How Diet May Affect Alzheimer's Disease Through the Gut-Brain Connection

Alzheimer’s disease (AD) is a progressive neurodegenerative disorder characterized by cognitive decline, memory loss, and behavioral changes, affecting millions of aged individuals worldwide. It is an irreversible neurodegenerative process that progressively impairs brain function, causing disruptions in memory, cognition, personality, and other functions that interfere with everyday activities and eventually lead to death from complete brain failure. AD has emerged as one of the most lethal, economically burdensome, and socially impactful diseases of the 21st century. It has a major impact on both individuals who suffer from it and the healthcare system, as well as increasing the burden on caregivers. The exact cause of AD remains unclear but is attributed to a combination of genetic, environmental, and lifestyle factors influencing its onset and progression (Hickman et al., 2024). Age is the predominant risk factor, with the incidence nearly doubling every 5 years after 65 and markedly increasing by age 85 (Wang et al., 2025), highlighting its critical role in AD epidemiology. Currently, approximately 50 million people worldwide have AD, with projections estimating that this number will triple to 152 million by 2050 (WHO, 2025; Breijyeh and Karaman, 2020; Nichols et al., 2019).

According to the Alzheimer’s Association (2021), the prevalence of AD escalates with advancing age. Specifically, approximately 5% of individuals aged 65 to 74 are affected by AD. This figure rises to approximately 13% for those aged 75 to 84 and significantly increases to approximately 33% for individuals aged 85 and older (Alzheimer’s Association, 2021; Fang et al., 2025). These statistics highlight a crucial aspect of Alzheimer’s epidemiology: the older a person is, the higher their risk of developing the disease. Despite extensive research, the exact mechanisms underlying the onset and progression of AD remain mysterious, posing a significant challenge for effective treatment and prevention.

AD pathology is characterized by extracellular beta-amyloid (Aβ) peptide accumulation, intracellular hyperphosphorylated tau-containing neurofibrillary tangles, neuroinflammatory mediator deposition, and neuronal and synaptic loss in the central nervous system. These interconnected events lead to the cognitive deficits typical of AD and result in cortical and subcortical atrophy (Figure 1). Environmental, lifestyle, and biological factors, including poor dietary habits via the gut–brain axis, may contribute to Aβ accumulation and tau hyperphosphorylation. These changes trigger neuroinflammatory responses with microglial activation around amyloid plaques, which exacerbate neuronal and synaptic damage. While the brain’s innate immune system maintains central nervous system (CNS) integrity, chronic microglial activation is neurotoxic and significantly influences AD progression. Thus, inflammation is considered both a consequence and a major driver of the disease (Figure 1).

Amyloid-beta (Aβ) is a peptide generated through the sequential enzymatic cleavage by α-, β-, and γ-secretases of amyloid precursor protein (APP), a transmembrane protein predominantly expressed in neurons. Under normal physiological conditions, Aβ is produced at low levels and is effectively cleared from the brain via enzymatic degradation and transport across the blood–brain barrier. In a study done by Waly et al. (2023), a decline in neuronal plasticity associated with aging was observed, which is further exacerbated inan in vivo Alzheimer’s disease model and correlates with cognitive decline. In Alzheimer’s disease, however, there is an imbalance between Aβ production and clearance, resulting in its pathological accumulation (Huang et al., 2025a). As illustrated in Figure 2, the processing of APP differs between healthy and AD brains. Under normal physiological conditions, APP is predominantly cleaved by α-secretase, producing non-amyloidogenic peptides that are efficiently cleared. In contrast, in AD, APP is sequentially cleaved by β- and γ-secretases, generating Aβ peptides. These peptides undergo a progressive aggregation process, forming soluble oligomers and protofibrils that eventually assemble into insoluble extracellular amyloid plaques (Perneczky et al., 2024). The accumulation of these plaques is a defining neuropathological feature of AD and is implicated in synaptic dysfunction and neurodegeneration.

These Aβ aggregates exert neurotoxic effects through multiple mechanisms. They disrupt synaptic function by interfering with neurotransmitter release and receptor signaling, leading to impaired neuronal communication (Tang et al., 2025). Additionally, Aβ induces oxidative stress by generating reactive oxygen species (ROS), which damage cellular components including lipids, proteins, and DNA. Importantly, Aβ accumulation triggers chronic neuroinflammatory responses mediated by microglia and astrocytes. Microglial cells, the brain’s resident immune cells, initially respond to Aβ deposition by attempting to phagocytose and clear these aggregates (Cohen and Villemagne, 2025). However, persistent exposure to Aβ leads to microglial overactivation, resulting in the sustained release of pro-inflammatory cytokines, chemokines, and other neurotoxic mediators. This chronic inflammatory milieu exacerbates neuronal injury and contributes to synaptic loss.

In patients with AD, neuroinflammation is particularly prominent surrounding amyloid plaques, underscoring the critical involvement of neuroimmune mechanisms in disease progression. The interplay between Aβ pathology and neuroinflammation creates a vicious cycle that amplifies neuronal damage (Zhang and Jiang, 2015; Jorfi et al., 2023). The accumulation of Aβ is now widely recognized as a key initiating event in the cascade of AD pathology, precipitating downstream processes such as tau protein hyperphosphorylation and neurofibrillary tangle formation. These tau-related changes further disrupt neuronal cytoskeletal integrity and intracellular transport, leading to synaptic dysfunction and neuronal death (Aranda-Abreu et al., 2025). Collectively, these pathological events culminate in the progressive cognitive decline characteristic of AD (Figure 2).

In murine models, microglia, the resident immune cells of the central nervous system, have been demonstrated to mediate the clearance of Aβ primarily through processes of phagocytosis and lysosomal degradation. Recent studies indicate that microglia actively internalize Aβ aggregates, thereby facilitating a reduction in amyloid plaque burden in AD mouse models (van Olst et al., 2025). This clearance capacity is modulated by both intrinsic microglial activation states and extrinsic factors, such as the gut microbiota, which influence microglial phenotype and phagocytic efficiency (Wasén et al., 2024). In human AD brains, spatial transcriptomic analyses reveal microglia exhibiting distinct transcriptional profiles that cluster around Aβ plaques, indicative of an activated neuroinflammatory state that contributes to both amyloid clearance and disease progression (van Olst et al., 2025). Foundational research also supports the role of microglia in Aβ uptake and degradation, mediated by specific receptors and enzymatic pathways, alongside associated neuroinflammatory responses observed in AD pathology (Lee and Landreth, 2010). Collectively, these findings underscore the dual role of microglia in amyloid pathology: participating in the clearance of Aβ while potentially exacerbating neuroinflammation.

In Alzheimer’s disease brains, inflammation is particularly prevalent around Aβ plaques (Wang et al., 2023; Sun et al., 2024). The initiation of Aβ accumulation and brain inflammation in sporadic AD, where no mutant genes are involved, is not fully understood. In mouse models, microglia, the brain’s resident immune cells, participates in Aβ clearance through phagocytosis and degradation. However, in human sporadic AD, microglia often exhibit dysfunctional or overactivated phenotypes. Chronic inflammation surrounding Aβ plaques suggests an engaged but potentially ineffective or harmful immune response (Liu et al., 2024). The precise triggers for Aβ accumulation and neuroinflammation remain unclear but likely involve aging-related declines in clearance mechanisms, impaired blood–brain barrier function, environmental factors, and systemic metabolic or immune dysregulation (Devkota et al., 2025). These factors contribute to Aβ buildup and sustained neuroinflammatory responses that drive neurodegeneration in AD (Yan et al., 2024).

In an attempt to find a way to recover or at least slow down the progression of Alzheimer’s disease, recent single-nucleus RNA sequencing studies (da Rocha et al., 2025; Wang et al., 2025) highlight the cellular and molecular plasticity underlying this disease. Their work reveals that exercise induces protective transcriptomic changes within specific brain cell populations in the hippocampal dentate gyrus, a critical region for memory formation that is vulnerable early in Alzheimer’s pathology. These adaptive responses include restoration of dysregulated gene expression in immature neurons, activation of neurovascular-associated astrocytes, and modulation of disease-associated microglia and oligodendrocyte precursor cells. Furthermore, the study validated these findings in human Alzheimer’s brain tissue, emphasizing the translational relevance of exercise as a modulator of disease progression.

The human body is colonized by trillions of different microorganisms, collectively known as the microbiome. Microorganisms are considered as accessory organs of the human body, and the microbial communities gathered in different parts of the body to form a mutually beneficial symbiotic relationship with their host (Saad El-Den et al., 2024; Leser and Molbak, 2009). The gastrointestinal tract and the oral cavity are the main distribution sites of symbiotic microorganisms in the human body (Ogobuiro et al., 2020), and several studies have assessed the influence of oral microbiota on AD. In recent years, preclinical and limited clinical evidence has highlighted the gut microbiome as a critical factor influencing the pathogenesis of Alzheimer’s disease. The gut microbiome is a complex ecosystem comprising trillions of microorganisms, including bacteria, archaea, fungi, viruses, and protozoa, and their collective genomes residing primarily in the human gastrointestinal (GI) tract. This microbial community plays essential roles in physiological processes such as digestion, metabolism, immune regulation, and neural communication via the gut–brain axis, a bidirectional network linking the GI tract and the central nervous system (Figure 3).

Figure 5 illustrates the sequential steps by which changes in the gut microbiome contribute to the development of AD. It highlights the complex interactions connecting microbial dysbiosis, disrupted gut barrier integrity, systemic inflammation, and neuroinflammation that collectively drive AD pathogenesis. This figure provides a visual framework to understand how alterations in gut microbial composition and their metabolites influence brain health and disease progression:

Gut microbiome dysbiosis, characterized by reduced microbial diversity, depletion of beneficial commensals, and the overgrowth of opportunistic pathogens, can result from various factors, including environmental exposures, chronic stress, medications (particularly antibiotics), and notably, long-term dietary habits (Aguirre de Carcer, 2025; Saad El-Den et al., 2024). The gut microbiome, composed of a dynamic consortium of bacteria, archaea, fungi, viruses, and their collective genomes residing in the gastrointestinal tract, is highly dynamic and responsive to these external influences (Figure 6).

A healthy and balanced gut microbiome contributes to maintaining normal brain function, likely through the gut–brain axis involving neural, hormonal, and immune pathways. Disruption of this balance, known as dysbiosis, results from these factors indiscriminately affecting both beneficial and harmful microbes, leading to decreased microbial diversity and the proliferation of opportunistic pathogens. Such alterations in the gut microbiome can trigger a cascade of effects that extend beyond the gastrointestinal tract, influencing brain function through the gut–brain axis. These consequences may impair neurological health and cognitive function. Bidirectional communication via the gut–brain axis enables continuous two-way signaling between the CNS and the gastrointestinal tract. This complex connection involves neural (vagus nerve), endocrine, and immune pathways, explaining how external factors such as stress can influence digestive processes and how gut health, in turn, can modulate mood, cognition, and overall brain function.

Dysbiosis disrupts the homeostatic functions of the gut microbiota, leading to impaired metabolic activity and altered immune signaling. One key consequence is the compromise of intestinal barrier integrity, often referred to as a “leaky gut,” which increases permeability to microbial-derived components such as LPS. These pro-inflammatory molecules can translocate into systemic circulation, activating immune responses and promoting low-grade chronic inflammation. In the meantime, a healthy and balanced gut microbiome, composed of beneficial bacterial groups, like Bifidobacterium, Lactobacillus, and Faecalibacterium, plays a critical role in maintaining normal brain function via the gut–brain axis (Zhang et al., 2025).

Through the gut–brain axis, a complex bidirectional communication system involving neural (vagus nerve), endocrine (cortisol, gut hormones), and immune (cytokines) pathways, these inflammatory signals and microbial metabolites can influence CNS function (Park and Gao, 2024). Dysbiosis-induced inflammation has been linked to neuroinflammatory processes, altered neurotransmitter production, and impaired cognitive function. In contrast, a balanced and diverse gut microbiome supports brain health by reinforcing intestinal barrier function, regulating peripheral and central immune responses, and synthesizing neuroactive compounds such as SCFAs, tryptophan metabolites (Savonjie and Weaver, 2023), and gamma-aminobutyric acid (GABA).

Recent studies demonstrate that gut microbiota modulate dietary tryptophan metabolism, producing bioactive metabolites such as indole derivatives, kynurenines, and serotonin that influence neurophysiology, mood, cognition, and the gut–brain axis (Yuxuan et al., 2026; Qin et al., 2025) and regulate central nervous system function or impact peripheral pathways with downstream brain effects. Gut microbes achieve this by synthesizing metabolites or altering their availability, underscoring tryptophan’s essential role as a precursor for neuroactive kynurenine pathway products, serotonin, GABA, and indoles. Maintaining microbial homeostasis is therefore critical for preserving neuroimmune balance and mitigating the risk of neurodegenerative diseases such as Alzheimer’s disease.

Regarding diet-induced microbial dysbiosis, nutrients act as building blocks and regulators in metabolism, contributing to energy production, cellular function, and the regulation of gene expression. These nutrients come from either a healthy or an unhealthy diet. Diets high in unhealthy fats, sugars, and processed foods can reduce microbial diversity and promote the proliferation of harmful microbes, particularly bacteria. This imbalance not only disrupts normal gut function but also triggers systemic inflammation, which has been linked to various neurodegenerative diseases, including AD. The altered gut microbiome can produce neurotoxic metabolites that may exacerbate cognitive decline, creating a vicious cycle of worsening health. As Alzheimer’s disease progresses, the impact of microbial dysbiosis becomes increasingly evident. The inflammatory responses initiated by an imbalanced gut microbiome can contribute to the accumulation of amyloid plaques and tau tangles in the brain, hallmark features of Alzheimer’s pathology. Furthermore, the gut–brain axis plays a crucial role in this relationship, as signals from the gut can influence brain health and function. Thus, addressing dietary habits to restore microbial balance may offer a potential therapeutic avenue to slow the progression of Alzheimer’s disease and improve overall cognitive health.

The altered gut microbiome in Alzheimer’s disease can contribute to the development and progression of the disease through several interconnected mechanisms: Firstly, the dysbiotic microbiome can lead to increased intestinal permeability, allowing the translocation of bacterial metabolites, toxins, and inflammatory molecules into the systemic circulation. These microbial products, such as LPS and amyloid proteins, can then cross the blood–brain barrier and induce neuroinflammation, oxidative stress, and neuronal dysfunction, hallmarks of Alzheimer’s pathology (Figure 7).

The altered gut microbiome in Alzheimer’s disease can contribute to the development and progression of the disease through several mechanisms. These mechanisms illustrate the complex interplay between gut health and neurodegenerative processes in Alzheimer’s disease as follows:

Although the majority of butyrate is consumed locally by colonocytes as a primary energy source, a remaining fraction enters the systemic circulation, crosses the blood–brain barrier, and retains potent neuroprotective actions, making it both a key colonic fuel and a systemically active neuromodulatory metabolite. Butyrate exerts its neuroprotective effects through multiple complementary mechanisms. It is transported into neural cells via monocarboxylate transporters (MCT1), where it activates Nrf2 signaling and upregulates antioxidant enzymes such as superoxide dismutase, catalase, and glutathione peroxidase, thereby limiting reactive oxygen species-mediated neuronal damage (Saikachain et al., 2023). As a histone deacetylase (HDAC) inhibitor, butyrate also promotes the expression of genes involved in neuroprotection, neurogenesis, and mitochondrial stability, including fatty acid binding protein 7 (FABP7/BLBP), which supports mitochondrial function and reduces ROS generation during metabolic stress (Ahmed et al., 2019; Liu et al., 2021).

In parallel, SCFAs attenuate neuroinflammation by dampening microglial TLR4/NF−κB signaling, favoring a shift from pro−inflammatory M1 toward anti−inflammatory M2 phenotypes and lowering the production of ROS−promoting cytokines such as TNF−α and IL−6. They also reinforce gut and blood–brain barrier integrity via upregulation of tight junction proteins, limiting endotoxin translocation and systemic oxidative stress (Aburto and Cryan, 2024). Collectively, adequate SCFA, particularly butyrate, production by a eubiotic microbiota represents a key mechanism through which the gut–brain axis maintains redox balance and neuronal health.

Evidence suggests that imbalances in gut microbiota can trigger systemic inflammation, compromise the blood–brain barrier, and modulate amyloid-ß accumulation, hallmarks of Alzheimer’s pathology (Figure 8). Multiple interrelated processes are involved in the pathological mechanisms by which a high-fat diet (HFD), especially one rich in saturated fats, contributes to the neurodegeneration, development, and progression of AD. These are discussed below.

Studies have shown that a Western-style diet, characterized by high intake of processed foods, sugar, and saturated fat, is associated with an increased risk of cognitive decline and Alzheimer’s disease. In contrast, a diet rich in fruits, vegetables, whole grains, and lean protein sources may help promote a healthy gut microbiome and reduce the risk of cognitive decline. By making informed dietary choices, individuals may be able to reduce their risk of developing Alzheimer’s disease and promote overall brain health. The Western-style diet is defined by a high intake of saturated fats, refined sugars, processed foods, red and processed meats, and sugary beverages, alongside a low consumption of fruits, vegetables, whole grains, nuts, and dietary fiber. This dietary pattern is prevalent in many industrialized nations and has become increasingly common worldwide due to the widespread availability of ultra-processed foods and shifts in food production and consumption habits. Over the long term, adherence to a Western diet has profound consequences for human health. The Western diet’s departure from traditional nutritional models has led to various health challenges, including obesity, diabetes, heart disease, and cancer, largely through mechanisms involving chronic low-grade inflammation, metabolic dysfunction, and oxidative stress.

Emerging evidence suggests that one of the key mechanisms linking the Western diet to AD is through its detrimental impact on the gut microbiome. Diet-induced microbial dysbiosis alters the composition and metabolic function of gut bacteria, reducing the production of beneficial metabolites such as SCFAs and increasing the generation of harmful compounds like LPS and TMAO. These changes compromise intestinal barrier integrity, leading to a “leaky gut” that allows bacterial products to enter systemic circulation. The resulting systemic inflammation and immune activation further impair the BBB, facilitating the entry of neurotoxic substances into the brain (Figure 9).

Within the central nervous system, these inflammatory processes activate microglia and astrocytes, shifting them toward a pro-inflammatory phenotype. Chronic neuroinflammation contributes to a hallmark of AD pathologies, including the accumulation of misfolded Aβ plaques and tau hyperphosphorylation, which lead to the formation of neurofibrillary tangles. Additionally, oxidative stress induced by mitochondrial dysfunction and pro-oxidant metabolites accelerates neuronal damage and synaptic loss.

The Western diet also contributes to deficits in essential nutrients, such as B vitamins, omega-3 fatty acids, antioxidants, and polyphenols, which are crucial for maintaining neuronal health and preventing cognitive decline. In contrast, adherence to a diet rich in whole, unprocessed foods, such as the Mediterranean or DASH diet, has been associated with a more diverse and balanced gut microbiota, improved metabolic outcomes, and reduced risk of cognitive impairment and AD.

In summary, the Western-style diet promotes a cascade of pathophysiological events—gut dysbiosis, systemic inflammation, BBB disruption, neuroinflammation, and protein misfolding—that converge to drive the onset and progression of Alzheimer’s disease. Adopting healthier dietary patterns may offer a promising preventive strategy to maintain cognitive function and reduce AD risk.

The oral microbiota occupies an extremely important position within the human microbiome and is the second-largest microbiota in humans after that in the gut (Fak et al., 2015). There is new scientific evidence recently published that aside from the gut microbiome, oral microflora is also able to influence brain functions (Orr et al., 2020). Numerous studies have shown that periodontal disease is associated with neurodegeneration and cognitive decline (Kamer et al., 2008; Cerajewska et al., 2016; Wang et al., 2019). In a mouse study, long-term consumption of a high-sugar diet altered gut microbiota composition, increasing harmful Firmicutes and decreasing beneficial Bacteroidetes, which is associated with gut barrier disruption (Alasmar et al., 2023). Another study using rats fed high-fructose diets showed increased gut permeability, endotoxemia, and hepatic lipid accumulation, linking sugar intake to intestinal barrier dysfunction and systemic inflammation (Ochoa-Repáraz and Kasper, 2014). In humans, excessive sugar intake promotes microbial dysbiosis in the oral microbiome by lowering pH and providing fermentable substrates that favor acidogenic and pathogenic bacteria such as Porphyromonas gingivalis and Streptococcus species. This leads to reduced microbial diversity and an altered biofilm structure conducive to periodontal inflammation. Dysbiosis in the gut similarly disrupts barrier integrity, increasing intestinal permeability (leaky gut) and allowing endotoxins to enter circulation while reducing beneficial SCFA-producing microbes. This microbial disruption drives chronic systemic inflammation, which may exacerbate neuroinflammatory and metabolic conditions.

The paths through which oral and intestinal microbiota enter the CNS include translocation via the bloodstream and lymphatic system following increased intestinal permeability, direct neural pathways such as the vagus nerve, and disruption of the BBB through inflammatory mediators. These routes allow microbial components and metabolites to trigger neuroinflammation and modulate CNS function, forming the basis of the oral–gut–brain axis communication network.

Oral bacterial species and their products can affect the brain either directly through neural pathways such as the trigeminal, olfactory, and facial nerves, as well as via the circulating bloodstream, or indirectly through disturbances in the gut microbiota that promote systemic inflammation and neuroinflammatory responses (Figure 10). Meanwhile, gut microbiota and their products affected the brain either directly through the enteric nervous system or indirectly through mediating systemic inflammation. Both direct and indirect effects from oral and intestinal microbiota contributed to microglia-mediated neuroinflammation, resulting in AD-related pathologies.

Emerging research has identified several microorganisms that may play a role in the development and progression of AD. Among them, oral pathogens such as P. gingivalis (Huang et al., 2025b), a key bacterium in periodontal disease, have been found in the brains of AD patients, suggesting a potential link between chronic oral infection and neurodegeneration. Fusobacterium sp. Also has well-documented roles in dysbiosis and systemic inflammation. This bacterium, particularly Fusobacterium nucleatum, is a well-documented contributor to microbial dysbiosis and systemic inflammation. It promotes inflammation by disrupting the intestinal epithelial barrier, inducing pro-inflammatory cytokines, such as IL-1β, IL-6, IL-17F, and TNF-α, and activating signaling pathways including NF-κB and the IL-17F axis (Zheng et al., 2025). Additionally, it modulates immune responses by promoting macrophage polarization toward the pro-inflammatory M1 phenotype, further compromising mucosal barrier integrity (Li et al., 2025).

Moreover, important pathogenic factors include LPS, gingipains, and TMAO. Additionally, herpes simplex virus type 1 (HSV-1), a common neurotropic virus, has been implicated in AD due to its ability to establish latent infections in the nervous system and reactivate under stress or immunosuppression. Certain strains of gut bacteria, including E. coli and B. fragilis, may also contribute to cognitive decline by influencing systemic inflammation and producing neurotoxic metabolites. These microorganisms, through Various direct and indirect pathways can trigger neuroinflammation, promote Aβ(Aβ) accumulation, and impair neuronal function, key processes involved in the pathogenesis of AD. Several microbial species, originating from both the oral cavity and the gut, have been identified in brain tissue or cerebrospinal fluid of patients with AD. For instance, P. gingivalis, a predominant periodontal pathogen, has been detected in the hippocampal and cortical regions of AD patients, correlating with classic AD-like pathology such as neuroinflammation, neurodegeneration, tau phosphorylation, and the formation of both intracellular and extracellular Aβ plaques and neurofibrillary tangles. Similarly, Treponema denticola, another oral spirochete, has been found in higher concentrations in the brain tissues of AD patients compared to healthy controls, suggesting a potential association between spirochetes and cognitive impairment (Li et al., 2024).

In addition to oral microbiota, gut microbiota dysbiosis has been implicated in AD pathogenesis. Alterations in the gut microbiota are associated with elevated levels of inflammatory cytokines, oxidative stress, and neurotoxicity in the brains of both AD patients and animal models. Gut microbes release a range of neuromodulatory metabolites, including SCFAs, which can cross the BBB and influence brain function. However, enteric dysbiosis leads to attenuated SCFA generation, resulting in neurological dysfunction and disease (Yang et al., 2024). Several microbial species, originating from both the oral cavity and the gut, have been identified in the brain tissue or cerebrospinal fluid of patients with AD (Tables 1, 2). These microorganisms are increasingly recognized as potential contributors to disease progression by disrupting immune homeostasis, crossing the blood–brain barrier, and influencing the gut–brain axis.

Future research on diet and AD should focus on elucidating the precise molecular and cellular mechanisms through which dietary patterns influence neurodegeneration. This includes deeper investigation into how specific nutrients and bioactive compounds modulate neuroinflammation, amyloid-beta accumulation, tau pathology, oxidative stress, and mitochondrial function in the aging brain. There is growing interest in the role of the gut microbiome as a mediator of diet’s effects on brain health, including how diet-induced microbial shifts affect gut barrier integrity, systemic inflammation, and the microbiota–gut–brain axis in AD progression.

The lack of causal treatment for Alzheimer’s disease is mainly due to the unknown disease etiology. Currently, there are several hypotheses regarding the etiology of Alzheimer’s disease, e.g., amyloid, ischemic, or hygiene theory, which attempt to explain the mechanism of development of Alzheimer’s disease, but none of these hypotheses fully explain the disease’s origin. Currently, the causative agents of this disease are based on many universally known mechanisms of neurodegeneration, including dysregulation of calcium homeostasis, abnormal accumulation of amyloid and dysfunctional tau protein, imbalance of neurotransmitters, necrotic and apoptotic neuronal death, disappearance of synapses, neuroinflammation with pathological microglia and astrocyte activation in the brain, white matter changes, and finally, brain atrophy. Recent studies strongly suggest that gut and oral microbiome are capable of modulating the neurochemical and neurometabolic signaling pathways of the brain through the formation of a two-way communication axis involving the endocrine and immune systems and contribute to the development of neuron inflammation and neurodegeneration. In turn, there is a strong correlation that exists between AD and the type of diet and food ingredients. Consequently, oral- and intestinal-specific bacterial species and their products, considered potential biomarkers for the prevention and clinical diagnosis of AD, can be modulated by a healthy diet and probiotic bacteria. Emerging evidence highlights the significant role of diet in modulating these pathological processes, particularly through its impact on the gut microbiome and systemic inflammation. High-fat, Western-style diets, characterized by high saturated fats, refined sugars, and low fiber, have been associated with gut dysbiosis, increased neuroinflammation, and exacerbation of Alzheimer’s pathology, including Aβ aggregation and tau hyperphosphorylation. Conversely, dietary patterns such as the Mediterranean diet, rich in antioxidants, polyunsaturated fatty acids, and anti-inflammatory components, have demonstrated protective effects against cognitive decline and neurodegeneration, potentially by preserving gut microbiota balance and reducing systemic and neuroinflammation. Therefore, understanding the influence of specific dietary patterns on neuroimmune mechanisms and gut–brain axis communication is critical for developing preventive and therapeutic strategies targeting Alzheimer’s disease. Integrating dietary interventions with modulation of the gut microbiome represents a promising avenue for mitigating disease progression and improving cognitive outcomes in at-risk populations.

The author(s) declared that financial support was not received for this work and/or its publication.

SM: Conceptualization, Validation, Visualization, Writing – original draft, Writing – review & editing. MK: Investigation, Writing – original draft. MAM: Formal analysis, Methodology, Validation, Writing – original draft. MMo: Resources, Validation, Writing – original draft. AM: Formal analysis, Validation, Visualization, Writing – review & editing.

The author(s) declared that this work was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

The author(s) declared that generative AI was used in the creation of this manuscript. Generative AI was used in the preparation of some illustrative figures (2, 4, 5, 7, and 8) based on the information and data provided by the authors.

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