Gut Microbiota and Alzheimer’s Disease: The Role of the Gut–Brain Axis in Cognitive Decline

Claudia Méndez Rodríguez analyzes gut microbiota and Alzheimer’s disease, highlighting the role of the microbiota–gut–brain axis in neurological health. The article explores how dysbiosis and neuroinflammation shape the relationship between gut microbiota and cognitive decline for early diagnosis and new therapeutic approaches.

Gut microbiota and Alzheimer’s disease are connected through the microbiota–gut–brain axis, a bidirectional system that regulates brain activity and cognitive status.

Dysbiosis and neuroinflammation associated with aging increase intestinal permeability and the accumulation of beta-amyloid in the brain. This relationship between gut microbiota and cognitive decline makes it possible to use specific bacteria as biomarkers for the early diagnosis of Alzheimer’s disease (AD) and mild cognitive impairment (MCI).

Introduction

Aging is associated with cognitive changes that may be part of the normal process or related to neurodegenerative conditions. Among them, Alzheimer’s disease is the most common cause of dementia and is characterized by progressive deterioration of cognitive functions. In recent years, interest has grown in the possible role of gut microbiota in the etiology and progression of this neurodegenerative disease, owing to the influence of the microbiota–gut–brain axis.

In this context, this article reviews normal and pathological aging, Alzheimer’s disease (AD), and the possible relationship between gut microbiota and cognitive decline.

Normal and pathological aging

In normal aging, there is a decline in cognitive functions without indicating pathology: lower performance is seen in visuoconstructive, procedural, and verbal memory, along with cognitive and motor slowing, impairment of executive components (working memory, cognitive flexibility, and semantic and action fluency), premotor functions, visuoconstructive, visuoperceptual, and visuospatial abilities, and naming (García-Cabello, et al., 2021; Junqué y Barroso, 2009; Machado et al., 2018).

However, in pathological aging, cognitive functions are particularly compromised, so that cognitive performance is well below the mean for the corresponding age group. Several stages can be distinguished according to the level of cognitive impairment:

• subjective cognitive decline (SCD), characterized by the patient’s subjective cognitive complaints without evidence of cognitive impairment on neuropsychological assessment;
• mild cognitive impairment (MCI), in which cognitive impairment is present while functional capacity is preserved;
• and dementia of any type, in which there is substantial cognitive impairment together with loss of functional capacity (Junqué y Barroso, 2009).

Alzheimer’s disease (AD)

Alzheimer’s disease is a neurodegenerative disease in which cognitive functions (memory, language, attention, visuospatial and visuoconstructive functions, and executive functions) and behavior are impaired compared with a previous level of normal functioning, as established through a neuropsychological assessment protocol (Atri, 2019; Junqué y Barroso, 2009).

More specifically, Alzheimer’s disease involves insidious, slow, and progressive cognitive decline due to the presence of amyloid plaques and neurofibrillary tangles, which are biomarkers of the pathology (Jagust, 2018). Regarding the stages, following the classification mentioned above, there are mild cognitive impairment (MCI) due to Alzheimer’s disease and dementia due to Alzheimer’s disease.

The etiology of Alzheimer’s disease is multifactorial:

• One factor is the genetic basis. Different gene mutations are associated with the onset of the pathology: Amyloid Precursor Protein (APP), presenilin-1 (PSEN1), presenilin-2 ([PSEN2]; Viña y Sanz-Ros, 2018), and Apolipoprotein E ([APOE]; Khodabakhsh et al., 2021).

• The environmental factor based on epigenesis (Angelucci et al., 2019).
• Age (Megur et al., 2020).
• Immune system dysfunction (Ahmad et al., 2019).

Sociodemographic variables such as gender, education, lifestyle, comorbidities with other conditions, and psychiatric symptoms (depression or anxiety) are also relevant (Megur et al., 2020).

According to the Spanish Society of Neurology (SEN), Alzheimer’s disease affects approximately 800,000 people in Spain, with an average of 40,000 new cases diagnosed each year. In addition, 80% of all people in the mild stages remain undiagnosed, and between 30% and 40% of all cases have not been diagnosed (Instituto Nacional de Estadística, 2022; Pérez, 2019).

Relationship between the microbiota and Alzheimer’s disease (AD)

In recent years, it has been proposed that the gut microbiota may play a role in the etiology of Alzheimer’s disease and may even act as a potential biomarker, although the evidence is still limited and the mechanisms involved are not fully understood (Megur et al., 2020; Fink y Tamgüney, 2021; Sheng et al., 2023).

Research findings are heterogeneous: some studies have found differences in bacterial proportions and diversity between patients with Alzheimer’s disease and healthy individuals (Nagpal et al., 2019; Vogt et al., 2017; Yıldırım et al., 2022), whereas others have found no significant differences in gut microbiota between the two groups (Cirstea et al., 2022).

Interest in this relationship is based on the existence of the microbiota–gut–brain axis, a bidirectional communication system between the gut and the central nervous system, mediated in part by the vagus nerve, which allows the microbiota to influence brain activity, neurotransmitter production, and cognitive status (Megur et al., 2020; Faulin y Estadella, 2023; Ghosh et al., 2022).

Composition and functions of the gut microbiota

The gut microbiota is made up of numerous microorganisms organized into different taxonomic levels, with the main phyla being Firmicutes, Bacteroidetes, Actinobacteria, Proteobacteria, Fusobacteria, and Verrucomicrobia, and a number of genes far greater than that of the human genome (Queiroz et al., 2022). Among them, Firmicutes and Bacteroidetes are the most abundant and participate in essential metabolic processes such as carbohydrate metabolism, energy production, and amino acid metabolism (Ottman et al., 2012).

The microbiota performs key functions in the body, such as regulating the immune system, metabolizing nutrients, producing vitamins, and protecting against pathogens (Faulin y Estadella, 2023). However, aging brings changes in its composition, with a decrease in beneficial bacteria such as Lactobacillus, Bifidobacterium, Faecalibacterium , or Roseburia, and an increase in others such as Enterobacteriaceae or Clostridium (Queiroz et al., 2022; Ghosh et al., 2022). This imbalance, known as dysbiosis, can increase intestinal permeability, activate the immune system, and trigger systemic inflammatory processes (Leblhuber et al., 2021; Escobar et al., 2022).

Gut microbiota, cognitive functions, and biomarkers

Gut dysbiosis may promote neuroinflammation and contribute to the accumulation of β-amyloid (Aβ), one of the main pathological markers of Alzheimer’s disease (Tan et al., 2021; Faulin y Estadella, 2023). Some studies have also found relationships between gut microbiota and functional brain connectivity, observing associations between bacteria such as Bacteroides and Prevotella and brain regions involved in processes such as attention, recognition, episodic memory, and visual or linguistic processing (Cooke et al., 2022).

Because neuroinflammation plays a key role in the pathophysiology of Alzheimer’s disease and mild cognitive impairment (MCI) (Barrio y Martín-Monzón, 2022), the study of the microbiota–gut–brain axis has been proposed as a potential avenue for preventing and treating the disease (Queiroz et al., 2022). In this regard, strategies such as dietary interventions, probiotics, or fecal microbiota transplantation could help restore the balance of the gut microbiome and improve symptoms associated with Alzheimer’s disease (Faulin y Estadella, 2023).

Likewise, the presence of β-amyloid in the intestines of patients with Alzheimer’s disease suggests that intestinal inflammation could eventually be used as an early biomarker of the disease (Molinero et al., 2023).

Scientific evidence and the microbiota–gut–brain axis

In some studies, findings show that the gut microbiota is altered in people with cognitive impairment, with differences in alpha diversity (species richness) and beta diversity (bacterial community structure) compared with healthy individuals (Ling et al., 2021; Zhuang et al., 2018; Guo et al., 2021; Liu et al., 2019; Xi et al., 2021).

Although microbial profiles were not completely consistent across studies, general patterns of changes in several bacterial groups were identified, including variations in Firmicutes, Bacteroidetes, Proteobacteria, and Verrucomicrobia (Liu et al., 2019; Ling et al., 2021; Zhuang et al., 2018). These differences partially align with previous research on the microbiota and Alzheimer’s disease (Megur et al., 2020; Nagpal et al., 2019; Vogt et al., 2017; Yadav et al., 2023; Yıldırım et al., 2022).

Likewise, certain bacteria were found to be related to cognitive functions such as memory, executive functions, language, and visuospatial abilities (Zhu et al., 2022; Cooke et al., 2022). This suggests that the gut microbiota could serve both as an indicator of cognitive performance and as a potential therapeutic target in cognitive decline associated with Alzheimer’s disease.

In addition, various microorganisms that could act as biomarkers for detecting or differentiating mild cognitive impairment (MCI) and Alzheimer’s disease (AD) were identified, including Actinomycetaceae, Erysipelotrichaceae, Faecalibacterium, Bifidobacterium , and Pseudomonas (Liu et al., 2019; Ling et al., 2021; Xi et al., 2021; Zhu et al., 2022). Some bacteria were also associated with the APOE4 gene, one of the main genetic risk factors for Alzheimer’s disease (Zhu et al., 2022; Camman et al., 2023; Khodabakhsh et al., 2021). Likewise, microorganisms with possible risk effects, such as Pseudomonas (Xi et al., 2021), and others with protective effects, such as Eubacterium (Guo et al., 2021), were identified.

On the other hand, gut dysbiosis could promote inflammatory processes and the accumulation of β-amyloid in the brain, contributing to the cognitive decline characteristic of the disease (Faulin y Estadella, 2023; Connell et al., 2022). These changes are also associated with reduced gut microbiome diversity in patients with Alzheimer’s disease compared with healthy individuals (Cirstea et al., 2022; Vogt et al., 2017; Yıldırım et al., 2022).

The gut microbiota could play an important role in the etiology and progression of Alzheimer’s disease, as it differs in richness and structure between patients with mild cognitive impairment or Alzheimer’s disease and healthy individuals, according to some studies (Ling et al., 2021; Zhuang et al., 2018). In addition, certain bacteria are associated with performance in different cognitive functions and could be used as biomarkers or therapeutic targets. These findings open new avenues for early detection and the development of preventive or therapeutic strategies based on gut microbiota modulation.

Conclusions

The gut microbiome of people with mild cognitive impairment and dementia due to Alzheimer’s disease has been observed to differ from that of healthy participants, owing to changes in the proportions of a wide range of bacteria and the broad diversity identified. Nevertheless, further studies are needed to establish a common microbiota profile in Alzheimer’s disease.

Consequently, gut microbiota is proposed as a possible novel biomarker for detecting Alzheimer’s disease and thereby increasing knowledge about the pathology. Future research should focus on studying gut microbiota as a predictive and treatment variable in Alzheimer’s disease by examining stages preceding dementia due to Alzheimer’s disease (subjective cognitive decline (SCD) and mild cognitive impairment (MCI)) as well as dementia itself, longitudinally assessing cognitive functions as thoroughly as possible using standardized neuropsychological tests, studying richness and structure within the same taxon, and correlating microbiota with cognitive and clinical variables and with the level of cognitive impairment identified across the sample groups.

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