Dementia is a growing global health concern, with projections indicating a substantial increase in cases by 2050. Neurodegenerative diseases like mild cognitive impairment (MCI) and dementia are characterized by decreased cognitive skills and neuroinflammation linked to increased intestinal permeability. This is partly due to changes in gut microbiome diversity during aging, influenced by various factors including treatments, physiological alterations, and diet, along with inflammaging (a chronic proinflammatory response). While cognition was initially considered solely regulated by the nervous system, it's now recognized that gut bacteria play a role in cognitive function. Alzheimer's disease (AD), accounting for a significant portion of dementias, is a costly neurodegenerative syndrome. This study aimed to investigate the gut microbiota-brain axis in relation to aging, MCI, and dementia, focusing on specific proteins and inflammatory markers.

Existing literature highlights the increasing global burden of dementia and the association of neuroinflammation and altered intestinal permeability with cognitive decline. Studies have established the role of inflammaging in age-related diseases. The gut microbiome's influence on cognitive function is increasingly recognized. Alzheimer's disease, the most prevalent dementia, is linked to amyloid plaques and neurofibrillary tangles. Previous research has implicated the ApoE gene, particularly the ε4 allele, in increasing the risk of developing Alzheimer's disease. The gut microbiota has been shown to impact amyloid formation and the pathogenesis of Alzheimer's disease. Studies have also linked branched chain amino acids (BCAA) with type 2 diabetes and Alzheimer's disease.

This cross-sectional study included 154 volunteers from Central Mexico (young subjects, healthy adults over 60, adults with MCI, and adults with dementia). A preclinical study using aging male Wistar rats was also conducted. Participants underwent medical examinations, anthropometric measurements, cognitive assessment (MMSE), and blood and stool sample collection. Blood samples were analyzed for various biochemical parameters, including glucose, lipids, LPS, tau protein, β-amyloid, and BCAAs. ApoE gene polymorphism was also determined. Stool samples were analyzed for gut microbiota composition using 16S rRNA sequencing and for curli protein abundance using PCR and Western blot. In the rat study, serum and fecal samples were collected at different ages (2, 12, 18, and 24 months), and brain samples were collected at the end. Statistical analyses included ANOVA, Tukey's post hoc test, Spearman correlation, and principal component analysis (PCA).

The study revealed significant increases in BMI, body fat mass, visceral fat, and serum glucose levels in the older adult groups (A, MCI, D) compared to the young group. The dementia group exhibited significantly lower skeletal muscle mass. Serum LPS, tau protein, and β-amyloid concentrations were significantly higher in the MCI and D groups, reflecting low-grade inflammation. Bacterial diversity decreased with age, with the MCI and D groups showing the lowest Shannon index. The D group showed increased abundance of Escherichia coli and Coprococcus eutactus. PICRUSt analysis indicated increased LPS and peptidoglycan biosynthesis, BCAA biosynthesis, and tryptophan metabolism in the older groups, along with decreased glutamatergic synapse system activity. All dementia patients showed the presence of curli protein in feces, with abundance positively correlated with E. coli. A significant negative correlation existed between curli protein abundance and MMSE scores. The rat study showed increased curli protein in stool and brain, increased LPS, and increased TNFα with age, indicating neuroinflammation. PCA revealed three distinct groups (A, MCI, D) characterized by different variables: The A group showed higher MMSE scores and F. prausnitzii abundance; the D group showed higher β-amyloid, tau, LPS, and curli protein levels; and the MCI group showed increased fat mass and serum triglycerides. Correlations indicated positive associations between β-amyloid, curli protein, tau protein, LPS, and BCAAs and negative correlations with MMSE scores. E. coli was positively correlated with curli protein and β-amyloid, while serum HDL was negatively correlated.

The findings demonstrate a strong link between gut dysbiosis, increased serum levels of inflammatory markers (LPS, tau, β-amyloid), curli protein, and cognitive decline. The increased abundance of E. coli, producing curli amyloid protein, suggests a potential mechanism linking gut microbiota alterations to neurodegeneration. The preclinical rat model confirmed the age-related increase in curli protein and inflammation in the brain, supporting the gut-brain axis involvement. The correlation analyses and PCA effectively highlight the associations between gut microbiota composition, inflammatory markers, and cognitive performance. The inverse correlation between F. prausnitzii (known for anti-inflammatory properties) and LPS further emphasizes the role of gut microbiota balance in modulating inflammation. The observed alterations suggest the potential use of these markers for early detection of cognitive impairment.

This study provides evidence supporting the gut-brain axis involvement in cognitive decline. Dysbiosis, increased serum levels of tau protein, β-amyloid, LPS, and fecal curli protein, and increased E. coli abundance are associated with MCI and dementia. These findings suggest potential biomarkers for early detection of cognitive impairment. Further research with larger populations is needed to confirm these findings and explore therapeutic interventions targeting the gut microbiota.

The cross-sectional nature of the human study limits the establishment of causal relationships. The sample size, particularly for the dementia group, could be considered a limitation. The rat model, while valuable, may not fully capture the complexity of human aging and disease. Further investigation is required to determine the precise mechanisms underlying the observed correlations and the direct impact of bacterial amyloids on neuronal amyloid aggregation.