Alzheimer's disease (AD) is a complex neurodegenerative disorder characterized by amyloid-beta and tau protein accumulation, leading to cognitive impairment. The global burden of AD is substantial, with millions affected and a projected increase in cases and costs. While recent FDA approvals of amyloid-beta targeting therapies offer hope, effective disease-modifying interventions are crucial to slow cognitive decline and improve quality of life. Historically, AD research focused on brain dysfunction. However, the gut-brain axis highlights the influence of the body's immune and metabolic states on brain development and function. The gut microbiota, resident bacterial communities, significantly contributes to neurological, immune system development, and metabolism, impacting various organs via the circulatory system. Advances in sequencing technologies have facilitated research into microbiota-gut-brain associations, revealing the gut microbiome's potential role in modulating behavior and brain function in AD. The gut microbiome produces numerous metabolites detectable via metabolomics, impacting intestinal homeostasis and brain health. Dietary changes are a major environmental factor influencing gut microbiome composition and metabolite production. Previous research has explored various dietary interventions to prevent cognitive decline and reduce AD risk, indicating potential benefits from personalized approaches tailored to factors like APOE genotypes. This review focuses on the potential of dietary interventions to prevent AD progression by regulating gut microbiota and their metabolites.

Existing literature demonstrates the involvement of quantitative and qualitative changes in the gut microbiome in various neurological disorders, including AD, Parkinson's disease, and autism spectrum disorder. Animal studies have shown significant gut microbiome alterations in AD animal models, with changes escalating with age and sex-dependent differences observed. Antibiotic administration disrupts the gut microbiota, affecting Aβ accumulation. Fecal microbiota transplantation from older AD mice exacerbates Aβ pathology in antibiotic-treated mice, while transplanting microbiota from young mice to old mice attenuates age-associated cognitive impairment. Human studies have revealed decreased microbial diversity and altered composition in AD patients compared to healthy controls, although inconsistencies exist across studies regarding alpha-diversity. Numerous studies have identified associations between the abundance of specific gut bacteria (at phylum or genus level) and AD, with differing results across various populations. While cross-sectional studies reveal compositional differences, longitudinal studies exploring causal associations are needed. Metagenomic analyses have revealed lower abundance of butyrate-producing species in older individuals with AD, providing a causal link between microbiome and inflammation in AD pathogenesis.

This is a review article. The authors systematically reviewed existing literature on the relationship between gut microbiota, microbial metabolites, dietary components, and Alzheimer's Disease. The methodology involves searching databases (likely PubMed, Scopus, Web of Science etc.) for relevant research articles using keywords such as "Alzheimer's disease", "gut microbiota", "microbial metabolites", "microbiota-gut-brain axis", and "dietary interventions." Inclusion and exclusion criteria were likely applied to select studies meeting specific quality standards. The selected articles were then analyzed to extract information on the composition and diversity of the gut microbiome in AD patients and animal models, the mechanisms by which gut microbiota and microbial metabolites influence AD, and the effects of dietary components on gut microbiota, metabolites, and brain function. The authors synthesized this information to build a comprehensive overview of the gut-microbiota-brain axis in the context of AD and the potential of dietary interventions. Data extraction likely involved creating tables summarizing key findings from individual studies. The analysis likely focused on identifying patterns and trends across studies, including consistent findings regarding changes in the gut microbiome composition in AD, the key metabolites involved, and the efficacy of different dietary interventions. This involved qualitative synthesis of results across various study designs and populations, focusing on highlighting consistent findings and areas of discrepancy for future research.

The review highlights multiple pathways through which the gut microbiome and its metabolites affect brain function in AD. These include: **Neuronal signaling via the gut-brain axis:** The vagus nerve and the enteric nervous system (ENS) are key communication pathways. Studies show that specific probiotic strains can modulate neuronal activity and behavior via vagus nerve activation, although human studies are limited due to the difficulty of investigating the vagus nerve directly. The ENS, the largest component of the peripheral nervous system, is also modulated by gut microbes, impacting enteric homeostasis and gut barrier function, though its role in neurodegenerative diseases requires further research. **Immune-mediated signaling:** Gut microbiota influences the activation of immune cells in the brain, impacting the neuroimmune system. Chronic inflammation, potentially due to increased intestinal permeability and gut dysbiosis, plays a role. Microbiota dysbiosis increases amino acid concentrations, activating pro-inflammatory T helper 1 cells, which are linked to AD-related neuroinflammation. The communication between brain and intestinal microbiota involves circulating cytokines, influencing brain function and host health. Age-induced peripheral and hippocampal immunity, alongside microbiota transplantation from young mice, remodels the microbiome, promoting immune and brain function restoration. **Microbial metabolites regulate AD:** The review categorizes microbial metabolites into three types: diet-derived products (SCFAs, amino acids, polyphenols), microbe-host co-metabolites (bile acids), and metabolites shared by the host and bacterial metabolic pathways (neurotransmitters, polyamines). SCFAs, produced from fiber fermentation, have neuroprotective effects, potentially by inhibiting HDACs and reducing neuroinflammation. Amino acids, crucial for neurochemical synthesis, show altered concentrations in AD, with tryptophan metabolism (serotonin, kynurenine pathways) being particularly relevant. Polyphenols, plant-derived metabolites, exhibit neuroprotective effects, potentially through microbiota modulation. Bile acids, modified by gut bacteria, also play a role, with altered concentrations linked to cognitive decline. Neurotransmitters and polyamines, produced by both the host and bacteria, also influence AD pathogenesis. **Microbiome-based Dietary Interventions:** The review explores dietary components (fats, carbohydrates, proteins, vitamins, polyphenols) and dietary patterns (Mediterranean, DASH, MIND, ketogenic diets) that influence gut microbiota and AD progression. Omega-3 PUFAs, dietary fiber, and plant-based proteins show potential benefits, while high sugar and animal protein intake may be detrimental. Vitamins, particularly vitamins D and E, have shown varying effects. Polyphenols-rich foods modify microbiota and exert neuroprotective effects. Among dietary patterns, Mediterranean, DASH, and MIND diets exhibit neuroprotective associations. The ketogenic diet also shows promise, but requires further research on its interactions with gut microbiota. The review also discusses microbiome-targeted interventions, such as probiotics, prebiotics, and synbiotics, highlighting their potential benefits, although inconsistencies exist across studies. Natural products, including fruits, vegetables, mushrooms, and medicinal plants, offer potential benefits, requiring more clinical research.

This review synthesizes evidence supporting a strong link between gut microbiota, microbial metabolites, and Alzheimer's disease. The multiple pathways highlighted—neuronal signaling, immune-mediated signaling, and metabolite modulation—emphasize the complexity of the gut-brain axis in AD pathogenesis. The review emphasizes the potential for dietary interventions and microbiome-targeted strategies to mitigate AD progression. While promising preclinical results exist, the translation into clinical therapies faces challenges, such as maintaining long-term dietary compliance and addressing the resilience and variability of the human gut microbiome. Personalization of interventions may also be necessary, considering individual factors like APOE genotype. The inconsistent findings across various studies highlight the need for more rigorous, well-designed clinical trials addressing factors like dosage, disease severity, and individual differences. The findings from the review strongly suggest a need for future research focusing on exploring causal relationships and mechanisms, particularly regarding the specific roles of gut-derived metabolites and their interactions with brain function.

The gut microbiota and its metabolites represent promising targets for AD prevention and treatment. Dietary interventions and microbiome-targeted strategies show potential to delay AD progression by modulating inflammation and neuronal signaling. However, the field requires further investigation into causal relationships and mechanisms, particularly regarding gut-derived metabolites' effects on brain function. Well-designed clinical trials are needed to translate preclinical findings into effective dietary guidelines and clinical therapies.

This review, being a synthesis of existing literature, is subject to the limitations of the included studies. Inconsistent findings across studies, particularly regarding alpha-diversity changes in the gut microbiome of AD patients and the effects of specific dietary interventions, highlight the need for further, more robust research. The challenges of establishing causal relationships between gut microbiota alterations, metabolite changes, and AD progression are also acknowledged. Differences in study designs, populations, and methodology across the reviewed studies limit the generalizability of findings. Furthermore, the translation of preclinical findings into clinically applicable dietary recommendations and therapies remains challenging.