy Eating Index Greens and Beans component, were associated with microbial composition and metabolomic structure. Mediation analyses supported a diet–microbe–metabolite–cognition pathway, while metabolites remained associated with cognition after accounting for microbial features. These findings highlight the metabolome as a central integrator of diet, microbial activity, and cognitive function.

Introduction: We examined the extent to which insulin resistance (IR), type 2 diabetes mellitus, obesity, and kidney function are associated with plasma phosphorylated tau (p‐tau) concentrations (p‐tau181, p‐tau217, p‐tau231) in the same cohort and the contribution of these factors on amyloid positron emission tomography (PET) concordance and longitudinal p‐tau levels. Methods: We analyzed data from 287 participants using partial Spearman rho, Mann–Whitney U , receiver operating characteristic analysis, and linear mixed models. Results: Concordance between plasma p‐tau217 and amyloid PET was not influenced by IR or estimated glomerular filtration rate (eGFR). Accounting for eGFR improved concordance of p‐tau181 and p‐tau231 with amyloid PET. Age, binarized waist‐to‐hip ratio, and amyloid status were associated with all longitudinal p‐tau concentrations, and eGFR associated with longitudinal p‐tau231. Discussion: Metabolic factors may influence the interpretation of longitudinal plasma p‐tau concentrations and kidney function may influence amyloid PET concordance for p‐tau181 and p‐tau231, potentially necessitating analyte‐specific adjustments or considerations in clinical interpretation.

INTRODUCTION: 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. METHODS: 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. RESULTS: 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. DISCUSSION: 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. Highlights: 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 pTau ₂₁₇ accumulation in females. SCFAs are associated with slower cognitive decline.

INTRODUCTION: 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. METHODS: 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. RESULTS: 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 CSF biomarkers. SCFA levels are associated with slower cognitive decline. DISCUSSION: 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.

INTRODUCTION The interpretation of plasma phosphorylated tau (pTau) levels may be influenced by metabolic conditions, such as insulin resistance (IR), type 2 diabetes mellitus (T2DM), obesity, and kidney function. We examined the extent to which metabolic factors are associated with plasma pTau concentrations (pTau181, pTau217, pTau231) and the contribution of these factors on analytical outcomes. METHODS We analyzed data from 287 participants using partial Spearman’s rho, Mann Whitney U, ROC analysis, and linear mixed models. RESULTS Concordance between plasma pTau217 and amyloid PET was not influenced by IR or estimated-glomerular-filtration-rate (eGFR). Accounting for eGFR improved concordance of pTau181 and pTau231 with amyloid PET. Age, binarized waist-to-hip ratio, and amyloid status were associated with all longitudinal pTau concentrations, and eGFR associated with longitudinal pTau231. DISCUSSION Metabolic health may influence the interpretation of some plasma pTau biomarkers, potentially necessitating adjustments for metabolic factors in research and clinical settings.

The gut microbiome influences metabolic, immune, and neuroinflammatory processes that are increasingly implicated in the pathophysiology of Alzheimer’s disease (AD). Alterations in microbial composition have been associated with cognitive decline, systemic inflammation, and disruptions in the gut-brain axis observed in AD. Despite a growing number of studies linking gut dysbiosis to AD-related brain changes, the underlying mechanisms remain poorly understood. The bacterial metabolite imidazole propionate (ImP) has been previously associated with dementia risk factors, including type 2 diabetes and cardiovascular disease, however, the impact of ImP on brain remains relatively unknown. Here, we show that elevated plasma ImP levels are associated with lower cognitive performance and biomarkers of AD pathology in a large cohort of cognitively unimpaired individuals (>1,100). Furthermore, high plasma ImP levels predicted accelerated progression of AD-related pathology. Metagenomic profiling of stool samples identified gut bacteria encoding predicted orthologs of the ImP-synthesizing enzyme, urocanate reductase (UrdA), whose abundance correlated with both cognitive measures and multiple AD biomarkers. Supporting the human observations, chronic ImP administration in AD mouse model activated neurodegenerative pathways, exacerbated AD pathology, and increased blood-brain barrier (BBB) permeability. Finally, in vitro studies showed that ImP compromised the integrity of human brain endothelial cells. Together, these findings implicate ImP in AD progression and position it as a potential target for early intervention.

BACKGROUND: The gut microbiome is a potentially modifiable risk factor for Alzheimer's disease (AD); however, understanding of its composition and function regarding AD pathology is limited. METHODS: Shallow‐shotgun metagenomics was used to analyze the fecal microbiome of participants in the Wisconsin Microbiome in Alzheimer's Risk Study, leveraging clinical data and cerebrospinal fluid (CSF) biomarkers. Differential abundance and ordinary least squares regression analyses were performed to find differentially abundant gut microbiome features and their associations with CSF biomarkers of AD and related pathologies. RESULTS: Gut microbiome composition and function differed between individuals with and without AD dementia. The compositional difference was replicated in an independent cohort. Differentially abundant gut microbiome features were associated with CSF biomarkers of AD and related pathologies. DISCUSSION: These findings enhance our understanding of alterations in gut microbial composition and function in AD, and suggest that gut microbes and their pathways are linked to AD pathology. Highlights: Gut microbiome composition and function differ between people with Alzheimer's disease (AD) dementia and cognitively unimpaired (CU) individuals. Co‐occurring gut microbes show differential abundance across AD‐related groups (AD vs CU, amyloid status+ vs amyloid status−, and apolipoprotein E ( APOE ) ε4 status+ vs APOE ε4 status−). Gut microbiome composition also differs between people with AD dementia and CU individuals in a larger validation cohort. Differentially abundant gut microbiome composition and function between AD and CU groups are correlated with cerebrospinal fluid biomarkers for AD and related pathologies.

Background: Depression earlier in life is a risk factor for dementia later in life. Physical activity is associated with less risk of depression and dementia. However, prevention of Alzheimer's disease may be most effective before the onset of brain pathology, which precedes dementia symptoms by 20 + years, requiring the measure of physical activity across the life course. Objective: Assess the reliability and validity of the Lifetime Total Physical Activity Questionnaire (LTPAQ) in community-dwelling cognitively intact adults with and without a history of depression. Methods: Test-retest reliability was assessed with intraclass correlations (ICC). Evidence of construct validity was assessed with descriptive statistics using the contrasted group approach and a priori hypotheses testing with each intensity (sedentary, light, moderate, vigorous) within each domain (school/occupation, transportation, household, leisure-time) across the life course (school-age, adolescence, young adult, middle adult). Results: Evidence of test-retest reliability and construct validity was found during school-age and adolescence for moderate school/occupation (ICC = 0.562, p  = 0.006; ICC = 0.605, p  = 0.003, respectively) and household (ICC = 0.945, p  < 0.001; ICC = 0.829, p  < 0.001, respectively); during young adulthood for moderate school/occupation (ICC = 0.844, p  < 0.001), transportation (ICC = 0.747, p  < 0.001), and household (ICC = 0.608, p  = 0.002); and during middle adulthood for moderate transportation (ICC = 0.977, p  < 0.001). At both time points, there were zero reported school-age vigorous school/occupation and household; adolescent vigorous transportation; young adult vigorous household; and middle adult vigorous transportation and household physical activity. Conclusions: The LTPAQ may be used to examine physical activity across the life course and risk for Alzheimer's disease in community-dwelling cognitively intact adults with and without a history of depression.