Alzheimer’s disease (AD), the most prevalent form of dementia, is characterized by the accumulation of amyloid-beta (Aβ) plaques and hyperphosphorylated tau tangles. Currently, Alzheimer’s disease (AD) impacts 50 million individuals, with projections anticipating an increase to 152 million by the year 2050. Despite the increasing global prevalence of AD, its underlying pathology remains poorly understood, posing challenges for early diagnosis and treatment. Recent research suggests a link between gut dysbiosis and the aggregation of Aβ, the development of tau proteins, and the occurrence of neuroinflammation and oxidative stress are associated with AD. However, investigations into the gut–brain axis (GBA) in the context of AD progression and pathology have yielded inconsistent findings. This review aims to enhance our understanding of microbial diversity at the species level and the role of these species in AD pathology. Additionally, this review addresses the influence of confounding elements, including diet, probiotics, and prebiotics, on AD throughout different stages (preclinical, mild cognitive impairment (MCI), and AD) of its progression.

Alzheimer’s disease (AD) is a progressive neurodegenerative disorder that develops many years before clinical symptoms appear. The biological changes involved in the earliest stages remain poorly understood, particularly during the preclinical stage. Our previous work has identified gradual gut microbial and metabolic changes during this stage, suggesting these may represent early biological shifts that precede disease progression. Recent studies suggest that the gut microbiome may contribute to early AD processes through its effects on immune regulation, metabolism, and gut–brain communication. Changes in gut microbial composition, including reduced levels of short-chain fatty acid (SCFA)-producing bacteria, such as Faecalibacterium, Roseburia, and Eubacterium, have been reported in individuals with AD and mild cognitive impairment. These microbial alterations have also been linked to disrupted metabolic activity, impaired gut barrier function, and increased neuroinflammatory responses. Diet is an important factor influencing gut microbial composition and metabolic activity. Mediterranean, DASH, and prudent dietary patterns are generally associated with beneficial microbial profiles and increased SCFA production, whereas Western dietary patterns are linked to lower microbial diversity and increased pro-inflammatory taxa. This review summarises the current evidence linking gut microbiota, SCFAs, microbial metabolism, and dietary patterns with early AD pathology, while highlighting important gaps in the existing literature.

Short-chain fatty acids (SCFAs) produced by gut microbial fermentation influence host metabolism and neuroinflammatory processes implicated in Alzheimer’s disease (AD). However, the relationship between fecal SCFAs, microbial taxa, and cerebral amyloid-β (Aβ) burden in cognitively unimpaired individuals remains unclear. Fecal SCFAs were quantified using GC-MS, and microbial species were profiled by shotgun metagenomics in 87 participants. Associations between SCFAs, demographics, APOE ε4 status, and Aβ burden were tested using nonparametric statistics and multivariable regression. Microbial–SCFA links were evaluated using Spearman correlations and multivariate ordinations, with mediation analysis exploring potential indirect pathways. Acetate was the predominant SCFA and demonstrated the most robust microbial associations. Higher acetate concentrations were positively associated with Bacteroides ovatus and Faecalibacterium prausnitzii, whereas lower acetate levels were linked to species such as Bifidobacterium animalis and Lachnoclostridium scindens. Stratified analyses indicated that individuals with elevated Aβ burden exhibited more pronounced species–SCFA relationships, including a notable association between Bacteroides thetaiotaomicron and butyrate. Multivariate ordination further identified a significant overall coupling between SCFA profiles and microbial community structure. Mediation analysis suggested that an Oscillospiraceae species may represent a potential intermediary linking valerate concentrations with Aβ status. SCFA concentrations were not strongly influenced by demographic or genetic factors, but specific species demonstrated robust associations with acetate levels. Distinct SCFA–microbial interaction patterns in Aβ High individuals suggest subtle early gut microbial alterations linked to amyloid burden. These findings highlight the potential role of SCFA-related microbial pathways in preclinical AD.

Background: Current literature focuses on the association between gut dysbiosis and the aggregation of Aβ, the development of tau protein, as well as neuroinflammation and oxidative stress associated with AD. Since the brain and gut are connected (gut‐brain axis), gut microbiota and their metabolites may influence AD progression, or vice versa, if AD pathogenesis impacts the microbiome. Observational studies have shown an altered taxonomic composition of gut microbiota in AD patients compared to cognitively normal (CN) controls.Method: This perspective study will explore taxonomic composition and gut microbial function (using metagenomic analysis) compared with Aβ aggregation, deposition of tau, and inflammatory biomarkers in cognitively normal individuals and preclinical AD individuals. We will also address the effect of dietary intake on gut dysbiosis to assess the effectiveness of healthy diet patterns as preventive approaches in AD.Results: The faecal samples of people with AD have been shown to have decreased microbial diversity and compositionally distinct microbiota. At the same time, correlations were found between gut microbiome differences and cerebrospinal fluid (CSF) tau levels, and plasma β‐amyloid (Aβ) biomarkers levels early in the progression of the disease. However, research into the gut and brain concerning AD progression and AD pathology remains very inconsistent with the reported data. Therefore, evaluation of the potential role of microbiota taxonomy in stool in the early detection of preclinical AD may lead to the development of novel directions in the investigation of the potential role of the gut in AD progression.Conclusion: The altered gut microbiota can influence increased Aβ deposits, tau phosphorylation, and neuroinflammation. Therefore, it is necessary to gain a better understanding of microbial community diversity at the species level and the function of these communities due to AD pathology as well as the effect of confounding factors like dietary intake.

Background: Gut microbiota and their metabolites, particularly short‐chain fatty acids (SCFAs), play a vital role in the gut‐brain axis, and have been associated with neurodegenerative diseases like Alzheimer's disease (AD). However, the changes in gut microbiota composition and SCFA levels during the progression of AD are not yet well understood. This study seeks to investigate these variations to gain deeper insights into their potential role in disease development. Method: This study examined changes in gut microbiota and SCFA across three groups; Cognitively unimpaired individuals with low amyloid‐beta ((CU) Aβ Low ( n = 71)), CU Aβ High ( n = 19), and those diagnosed with mild cognitive impairment (MCI) or AD (Disease Group (DG), n = 10). Participants were selected from well characterised cohorts and underwent Pittsburg compound B‐positron emission tomography to determine cerebral amyloid status. Faecal microbiota composition was assessed using shotgun metagenomics, while faecal SCFA concentrations were quantified via Gas Chromatography‐Mass Spectrometry (GC‐MS). Associations between taxa and SCFAs were assessed using Spearman correlation and MaAsLin2. Result: Firmicutes, Proteobacteria, and Bacteroidetes exhibited significant correlations with SCFAs across all groups. In the CU Aβ Low and Disease Group (DG), Firmicutes showed Positive correlations with butyric acid. Group‐specific patterns included negative correlations between Bacteroidetes and propionic acid in the DG group, a positive correlation between Firmicutes and total SCFAs in the CU Aβ Low group, and a positive correlations between Proteobacteria and Actinobacteria with butyric acid in the CU Aβ High group, alongside notable interactions with isovaleric acid. Furthermore, specific taxa such as Corynebacterium falsenii (Phylum: Actinobacteria), Ruthenibacterium lactatiformans (Phylum: Firmicutes), and Streptomyces capitiformicae (Phylum: Actinobacteria) showed significant associations with SCFAs, particularly propionic acid and butyric acid. Conclusion: These findings suggest that changes in gut bacteria and their metabolites vary at different stages of AD. Key results show that certain bacteria, such as Firmicutes, Bacteroidetes, and Proteobacteria, are linked to SCFAs, especially butyric acid, which plays a role in gut and brain health. This suggests that modifying gut bacteria could help regulate SCFA levels and potentially slow the progression of AD. However, more research is needed to fully understand this connection.