Background: Alzheimer’s disease (AD) is characterised by abnormal protein aggregates in the brain that lead to cognitive decline. While current therapies only treat symptoms, disease-modifying treatments are urgently needed. Studies suggest that the composition of the microbiota is altered in people with AD, suggesting a link between gut bacteria and AD-related brain changes. Summary: In our narrative review, we explore various microbial interventions, such as faecal microbiota transplantation, probiotics, and diet, as powerful potential treatments. Studies suggest changes in microbiota composition following these interventions, with some beneficial effects on cognitive function. However, the mechanism of action of these microbial interventions is still unknown. Key Message: Our aim was to highlight the importance of personalised approaches, taking into account individual metabolic and microbiome profiles. We try to address gaps in current research and emphasise the need for microbiota analysis at different stages of the disease and its integration with clinical parameters and lifestyle information for a comprehensive understanding of AD progression (summarised in online suppl. Fig. 1; for all online suppl. material, see https://doi.org/10.1159/000535869).

The gut-microbiota-brain axis is the bidirectional communication system that exists between the gastrointestinal (GI) tract, its resident microbiota, and the brain. It relies on a network of signalling pathways, including hormonal, immune, and neural connections, to enable constant communication between these organs and influence various aspects of health.

The gut microbiota, the diverse community of bacteria, viruses, fungi and other microorganisms that live in the digestive tract, plays a key role in breaking down food, producing essential nutrients, protecting against infection and regulating the immune system. In addition, some of its members release metabolites and signalling molecules, such as the neurotransmitters serotonin, histamine and dopamine, and metabolites such as short-chain fatty acids, tryptophan, and GABA. Collectively, these can influence brain function and have anti-inflammatory and potentially neuroprotective properties [1].

In addition, the gut microbiota can modulate the immune system, influence neuroinflammation, and potentially contribute to the development of neurological disorders such as Alzheimer’s disease (AD) and Parkinson’s disease. In addition, disturbances in the gut microbiota, often caused by factors such as diet, stress, antibiotics, or infections, can lead to dysbiosis, an imbalance that can exacerbate disease states. Dysbiosis can lead to chronic inflammation in the gut, known as leaky gut syndrome. This inflammation can trigger a systemic immune response, including activation of microglia, the innate immune cells found in the brain. Chronic neuroinflammation is a hallmark of AD and is thought to contribute to neuronal damage.

The brain can also influence the gut and its microbiota through the release of stress hormones such as cortisol, which can alter gut motility and microbial composition. This can lead to a feedback loop where stress negatively affects the gut, and in turn gut dysbiosis can exacerbate certain neural conditions. Dysbiosis and associated inflammation in the gut can compromise the blood-brain barrier, allowing harmful substances, and immune cells to enter the brain more easily. This breach of the blood-brain barrier may exacerbate neuroinflammation and contribute to the progression of neurodegenerative diseases.

In this review, we focus on the gut-brain axis in AD, as it is the only neurodegenerative disease in the top ten causes of death [2]. AD is the most common form of dementia, potentially accounting for 60–70% of all cases. More than 55 million people worldwide are currently living with dementia, and more than 60% of them live in low- and middle-income countries. There are nearly 10 million new cases of dementia each year. In 2019, dementia will have a staggering global economic cost of US $1.3 trillion, with approximately half of this cost attributed to caregivers.

The involvement of the gut-brain axis in AD is an emerging area of research that suggests a potential link between the gut microbiota and the development or progression of this neurodegenerative disorder. We believe that a better understanding of the role of the microbiota in the pathogenesis of AD will help understand how to intervene and improve various aspects of the lives of patients and their carers. Here, we will focus mainly on studies in patients, highlighting the open questions in the field.

AD is characterised by the accumulation of abnormal protein aggregates in the brain, due to alterations in the cleavage of amyloid precursor protein (APP) and the production of the APP fragment beta-amyloid (Aβ) in the extracellular compartment, and the aggregation of hyperphosphorylated tau protein in the intracellular compartment of neurons, leading to a reduction in synaptic strength, synaptic loss, and neurodegeneration. These brain changes lead to a progressive decline in memory, thinking, learning, and organisational skills, affecting a person’s ability to carry out basic daily activities. Currently, available therapies treat only the symptoms of the disease with modest, clinically measurable effects on cognition, but disease-modifying therapies are sorely lacking and urgently needed. AD is a complex disease and its development is associated with several risk factors: age (over 65 years), family history, genetics, such as carrying at least one APOEε4 allele [3] and TREM2 genetic variants (Arg47His, Arg62His, and Asp87Asn), and mutations in genes such as APP, presenilin 1 (PSEN1), and presenilin 2 (PSEN2) [4‒6].

Cardiovascular risk factors and an unhealthy lifestyle have been associated with an increased risk of dementia, but not of AD [7‒9]. AD develops in stages: an early, preclinical stage without symptoms, a middle stage of mild cognitive impairment, and a final stage characterised by symptoms of dementia. The preclinical stage is characterised by brain changes, including amyloid deposition and other neuronal, microglial, and astroglial changes, which may be present without significant overt clinical symptoms for 15–25 years before the diagnosis of AD. Mild cognitive impairment (MCI) is characterised by symptoms of memory and/or other thinking problems that are greater than normal for the person’s age and education, but which do not interfere with the person’s independence. People with MCI may or may not progress to Alzheimer’s dementia. People with MCI may or may not progress to Alzheimer’s dementia, the final stage of the disease, which is characterised by symptoms of Alzheimer’s, such as memory loss, word-finding difficulties and visual/spatial problems that are severe enough to affect a person’s ability to function independently [10]. The complications that accompany the advanced stages of the disease, such as dehydration, malnutrition, or infection due to severe loss of brain function, are the causes that can lead to the death of people with AD. In 2019, the WHO published the first guidelines for reducing the risk of cognitive decline and dementia [11]. However, to date, for some environmental and lifestyle factors (e.g., physical activity, diet, overweight or obesity, tobacco and alcohol use, high blood pressure, and diabetes), there is no clear evidence that they are effective in reducing dementia. Nevertheless, several landmark studies have tried to understand whether certain environmental and lifestyle interventions can be combined with pharmacological therapies to personalise the various approaches to treating AD.

Microbiota and AD

Recent studies have suggested that the gut microbiota may influence the development and progression of AD (summarised in Table 1). Some gut bacteria can also produce amyloid proteins similar to those found in the brain, potentially contributing to the formation of amyloid-beta plaques [12]. More specifically, bacterial-derived amyloids such as curli protein, tau, Aβ, α-synuclein, and prion proteins have been identified as potential initiators of amyloid-β peptide aggregation in AD. These amyloids are produced by several bacterial strains, including curli in Escherichia coli, TasA in Bacillus subtilis, CsgA in Salmonella typhimurium, FapC in Pseudomonas fluorescens, and phenol-soluble modules in Staphylococcus aureus. They contribute to the development of AD by promoting the misfolding of Aβ oligomers and fibrils [12] Researchers have observed changes in the composition of the gut microbiota in individuals with AD, including changes in the abundance of specific bacterial species. The stool microbial profile of individuals with symptomatic AD (n = 25) shows decreased abundance of Firmicutes and Actinobacteria and increased abundance of Bacteroidetes compared to controls (n = 25). Within the Firmicutes, the families Ruminococcaceae, Turicibacteraceae, and Clostridiaceae were all less abundant in patients with AD [13]. In another study comparing 43 patients with AD and 43 age- and sex-matched cognitively normal controls, the composition of the gut microbiota differed between the two groups in terms of the abundance of Bacteroides, Actinobacteria, Ruminococcus, Lachnospiraceae, and Selenomonadales.

Table 1.

Summary of the latest discoveries and ongoing studies on the microbiota in patients suffering from AD: in this table, we highlight the main results regarding the intestinal microbiota in patients with AD

StudySexAgeResultsReference
Cohort Study Control group: females = 72% (18/25) Age, years, mean±SD The families Ruminococcaceae, Turicibacteraceae, and Clostridiaceae were all ↓ abundant in AD patients Vogt et al. [13] (2017) 
US cohort of 25 controls and 25 Patients with AD AD group: females = 68% (17/25) Control group = 69.3±7.5 
AD group = 71.3±7.3 
Cohort study Control group: females = 20 (46.5%) Age, years (SD) ↓ abundance of Bacteroidetes, ↑ abundance of Actinobacteria in AD patients Zhuang et al.[14](2018) 
Chinese cohort of 43 controls and 43 patients with AD AD group: females = 20 (46.5%) CN group = 69.72 (9.24) ↑ abundance Ruminococcus, ↓ abundance of Lachnospiraceae, and ↓ abundance of Selenomonadales in AD patients 
AD group = 70.12 (8.78) 
Observational study Control group: females = 35 (81.4%) Age in years, median (IQR) ↑ amounts of genera like Christensenellaceae R-7 group, Prevotella, Alloprevotella, Eubacterium coprostanoligenes group, Ruminococcus, Flavobacterium, Ohtaekwangia, Akkermansia, Bacteroides sp. Marseille-P3166 Kaiyrlykyzy et al. [15] (2022) 
Kazakhstan cohort of 43 controls and 41 patients with AD AD group: females 30 (73.2%) Controls = 68 (61–75) ↓ amounts of genera like in Levilactobacillus, Lactiplantibacillus, Tyzzerella, Eubacterium siraeum group, Monoglobus, Bacteroides, Erysipelotrichaceae UCG-003, Veillonella, Faecalibacterium, Roseburia, Haemophilus were observed in patients with AD 
AD = 68 (62–74) 
Case-control study CU group: females = 7 (54%) Age, years (SD) CI-AD patients respect other groups: ↑ abundance of Clostridia_UCG-014 and ↓ abundance of Moryella and Blautia; ↑ levels of LPS, CAMs, IL1β, IL6, and TNFα and ↓ IL10, ↑ brain amyloid, pTau-181, and NfL Marizzoni et al. [16] (2023) 
Italian cohort of 13 cognitively CU patients, 38 CI-NAD patients and 34 CI-AD patients CI-NAD group: females = 21 (55%) CU group = 69.6 (7.1) 
CI-AD group: females = 16 (47%) CI-NAD group = 69.8 (7.4) 
CI-AD group = 70.8 (6.1) 
Translational observational study ND group: males = 8 (15.7%) Age in years, mean (SD) AD elder group: ↑ proportions of species of BacteroidesAlistipesOdoribacter and Barnesiella and ↓ proportions of Lachnoclostridium species; ↓ proportion and prevalence of bacteria with the potential to synthesize butyrate; ↓ P-gp expression levels in vitro compared to samples from elders without dementia or with other dementia types Haran et al. [17] (2019) 
US cohort of 51 elders (47.2%) had no dementia, 24 elders (22.2%) had AD and 33 elders (30.6%) had other dementia types AD group: males = 4 (16.7%) ND = 83.0 (10.2) Another dementia elder group: ↑ proportions of species of Odoribacter and ↓ Barnesiella proportions of Eubacterium, Roseburia, Lachnoclostridium and Collinsella 
Another dementia group: males = 6 (18.2%) AD = 84.7 (8.1) 
Other dementia = 87.9 (7.9) 
Translational observational study HC group: males = 49 (42.6%) Age in years, mean (SD) Preclinical AD group: presence of Dorea formicigenerans, Oscillibacter sp. 57_20, Faecalibacterium prausnitzii, Coprococcus catus, Anaerostipes hadrus, Ruminococcus lactaris;l-arginine, l-ornithine, and 4-amino-butanoate degradation pathways Ferreiro et al. [18] (2023) 
US cohort of 115 healthy patients and 49 preclinical AD patients Preclinical AD group: males = 24 (49.0%) HC = 77.02 (5.80) Healthy Patients group: presence of Methanosphaera stadtmanae and l-glutamate degradation pathway 
Preclinical AD group = 78.96 (4.51) 
Case-control and cross-sectional study (Male/female) in Discovery Sample (ADc12) Age, mean±SD in Discovery Sample (ADc12) Discovery sample: 20 gut microbiota genera were initially identified as genetically associated with AD case group/control group Eubacterium fissicatena (protective factor) and Collinsella, and Veillonella (risk factor); 10 genera significant correlation with AD and 4 significantly associated with APOE rs429358 risk allele risk and pro-inflammatory genus Collinsella (risk factor for AD), positively correlated with the APOE rs429358 risk allele in both samples Cammann et al. [19] (2023) 
Multi-ethnic cohorts of the MiBioGen study: Case group = 443/835 Case group = 76.57±6.71 
16 European cohorts: n = 13,266 Control group = 471/822 Control group = 70.27±10.29 
1 Middle Eastern cohort: n = 481 (Male/female) in Replication Sample (GenADA) Age, mean±SD in Replication Sample (GenADA) 
1 East Asian cohort: n = 811 Case group = 339/460 Case group = 72.24±8.41 
1 American Hispanic/Latin cohort: n = 1,097 Control group = 276/502 Control group = 73.40±7.92 
1 African American cohort: n = 114 
4 cohorts of multi-ancestry individuals: n = 2,571 
Multi-ethnic cohort of the NIA/LOAD study: African-American: n = 251 and Caucasian individuals: n = 2,320 
StudySexAgeResultsReference
Cohort Study Control group: females = 72% (18/25) Age, years, mean±SD The families Ruminococcaceae, Turicibacteraceae, and Clostridiaceae were all ↓ abundant in AD patients Vogt et al. [13] (2017) 
US cohort of 25 controls and 25 Patients with AD AD group: females = 68% (17/25) Control group = 69.3±7.5 
AD group = 71.3±7.3 
Cohort study Control group: females = 20 (46.5%) Age, years (SD) ↓ abundance of Bacteroidetes, ↑ abundance of Actinobacteria in AD patients Zhuang et al.[14](2018) 
Chinese cohort of 43 controls and 43 patients with AD AD group: females = 20 (46.5%) CN group = 69.72 (9.24) ↑ abundance Ruminococcus, ↓ abundance of Lachnospiraceae, and ↓ abundance of Selenomonadales in AD patients 
AD group = 70.12 (8.78) 
Observational study Control group: females = 35 (81.4%) Age in years, median (IQR) ↑ amounts of genera like Christensenellaceae R-7 group, Prevotella, Alloprevotella, Eubacterium coprostanoligenes group, Ruminococcus, Flavobacterium, Ohtaekwangia, Akkermansia, Bacteroides sp. Marseille-P3166 Kaiyrlykyzy et al. [15] (2022) 
Kazakhstan cohort of 43 controls and 41 patients with AD AD group: females 30 (73.2%) Controls = 68 (61–75) ↓ amounts of genera like in Levilactobacillus, Lactiplantibacillus, Tyzzerella, Eubacterium siraeum group, Monoglobus, Bacteroides, Erysipelotrichaceae UCG-003, Veillonella, Faecalibacterium, Roseburia, Haemophilus were observed in patients with AD 
AD = 68 (62–74) 
Case-control study CU group: females = 7 (54%) Age, years (SD) CI-AD patients respect other groups: ↑ abundance of Clostridia_UCG-014 and ↓ abundance of Moryella and Blautia; ↑ levels of LPS, CAMs, IL1β, IL6, and TNFα and ↓ IL10, ↑ brain amyloid, pTau-181, and NfL Marizzoni et al. [16] (2023) 
Italian cohort of 13 cognitively CU patients, 38 CI-NAD patients and 34 CI-AD patients CI-NAD group: females = 21 (55%) CU group = 69.6 (7.1) 
CI-AD group: females = 16 (47%) CI-NAD group = 69.8 (7.4) 
CI-AD group = 70.8 (6.1) 
Translational observational study ND group: males = 8 (15.7%) Age in years, mean (SD) AD elder group: ↑ proportions of species of BacteroidesAlistipesOdoribacter and Barnesiella and ↓ proportions of Lachnoclostridium species; ↓ proportion and prevalence of bacteria with the potential to synthesize butyrate; ↓ P-gp expression levels in vitro compared to samples from elders without dementia or with other dementia types Haran et al. [17] (2019) 
US cohort of 51 elders (47.2%) had no dementia, 24 elders (22.2%) had AD and 33 elders (30.6%) had other dementia types AD group: males = 4 (16.7%) ND = 83.0 (10.2) Another dementia elder group: ↑ proportions of species of Odoribacter and ↓ Barnesiella proportions of Eubacterium, Roseburia, Lachnoclostridium and Collinsella 
Another dementia group: males = 6 (18.2%) AD = 84.7 (8.1) 
Other dementia = 87.9 (7.9) 
Translational observational study HC group: males = 49 (42.6%) Age in years, mean (SD) Preclinical AD group: presence of Dorea formicigenerans, Oscillibacter sp. 57_20, Faecalibacterium prausnitzii, Coprococcus catus, Anaerostipes hadrus, Ruminococcus lactaris;l-arginine, l-ornithine, and 4-amino-butanoate degradation pathways Ferreiro et al. [18] (2023) 
US cohort of 115 healthy patients and 49 preclinical AD patients Preclinical AD group: males = 24 (49.0%) HC = 77.02 (5.80) Healthy Patients group: presence of Methanosphaera stadtmanae and l-glutamate degradation pathway 
Preclinical AD group = 78.96 (4.51) 
Case-control and cross-sectional study (Male/female) in Discovery Sample (ADc12) Age, mean±SD in Discovery Sample (ADc12) Discovery sample: 20 gut microbiota genera were initially identified as genetically associated with AD case group/control group Eubacterium fissicatena (protective factor) and Collinsella, and Veillonella (risk factor); 10 genera significant correlation with AD and 4 significantly associated with APOE rs429358 risk allele risk and pro-inflammatory genus Collinsella (risk factor for AD), positively correlated with the APOE rs429358 risk allele in both samples Cammann et al. [19] (2023) 
Multi-ethnic cohorts of the MiBioGen study: Case group = 443/835 Case group = 76.57±6.71 
16 European cohorts: n = 13,266 Control group = 471/822 Control group = 70.27±10.29 
1 Middle Eastern cohort: n = 481 (Male/female) in Replication Sample (GenADA) Age, mean±SD in Replication Sample (GenADA) 
1 East Asian cohort: n = 811 Case group = 339/460 Case group = 72.24±8.41 
1 American Hispanic/Latin cohort: n = 1,097 Control group = 276/502 Control group = 73.40±7.92 
1 African American cohort: n = 114 
4 cohorts of multi-ancestry individuals: n = 2,571 
Multi-ethnic cohort of the NIA/LOAD study: African-American: n = 251 and Caucasian individuals: n = 2,320 

AD, Alzheimer’s disease; HC, healthy controls; CN, cognitively normal; CU, cognitively healthy/unimpaired; CI-NAD, cognitive impairment not due to AD; CI-AD, cognitive impairment due to AD; ND, no dementia; CAM, cell adhesion molecule; pTau, plasma phosphorylated tau; NfL, neurofilament light chain; P-gp, P-glycoprotein.

In a similar study conducted in Kazakhstan with 41 AD patients and 43 healthy controls (both groups were over 55 years of age), an increase in genera such as Christensenellaceae R-7 group, Prevotella, Alloprevotella, Eubacterium coprostanoligenes group, Ruminococcus, Flavobacterium, Ohtaekwangia, Akkermansia, Bacteroides sp. Marseille-P3166, and a decrease in Levilactobacillus, Lactiplantibacillus, Tyzzerella, Eubacterium siraeum group, Monoglobus, Bacteroides, Erysipelotrichaceae UCG-003, Veillonella, Faecalibacterium, Roseburia, Haemophilus were observed in patients with AD. They correlated the presence of Acidimicrobiia, Faecalibacterium, Actinobacteria, Oscillospiraceae, Prevotella and Christensenellaceae R-7 with adiponectin, but also the Christensenellaceae R-7 group and Acidobacteriota with total bilirubin, and Firmicutes, Acidobacteriales, Castellaniella alcaligenes, Lachnospiraceae, Christensenellaceae, and Klebsiella pneumoniae with C-reactive protein in the blood of patients with AD. Using predictive metagenomic analysis, potential functional changes in the gut microbiome of participants with AD were observed, with upregulation of genes involved in metabolism and biosynthesis, such as oxidative phosphorylation, carbohydrate metabolism, amino acid metabolism, and downregulation of genes involved in protein transduction, cell signalling and motility, including bacterial chemotaxis, secretion systems, and signalling systems [13].

The microbiota of 84 individuals aged 50–85 years (cognitively healthy/unimpaired (n = 12), cognitively impaired not due to AD (n = 37), and cognitively impaired due to AD (n = 34)) was analysed [16]. Together with the microbiota composition analysis, additional parameters of the gut-brain axis, the amyloid cascade, immune and endothelial cell markers and bacterial products were analysed. Patients with amyloid-dependent cognitive impairment had higher abundance of Clostridia_UCG-014 and lower abundance of Moryella and Blautia; increased levels of LPS, upregulation of cell adhesion molecules, IL1β, IL6, and TNFα, and downregulation of IL10; increased brain amyloid, plasma phosphorylated tau (pTau-181, a marker of tau pathology), neurofilament light chain (a marker of neurodegeneration) compared to the other groups. However, it is still not understood exactly when changes in microbial communities or changes in certain metabolic or inflammatory parameters occur and whether these may play a causative role in the development of AD.

Only a few studies have attempted to address this issue. One of these prospectively enrolled 108 elderly nursing home residents and followed them for up to 5 months, collecting longitudinal stool samples for metagenomic sequencing and in vitro functional assays of intestinal epithelial cell expression of P-glycoprotein, a critical mediator of intestinal homeostasis. Compared with no dementia, elderly people with AD had increased proportions of Bacteroides, Alistipes, Odoribacter, and Barnesiella species and decreased proportions of Lachnoclostridium species, whereas elderly people with other types of dementia had increased proportions of Odoribacter and Barnesiella species and decreased proportions of Eubacterium, Roseburia, Lachnoclostridium, and Collinsella species. They also described that faeces from elderly people with AD can induce lower levels of P-glycoprotein expression in vitro compared to samples from elderly people without dementia or with other types of dementia, and that the microbiome of elderly people with AD shows a lower proportion and prevalence of bacteria with the potential to synthesise butyrate, as well as higher abundances of taxa known to cause pro-inflammatory states. The machine learning approach revealed microbial predictors of both preclinical AD status and clinical AD status, such as Alistipes, Barnesiella, and Odoribacter, whereas different Bacteroides species are highly associated with preclinical AD and healthy groups (Bacteroides intestinalis and Bacteroides caccae, respectively) [17, 18]. Recently, the presence of some bacterial species such as Dorea formicigenerans, Oscillibacter sp. 57_20, Faecalibacterium prausnitzii, Coprococcus catus, Anaerostipes hadrus, Ruminococcus lactaris has also been associated with a preclinical AD status, characterised by a clinical dementia score of 0 but positive for the presence of Aβ plaques. Conversely, Methanosphaera stadtmanae was associated with healthy status. Pathway analysis suggested that l-arginine, l-ornithine, and 4-amino-butanoate degradation pathways were associated with preclinical AD status, whereas l-glutamate degradation was associated with healthy status.

In addition, a study explored genetic links between gut microbes and AD using Polygenic Risk Score [PRS] analyses) [19]. Initial analyses in a discovery sample were validated in a replication sample and a meta-analysis. In the initial discovery sample cohort (1,278 cases and 1,293 controls), a total of 20 gut microbiota genera were identified as having genetic associations with AD case/control status. Three of these identified genera (Eubacterium fissicatena as a protective factor, Collinsella and Veillonella as a risk factor) showed independent significance when validated in a secondary replication sample cohort (799 cases and 778 controls) [19]. Subsequent meta-analysis of both the discovery and replication cohorts confirmed a significant association of ten genera with AD. Notably, four of these genera showed a statistically significant association with the APOE rs429358 risk allele, consistent with their respective roles as protective or risk factors associated with AD. Interestingly, the pro-inflammatory genus Collinsella, identified as a risk factor for AD, showed a positive correlation with the APOE rs429358 risk allele in both the discovery and replication samples. This suggests the potential use of these genera as biomarkers and targets for AD therapies, as the host genetic elements influencing the prevalence of the ten genera are significantly associated with AD. These findings suggest a potential role for pro-inflammatory gut microbiota in promoting AD development through interaction with APOE [19]. However, larger data sets and functional studies are needed to further understand their causal relationships.

Microbial Interventions in AD

Given the growing evidence of microbial involvement or influence in patients with cognitive impairment or dementia, several studies and trials have begun in recent years to investigate microbial interventions such as faecal microbiota transplantation (FMT) or probiotics as potential treatments for patients with AD (summarised in Table 2). For example, FMT has been suggested to have a beneficial effect on cognition in patients with dementia, with suggested changes in microbiota composition and various metabolic pathways before and after FMT [20].

Table 2.

Summary of the latest discoveries and ongoing studies on the microbial interventions in AD: in this table, we highlight the main results regarding the microbial interventions in patients with AD

StudySexAge, yearsInterventionsDrug TreatmentsDurationResultsMissing PointsRelevanceReference
Randomised controlled and longitudinal clinical study FMT group: females = 8 (80%) Age, years, median (IQR) FMT Antibiotic treatments all subject were treated with 1-2 cycles of oral antibiotics before FMT NA FMT Group: MMSE and CDR-SB of FMT improved compared to antibiotics; ↑ enrichment of Proteobacteria and Bacteroidetes; ↑ Alanine, aspartate, and glutamate metabolism pathways after FTM Comprehensive cognitive assessment; assessment of metabolic status (lipid profiles, glucose homeostasis, and inflammatory markers); mechanistic investigations; Assessment of AD markers FMT may be a potential treatment for cognitive decline in patients with CDI; link healthy gut to cognitive function; However, the primary goal of the FMT was to treat CDI and no causality was shown regarding the improvement of observed cognitive functions Park et al. [20] (2022) 
Republic of Korea cohort of 10 patients with severe CDI and 10 control patients Control group: females = 8 (80%) FMT group = 76 (63–90) 2 patients: oral vancomycin alone 
Control group = 77 (62–91) 2 patients: metronidazole alone 
6 patients: vancomycin+metronidazole 
Medication for Dementia Donepezil, 7 in FMT Group and 6 in Control Group 
Memantine, 1 in FMT Group and 2 in Control Group 
Donepezil + Memantine, 1 in FMT Group and 1 Control Group 
Case study Male 82-year-old FMT Antibiotic Treatments Vancomycin, Vancomycin and Metronidazole, Fidaxomicin and Bezlotoxumab NA Improvements in the patient's mental acuity and affect Comprehensive cognitive assessment: assessment of metabolic status (lipid profiles, glucose homeostasis, and inflammatory markers); mechanistic investigations; assessment for AD markers First report of FMT leading to rapid and sustained improvement in AD symptoms; FMT may be a safe and effective treatment for cognitive decline in patients with CDI Hazan et al. [21] (2020) 
US case Report of 1 CDI patient Medication for Dementia MMSE normal cognition. Memory improvement, without progression of symptoms, continued for up to 6 months However, only case report of improvements as a secondary effect to FMT as CDI treatment; not controlled 
Memantine (28 mg once daily), donepezil (23 mg once daily) 
Case study Female 90-years-old FMT Antibiotic treatments: Vancomycin (oral, 125 mg/qid) NA After second FMT: GI distress improved with negative CDI stool results and improvement in mood. After FMT: ↑ Bacteroidales, Bacteroidia, Tannerellaceae, and Actinobacteria are more abundant Larger, diverse sample population; control and placebo group limited microbiota analysis; long-term follow-up; metabolomic analysis Report of FMT leading to significant improvement in cognitive function in AD patient with advanced dementia; FMT may be a safe and effective treatment for cognitive decline in AD Park et al. [22] (2021) 
South Korea Case Report of 1 CDI patient Metronidazole (oral, 500 mg/tid) However, only case report of improvements as a secondary effect to FMT as CDI treatment; not controlled 
Medication for dementia 
Donepezil (10 mg/5 years duration) 
Preliminary study 3 Females Age year FMT N/A (Exclusion criteria: No history of taking probiotics and antibiotics within 1 month of the study) Every second week for 180 days MCI patients after FMT So far no long-term follow-up on effects of FMT on age-related cognitive impairments Pilot clinical trial on the effect of FMT treatment specifically on patients with MCI; FMT may improve or maintain cognitive function in patients with MCI; FMT may appears to be safe, with no serious adverse events reported within 6 months of FMT; FMT may influence the gut microbiota composition and reduce the leaky gut syndrome, potentially contributing to cognitive improvements Chen et al. [26] (2023) 
Chinese Cohort of 3 females (FTD, MCI and AD) and 2 males (AD and MCI) 2 Males Female: 68 years old, 77 years old and 54 years old ↑ slight in executive function: fluency, orientation, memory, abstraction, delayed recall, visual perception, naming, and attention compared with before treatment FMT had an effect on serum metabolomics 
Male: 74 years old and 80 years old ↓ daily independent activities: eating, dressing, bathing, cooking, going to and from the toilet, walking around the room, urine and defecation control, washing etc. However, no causality was shown 
↑ faecal relative abundance of Bacteroides than that before transplantation. AD patients after FMT: stable scores, ↓ faecal relative abundance of Bacteroides than that before transplantation. FTD Patient: ↓ faecal relative abundance of Bacteroides of patients with AD and FTD after FMT was lower than that before transplantation 
Randomized Gender (%) Age, years (SD) PB N/A 12 weeks PB treatment: positive effects on the patients MMSE score, hs-CRP, insulin metabolism marker and triglyceride levels Lack of executive function and language assessment; limited metabolic status assessment and lack of inflammatory markers and other relevant metabolic parameters; no gut microbiota analysis and no assessment for AD markers First randomized, double-blind, and controlled trial investigating the effects of probiotic supplementation on cognitive function and metabolic status in AD; demonstrates potential benefits of PB on improving cognitive function and some metabolic parameters in AD patients Akbari et al. [27] (2016) 
Controlled Trial PBO group: males = 6 (20.0%); females = 24 (80.0%) PBO group = 82.00±1.69 PBO However, the lack of analysis of the gut microbiota before and after PB treatment, prevents drawing conclusions other than correlations 
Iran cohort of 60 patients PB group: males = 6 (20.0%); females = 24 (80.0%) PB group = 77.67±2.62 
PBO group: n = 30 
PB group: n = 30 
Randomized Controlled Trial Ratio (male/female) Age, years ± SD PB N/A 12 weeks After PB treatment: improved several neural behaviours, sleep quality and, GI symptoms, ↑ abundances of Blautia, Lachnospiraceae, Muribaculaceae, Haemophilus, Coprococcus, Ruminococcus, Anaerostipes, Erysipelotrichaceae, Prevotellaceae, and Pantoea and ↑ serum brain-derived neurotrophic factor A Lack of healthy older adult controls; lack of assessment of biomarkers link with gut-brain axis; lack in longer term effects of PB supplementation; lack in direct link and underlying mechanisms between treatment and observed effects on MCI patients. No assessment of molecular markers for MCI Provides evidence that PB supplementation may improve cognitive function, sleep, quality, and mood in older adults with MCI; potential of probiotics as a safe and effective to improve certain symptoms of MCI Fei et al. [28] (2023) 
Chinese cohort of 42 patients PB group = 10/11 PB group: = 76.40±9.61 PBO However, does not provide a direct link or causality between changes in microbial composition and symptoms of MCI 
PBO group: n = 21 PBO group = 11/10 PBO group = 75.30±9.75 
PB group: n = 21 
Explorative Intervention Study 9 females Age, years±SD PB N/A 28 days After PB treatment: no significant change in all cognitive parameters, no significant change in the concentrations of tryptophan, phenylalanine and tyrosine Lack of an untreated control group; lack of a detailed dietary questionnaire; lack in advanced microbiome analysis, such as 16 s rRNA gene sequencing for microbiota pre and post-treatment; no assessment for AD markers (only MRI) PB supplementation led to significant improvements in cognitive function, as measured by MMSE, ADAS-Cog.; PB supplementation led to significant improvements in Mood, as measured by POMS Leblhuber et al. [29] (2018) 
Austrian cohort of 21 patients with symptoms of dementia 11 males 76.7±9.7 years ↑ kynurenine serum levels; no difference of the BDNF levels However, no causality was shown and no conclusions can be drawn on the effect of PB on AD 
Faecalibacterium prausnitzii between baseline and after 4 weeks of supplementation with PB 
StudySexAge, yearsInterventionsDrug TreatmentsDurationResultsMissing PointsRelevanceReference
Randomised controlled and longitudinal clinical study FMT group: females = 8 (80%) Age, years, median (IQR) FMT Antibiotic treatments all subject were treated with 1-2 cycles of oral antibiotics before FMT NA FMT Group: MMSE and CDR-SB of FMT improved compared to antibiotics; ↑ enrichment of Proteobacteria and Bacteroidetes; ↑ Alanine, aspartate, and glutamate metabolism pathways after FTM Comprehensive cognitive assessment; assessment of metabolic status (lipid profiles, glucose homeostasis, and inflammatory markers); mechanistic investigations; Assessment of AD markers FMT may be a potential treatment for cognitive decline in patients with CDI; link healthy gut to cognitive function; However, the primary goal of the FMT was to treat CDI and no causality was shown regarding the improvement of observed cognitive functions Park et al. [20] (2022) 
Republic of Korea cohort of 10 patients with severe CDI and 10 control patients Control group: females = 8 (80%) FMT group = 76 (63–90) 2 patients: oral vancomycin alone 
Control group = 77 (62–91) 2 patients: metronidazole alone 
6 patients: vancomycin+metronidazole 
Medication for Dementia Donepezil, 7 in FMT Group and 6 in Control Group 
Memantine, 1 in FMT Group and 2 in Control Group 
Donepezil + Memantine, 1 in FMT Group and 1 Control Group 
Case study Male 82-year-old FMT Antibiotic Treatments Vancomycin, Vancomycin and Metronidazole, Fidaxomicin and Bezlotoxumab NA Improvements in the patient's mental acuity and affect Comprehensive cognitive assessment: assessment of metabolic status (lipid profiles, glucose homeostasis, and inflammatory markers); mechanistic investigations; assessment for AD markers First report of FMT leading to rapid and sustained improvement in AD symptoms; FMT may be a safe and effective treatment for cognitive decline in patients with CDI Hazan et al. [21] (2020) 
US case Report of 1 CDI patient Medication for Dementia MMSE normal cognition. Memory improvement, without progression of symptoms, continued for up to 6 months However, only case report of improvements as a secondary effect to FMT as CDI treatment; not controlled 
Memantine (28 mg once daily), donepezil (23 mg once daily) 
Case study Female 90-years-old FMT Antibiotic treatments: Vancomycin (oral, 125 mg/qid) NA After second FMT: GI distress improved with negative CDI stool results and improvement in mood. After FMT: ↑ Bacteroidales, Bacteroidia, Tannerellaceae, and Actinobacteria are more abundant Larger, diverse sample population; control and placebo group limited microbiota analysis; long-term follow-up; metabolomic analysis Report of FMT leading to significant improvement in cognitive function in AD patient with advanced dementia; FMT may be a safe and effective treatment for cognitive decline in AD Park et al. [22] (2021) 
South Korea Case Report of 1 CDI patient Metronidazole (oral, 500 mg/tid) However, only case report of improvements as a secondary effect to FMT as CDI treatment; not controlled 
Medication for dementia 
Donepezil (10 mg/5 years duration) 
Preliminary study 3 Females Age year FMT N/A (Exclusion criteria: No history of taking probiotics and antibiotics within 1 month of the study) Every second week for 180 days MCI patients after FMT So far no long-term follow-up on effects of FMT on age-related cognitive impairments Pilot clinical trial on the effect of FMT treatment specifically on patients with MCI; FMT may improve or maintain cognitive function in patients with MCI; FMT may appears to be safe, with no serious adverse events reported within 6 months of FMT; FMT may influence the gut microbiota composition and reduce the leaky gut syndrome, potentially contributing to cognitive improvements Chen et al. [26] (2023) 
Chinese Cohort of 3 females (FTD, MCI and AD) and 2 males (AD and MCI) 2 Males Female: 68 years old, 77 years old and 54 years old ↑ slight in executive function: fluency, orientation, memory, abstraction, delayed recall, visual perception, naming, and attention compared with before treatment FMT had an effect on serum metabolomics 
Male: 74 years old and 80 years old ↓ daily independent activities: eating, dressing, bathing, cooking, going to and from the toilet, walking around the room, urine and defecation control, washing etc. However, no causality was shown 
↑ faecal relative abundance of Bacteroides than that before transplantation. AD patients after FMT: stable scores, ↓ faecal relative abundance of Bacteroides than that before transplantation. FTD Patient: ↓ faecal relative abundance of Bacteroides of patients with AD and FTD after FMT was lower than that before transplantation 
Randomized Gender (%) Age, years (SD) PB N/A 12 weeks PB treatment: positive effects on the patients MMSE score, hs-CRP, insulin metabolism marker and triglyceride levels Lack of executive function and language assessment; limited metabolic status assessment and lack of inflammatory markers and other relevant metabolic parameters; no gut microbiota analysis and no assessment for AD markers First randomized, double-blind, and controlled trial investigating the effects of probiotic supplementation on cognitive function and metabolic status in AD; demonstrates potential benefits of PB on improving cognitive function and some metabolic parameters in AD patients Akbari et al. [27] (2016) 
Controlled Trial PBO group: males = 6 (20.0%); females = 24 (80.0%) PBO group = 82.00±1.69 PBO However, the lack of analysis of the gut microbiota before and after PB treatment, prevents drawing conclusions other than correlations 
Iran cohort of 60 patients PB group: males = 6 (20.0%); females = 24 (80.0%) PB group = 77.67±2.62 
PBO group: n = 30 
PB group: n = 30 
Randomized Controlled Trial Ratio (male/female) Age, years ± SD PB N/A 12 weeks After PB treatment: improved several neural behaviours, sleep quality and, GI symptoms, ↑ abundances of Blautia, Lachnospiraceae, Muribaculaceae, Haemophilus, Coprococcus, Ruminococcus, Anaerostipes, Erysipelotrichaceae, Prevotellaceae, and Pantoea and ↑ serum brain-derived neurotrophic factor A Lack of healthy older adult controls; lack of assessment of biomarkers link with gut-brain axis; lack in longer term effects of PB supplementation; lack in direct link and underlying mechanisms between treatment and observed effects on MCI patients. No assessment of molecular markers for MCI Provides evidence that PB supplementation may improve cognitive function, sleep, quality, and mood in older adults with MCI; potential of probiotics as a safe and effective to improve certain symptoms of MCI Fei et al. [28] (2023) 
Chinese cohort of 42 patients PB group = 10/11 PB group: = 76.40±9.61 PBO However, does not provide a direct link or causality between changes in microbial composition and symptoms of MCI 
PBO group: n = 21 PBO group = 11/10 PBO group = 75.30±9.75 
PB group: n = 21 
Explorative Intervention Study 9 females Age, years±SD PB N/A 28 days After PB treatment: no significant change in all cognitive parameters, no significant change in the concentrations of tryptophan, phenylalanine and tyrosine Lack of an untreated control group; lack of a detailed dietary questionnaire; lack in advanced microbiome analysis, such as 16 s rRNA gene sequencing for microbiota pre and post-treatment; no assessment for AD markers (only MRI) PB supplementation led to significant improvements in cognitive function, as measured by MMSE, ADAS-Cog.; PB supplementation led to significant improvements in Mood, as measured by POMS Leblhuber et al. [29] (2018) 
Austrian cohort of 21 patients with symptoms of dementia 11 males 76.7±9.7 years ↑ kynurenine serum levels; no difference of the BDNF levels However, no causality was shown and no conclusions can be drawn on the effect of PB on AD 
Faecalibacterium prausnitzii between baseline and after 4 weeks of supplementation with PB 

AD, Alzheimer’s disease; CDI, C. difficile infection; CDR-SB, clinical dementia rating sum of boxes; FMT, faecal microbiota transplantation; FTD, frontotemporal dementia; hs-CRP, high-serum sensitivity C-reactive protein; MCI, mild cognitive impairment; PB, probiotic; PBO, placebo, MMSE, Mini-Mental State Examination; POMS, Profile of Mood States.

In a case report study, an 82-year-old man under the care of his primary care physician and neurologist for the treatment of AD was affected by recurrent Clostridioides difficile infection (CDI). The patient presented with symptoms of dementia, including confusion, memory loss, depression, and flat affect, and the Mini-Mental State Examination (MMSE) indicated mild cognitive impairment. Neuropsychiatric testing also revealed significant impairments in memory and semantic language, non-verbal learning and divided attention, and response inhibition. The patient underwent a single FMT infusion using stool from his 85-year-old wife as a donor, who was intellectually alert with normal affect and stable mood. Following the procedure, the patient’s CDI symptoms resolved and a repeat stool test 2 months later was negative. Two months after FMT, the patient’s wife reported improvements in the patient’s mental acuity and affect, and the MMSE indicated normal cognition. The improvement in memory, with no progression of symptoms, lasted up to 6 months [21].

A subsequent clinical trial involved a 90-year-old woman with significant impairments in short-term memory, semantic ability, attention, non-verbal learning, and response inhibition, who was also diagnosed with severe CDI. She received a first FMT from a healthy 27-year-old man [22]. After the transplant, the recipient’s GI symptoms improved and her stool test was negative for CDI. One month after the FMT, her cognitive function improved slightly. However, 3 months after the first FMT, she became CDI-positive and symptomatic again, so she underwent a second FMT identical to the first. After this second FMT, her GI symptoms improved and she again tested CDI negative, but also her cognitive scores were stable and she reported a marked improvement in mood and activities of daily living and showed more expressive affection [22]. Analysis of the microbiota composition showed differences in stool before and after FMT, with some bacteria, such as Bacteroidales, Bacteroidia, Tannerellaceae, and Actinobacteria, associated with cognition [27‒29] being more abundant after FMT, as well as the pentose phosphate cycle, the functional pathway associated with the production of short-chain fatty acids.

Another FMT pilot clinical trial was conducted in 5 patients with cognitive impairment, two with AD, two with mild cognitive impairment, and one with frontotemporal dementia. The patients received FMT from 20-year-old healthy donors every other week for 180 consecutive days. The two patients with mild cognitive impairment had a slight increase in scores after FMT compared to before treatment, which quantified the covered executive function, language fluency, orientation, memory, abstraction, delayed recall, visual perception, naming, and attention. However, other scores (including 20 items such as eating, dressing, bathing, cooking, going to and from the toilet, moving around the room, controlling urine and bowel movements, washing, moving around the neighbourhood, taking medication, cooking for oneself, doing housework, shopping, managing money, and using a mobile phone; and nine functional subtests, e.g., orientation, comprehension, memory, and carrying out orders; and two memory subtests, e.g., word recall and recognition) decreased. The scores of patients with AD were essentially stable. The composition of the gut microbiota community was different in patients before and after transplantation. In addition, the relative abundance of Bacteroides in faeces of patients with AD and frontotemporal dementia was lower after FMT than before transplantation, while the opposite was found in patients with mild cognitive impairment. After FMT, patients’ stools were enriched in Fusobacteria, Eggerthellaceae, while Lachnospira decreased. The main metabolites differentially expressed after FMT were lipids and lipid molecules, heterocyclic organic compounds and organic oxygen compounds. This small study suggests that FMT could maintain symptoms of cognitive impairment and improve “leaky gut” responses [23].

The studies cited in this paragraph highlight the potential of FMT as a future treatment strategy to improve symptoms and slow the progression of cognitive decline in people with AD. However, the majority of these studies were not conducted with the overt aim of treating the clinical manifestations of cognitive decline, but rather the observed improvements in symptoms were secondary to the treatment of bacterial infections. In fact, it is currently difficult to justify the use of FMT for the treatment of cognitive impairment in patients without underlying bacterial infections because of the lack of knowledge about potential (long-term) side effects. This condition raises the question of what the underlying mechanisms are that lead to improvements in cognitive function, and whether more specific criteria for donor selection, dosage and composition of faecal microbiota, frequency and route of administration could be used to develop more effective therapies specifically for the treatment of AD.

Other microbial interventions are based on the use of probiotics. A randomised, double-blind, controlled clinical trial was conducted in 26 patients with AD treated with probiotics (Lactobacillus acidophilus, L. casei, Bifidobacterium bifidum, and L. fermentum, administered for 12 weeks) and 26 patients with AD treated with vehicle alone (control group). Probiotic treatment showed beneficial effects on patients’ Mini-Mental State Examination (MMSE) score, serum high-sensitivity C-reactive protein (hs-CRP), insulin metabolism markers, and triglyceride levels [24].

In a recent report, 21 people over the age of 60 with mild cognitive impairment (MCI) were treated with probiotics (Lactobacillus plantarum BioF-228, L. lactis BioF-224, Bifidobacterium lactis CP-9, L. rhamnosus Bv-77, L.johnsonii MH-68, L. paracasei MP137, L. salivarius AP-32, L. acidophilus TYCA06, L. lactis LY-66). L. salivarius AP-32, L. acidophilus TYCA06, L. lactis LY-66, B. lactis HNO19, L. rhamnosus HNO01, L. paracasei GL-156, Bifidobacterium animalis BB-115, L. casei CS-773, L.reuteri TSR332, L. fermentum TSF331, B. infantis BLI-02, and L. plantarum CN2018 for 12 weeks. This treatment improved several neural behaviours, sleep quality and GI symptoms, which correlated with an increase in the abundance of Bacteroidetes, in particular with increased abundances of Blautia, Lachnospiraceae, Muribaculaceae, Haemophilus, Coprococcus, Ruminococcus, Anaerostipes, Erysipelotrichaceae, Prevotellaceae, and Pantoea after probiotic supplementation, serum brain-derived neurotrophic factor (BDNF) levels were also increased in the probiotic-treated group compared to the placebo group (n = 21) [25].

In addition, 9 women and 11 men aged 76.7 ± 9. 7 years, with symptoms of dementia were enrolled in a study to assess the effect of a 28-day treatment with probiotics (Lactobacillus casei W56, Lactococcus lactis W19, Lactobacillus acidophilus W22, Bifidobacterium lactis W52, Lactobacillus paracasei W20, Lactobacillus plantarum W62, Bifidobacterium lactis W51, Bifidobacterium bifidum W23, and Lactobacillus salivarius W24). The study assessed stool composition before and after treatment, as well as several other blood and neurological parameters. The study concluded that there was no significant change in any of the cognitive parameters measured after probiotic supplementation, nor was there a significant change in the concentrations of tryptophan, phenylalanine, and tyrosine. However, a significant increase in serum kynurenine levels was observed after probiotic supplementation, as well as a trend towards an increase in neopterin and nitrite concentrations. There was no difference in BDNF levels before and after probiotic supplementation. Faecalibacterium prausnitzii increased significantly between baseline and after 4 weeks of probiotic supplementation, whereas levels of Clostridium cluster I and Akkermansia muciniphila did not change [26]. The use of probiotics such as Lactobacillus acidophilus, Bifidobacterium bifidum and Bifidobacterium longum (2 × 109CFU/day each) in a randomised, double-blind, controlled clinical trial in 79 patients with AD showed improved cognitive function and metabolic characteristics when used together with selenium for 12 consecutive weeks [30].

These interventions appear to have some efficacy and could be used to complement conventional therapies to improve disease symptoms. However, further trials at different stages of the disease could provide valuable insights into the efficacy of these approaches as the disease progresses. Further research into the precise underlying mechanisms is also needed to develop optimal probiotic formulations and dosages specifically for Alzheimer’s patients by targeting specific pathways involved in the interaction between probiotics and cognitive function.

Dietary Interventions in AD

Diet is the most powerful factor influencing the host microbiota, so approaches based on dietary interventions to ameliorate the signs of disease must take into account the effects on the microbiota (summarised in Table 3). A diet rich in fruits and vegetables, moderate consumption of poultry, fish, eggs, and dairy products, and low consumption of red meat and processed foods may protect against chronic inflammation and related diseases, including AD [31].

Table 3.

Summary of the latest discoveries and ongoing studies on the dietary interventions in AD: in this table, we highlight the main results regarding the dietary interventions in patients with AD

StudySexAgeInterventionsDrug treatmentsDurationResultsMissing pointsRelevanceReference
Observational study Tertile 1 group: males = 26% Age, mean, years MIND Hypertensive medication use (%) 12 months (follow-up after 4.5 years) High adherence to MD and DASH diets may reduce AD risk and moderate to high adherence to the MIND diet may also decrease AD risk Longer follow-up period; Measurement of blood levels of nutrients and biomarkers; investigation of underlying mechanisms (e.g., reducing inflammation, oxidative stress, or amyloid-beta plaque formation); no analysis on gut microbial changes or metabolomics Preliminary evidence that the MIND diet may be a promising way to reduce the AD risk; the combination of the beneficial components of the Mediterranean and DASH diets may be particularly effective at protecting against AD Morriset al. [32] (2015) 
US cohort of 923 participants Tertile 2 group: males = 25% Tertile 1 group = 81.7 DASH Tertile 1 = 57 No causal relationship between the MIND diet and reduced risk of cognitive decline. Other factors, such physical exercises, cognitive training and socio-economic status, may have a contributed to the study’s findings 
Tertile 3 group: males = 22% Tertile 2 group = 81.4 MD Tertile 2 = 53 
Tertile 3 group = 80.4 Tertile 3 = 53 
Randomized controlled trial Intervention group: females = 45% Age, years 100–20% of daily energy from proteins N/A 2 years Benefits on cognition, even in people with genetic susceptibility to AD Targeted mainly healthy elderly people (often volunteers); no discovery of underlying mechanisms; no information about other medication; no long-term follow-up after end of intervention; outcome assessments not blinded, no intention-to-treat analyses, or cognitive training effects assessed only on the trained tasks; no assessment for AD markers; no analysis on gut microbial changes or metabolomics Multidomain intervention can improve cognitive function in at-risk elderly people; combination of diet, exercise, cognitive training, and vascular risk monitoring may be an effective way to prevent cognitive decline; foundation for further research on the use of multidomain interventions for the prevention of cognitive decline. However, it is not possible to establish a causal relationship between the FINGER intervention diet and cognitive declines. Other factors, such genetics, underlying health conditions, age, sex, and socio-economic status, may have contributed to the study findings. The study was conducted on elderly people, so the findings may not be applicable to younger people Ngandu et al. [34] (2015) 
Finnish cohort of 1,190 patients Control group: females = 47% Intervention group = 69·5 (4·6) 25–25% daily of energy from fat: <10% from saturated plus trans fatty acids, 10–20 from monosaturated fatty acids, and 5–10% from polyunsaturated fatty acids (including 2·5-3 g/day of omega-3 fatty acids-) The FINGER intervention may help slow the rate of cognitive decline but it cannot prevent dementia 
Intervention group: n = 591 Control group = 69·2 (4·7) 45–55% daily energy from carbohydrates (<10% from refined sugar), 25–35% g/day of dietary fibre, less than 5 g/day of salt, and less than 5% daily energy from alcohol 
Control group: n = 599 
Randomized, double-blind, controlled trial Males Age (years), mean (SD), median (range) Active Group: 125 mL/day of Medical Food Souvenaid (consisting of docosahexaenoic acid, eicosapentaenoic acid, uridine monophosphate, choline, vitamins B12, B6, C, E, and folic acid, phospholipids, and selenium AD Medication (see details in Soininen 2017) 24 months No significant effect on the NTB primary endpoint in prodromal AD. Cognitive decline much ↓ than expected and decline in the control group was ↓ then the pre-study estimates of −0·4 during 24 months No investigation of underlying mechanisms; no measurement of blood levels of nutrients and biomarkers; no analysis on gut microbial changes or metabolomics Preliminary evidence that a multi-nutrient supplement may not be an effective treatment for prodromal AD; it suggests that larger, longer term trials are needed to confirm these findings and to determine the optimal dose and duration of Medical Food Souvenaid intake for preventing cognitive decline Soininen et al. [36] (2017) 
Finnish, German, Dutch, and Swedish cohort of 311 patients Control group = 73 (46%) Control group = 70·7 (6·2), 71 (52–84) Control group: 125 mL/day of control drink 
Control group: n = 158 Active group = 81 (53%) Active group = 71·3 (7·0), 72 (50–86) 
Active group: n = 153 Females 
Control group = 85 (54%) 
Active group = 72 (47%) 
Randomized controlled trial Female (%) Age, years Multidomain intervention plus omega-3 polyunsaturated fatty acids N/A 36 months No significant differences in 3-year cognitive decline between any of the three intervention groups and the PBO group No investigation of the underlying mechanisms; no measurement of participants’ blood level of omega-3 polyunsaturated fatty acids Preliminary evidence that a multidomain intervention combined with omega-3 supplementation may not be an effective treatment for prodromal AD; it suggests that larger, longer term trials are needed to confirm these findings. An effective multidomain intervention strategy to prevent or delay cognitive impairment and the target population remains to be determined Andrieu et al. [37] (2017) 
French and Monegasque Cohort of 1,525 patients Overall: females = 978 (64%) Overall = 75·3 (4·4) Multidomain intervention plus placebo 
Multidomain plus polyunsaturated Multidomain plus polyunsaturated Multidomain plus polyunsaturated fatty acids = 75·4 (4·4) Omega-3 polyunsaturated fatty acids 
 fatty acids group: n = 374 fatty acids group: females = 229 (61%) Multidomain plus PBO = 75·0 (4·1) 
Multidomain plus PBO group: n = 390 Multidomain plus PBO group: females = 245 (64%) Polyunsaturated fatty acids = 75·6 (4·7) 
Polyunsaturated fatty acids group: n = 381 Polyunsaturated fatty acids group: females = 245 (64%) PBO = 75·1 (4·3) 
PBO group: n = 380 PBO group: females = 252 (66%) 
Systematic-Review Refer to Canhada et al. [35Refer to Canhada et al. [35Omega-3 fatty acids N/A  Most of the studies did not find statistically significant results for omega-3 fatty acids supplementation compared to PBO, some did show some benefit but only in a few cognitive assessment scales. Effects of omega-3 fatty acids appear to be most effectively demonstrated in patients with very mild AD Relatively small number of studies considered; different doses and types of omega-3 fatty acids which makes it difficult to compare the results; studies have different follow-up periods, from 6 months to 2 years Larger trials are needed to confirm findings; further research with larger trials with more consistent dosing, types, and follow-up are needed; Omega-3 fatty acids may be beneficial in disease onset when there is a slight impairment of brain function Canhada et al. [38] (2018) 
Meta-analysis of 7 studies 
Observational Study Ratio (male/female): 2/3 Age, years, mean±SD Dietary supplement: 1-month of 60-40 MCT oil (1-month supplementation of 30 g MCT oil (60% C10 + 40% C8)/day) N/A 1 month Brain ketone consumption doubled on both types of MCT supplement. Relationship between plasma ketones and brain ketone uptake was the same as in healthy young adults and types of kMCT increased total brain energy metabolism by increasing ketone supply without affecting brain glucose utilization Number of participants relatively small; assessment for AD markers (only MRI and PET, not, plasma, and CSF); no comparison with other interventions such as physical exercise and cognitive training The study provides preliminary evidence that kMCT diet improve brain energy metabolism, oxygen level and brain activity in AD people. Further large and long-term studies are required to confirm the results of the study. It is necessary to clarify the mechanisms through which the intake of kMCT could exert its beneficial effects in AD. Croteau et al. [39] (2018) 
Canadian cohort of 20 participants 73.5±7.1 years Dietary Supplement: 1 month of C8 kMCT oil. 1-month supplementation of 30 g MCT oil (100% C8)/day (1 month of C8 MCT oil) 
Randomized controlled trial NA Mean age (SD) = 74.7 (SD = 6.7) Emulsified MCTs N/A NA Significant ↑ in levels of β-OHB were observed 90 min after treatment when cognitive tests were administered; β-OHB elevations were moderated by APOE genotype; for ε4+ subjects, β-OHB levels continued to rise between the 90- and 120-min blood draws in the treatment condition, while the β-OHB levels of ε4− subjects held constant. On cognitive testing, MCT treatment facilitated performance on the ADAS-cog for ε4− subjects, but not for ε4+ subjects More detailed cognitive testing; longer follow-up; more rigorous statistical analyses; β-OHB supplementation's effects on cognitive domains were not assessed; no assessment of effects of β-OHB on memory-impaired adults with different conditions; no analysis on the impact of β-OHB supplementation on long-term cognitive function The administration of β-OHB could potentially serve as a promising therapeutic intervention for individuals experiencing cognitive impairment Reger et al. [40] (2004) 
US cohort of 20 patients with probable Emulsified long-chain triglycerides as a PBO However, the findings are still preliminary. Larger, longer term studies are needed to confirm the study findings and it is necessary to clarify the mechanism by which β-OHB supplementation could exert its beneficial effects for cognitive impairment 
AD 
Randomized crossover clinical trial Ketogenic-usual diet group: males = 10 (77%) Age (years), SD, range MKD Ketogenic-usual diet group: Donepezil 4 (31%), Beta Blocker 4 (31%), Statin 2 (15%), No medication at all 3 (23%) Two 12-week treatment periods separated by a 10-week washout period Patients on the KD ↑ their mean within-individual ADCS-ADL and QOL-AD scores compared with the usual diet Limited cognitive tests; more comprehensive cognitive testing, longer follow-up compared to the other studies; no examination of the effects of MKD on specific cognitive domains, such as working memory, long-term memory, or executive function; no examination of the effects of MKD on different stages of AD, such as mild, moderate, or severe; no examination of the effects of MKD on biomarkers of AD; lack of non-AD controls It suggests that MKD may be a promising treatment for AD but the small cohort size makes it difficult to generalize the findings to a larger population and the short duration of the study does not allow for the evaluation of the long-term effects of the MKD. Future studies should investigate the efficacy of more practical and tolerable forms of the MKD (without side effects, such as fatigue, constipation, and nausea) Phillips et al. [42] (2021) 
New Zealanders cohort of 26 patients Usual-KD group: males = 6 (46%) All patients group = 69.8±6.0 (range, 57–79) Usual diet supplemented with low-fat healthy-eating guidelines Usual-KD group: donepezil 4 (31%), beta blocker 1 (8%), Statin 2 (15%), no medication at all 4 (31%) 
Ketogenic-usual diet group: n = 13  Ketogenic-usual diet group = 68.0±5.4 (range, 57–77) 
Usual-ketogenic diet group: n = 13  Usual-ketogenic diet group = 71.7±6.2 (range, 61–79) 
Observational Study with control group Ratio males/females = 11/9 Age, years ±SD Ketogenic formula (Ketonformula®) containing 20 g of MTCs) N/A 12 weeks The first trial: no significant difference in any cognitive test results between the administrations of the KD and PO formulae No examination of the effects of ketogenic meals on specific cognitive domains; no analysis of the effects of ketogenic meals on different types of elderly adults (with or without CI); no examination of long-term effects of the ketogenic meals on cognitive function; no healthy individuals on the same diets Ketogenic meals may be a promising treatment for cognitive impairment but the small sample size makes it difficult to generalize the findings to a larger population and the single-meal intervention does not allow for the evaluation of the long-term effects of the ketogenic meals on cognitive function. The absence of a placebo-control group makes it difficult to establish a causal relationship between the ketogenic meal and the observed benefits. Future studies should investigate the efficacy of more practical and tolerable forms of the ketogenic meal (without side effects) Ota et al. [43] (2019) 
Japanese cohort of 20 patients with AD 73.4±6.0 Isocaloric PBO formula without MCTs 8 weeks: patients showed significant improvement in their immediate and delayed logical memory tests compared to their baseline scores 
12 weeks: significant improvements in the digit-symbol coding test and immediate logical memory test compared to the baseline 
Randomized, single-blinded, placebo-controlled trial Folate and vitamin B12 group: males = 30 (50.00%) Age, years ±SD Folic acid 1.2 mg/d + vitamin B12 50 μg/d All participants were on dementia medication as a basic routine therapy 6 months Folic acid plus vitamin B12 supplementation had a beneficial effect on the MoCA total scores, naming scores, orientation scores, and ADAS-Cog domain score of attention, as compared to those of the control subjects. Supplementation significantly ↑ plasma SAM and SAM/SAH, and significantly ↓ the levels of serum Hcy, plasma SAH and serum TNFα compared to the control subjects No individual personalized dosage; no long-term efficacy reported; no nutritional status assessment; no brain imaging evaluation; no subgroup analysis; generalizability; no evaluation of methylation levels of inflammatory markers Supplementation with folic acid and vitamin B12 improved cognitive performance and reduced inflammation in AD patients; B vitamins may have a neuroprotective role in AD by reducing homocysteine levels and promoting SAM synthesis; nutrient intervention with folic acid and vitamin B12 could offer a non-pharmacological strategy to slow cognitive decline and alleviate inflammatory burden in AD patients. However, larger and longer term studies are needed to confirm these findings and address the limitations of the current study Chen et al. [45] (2021) 
Chinese cohort of 101 patients PBO group: males = 26 (43.33%) Folate and vitB12 group 68.58±7.29 PBO 
Folate and vitamin B12 group: n = 51 PBO group 68.02±8.34 
PBO group: n = 50 
Randomized controlled trial CN group: sex female = 9 (81.8%) Age, years (SD) CN group = 64.9 (7.9) Low-fat AHA diet N/A 6 weeks Participants with MCI on the MMKD had ↓ levels of GABA-producing microbes Alistipes sp.CAG:514 and GABA, and ↑ levels of GABA-regulating microbes Akkermansia muciniphila. MCI individuals with curcumin in their diet had ↓ levels of bile salt hydrolase-containing microbes and an altered bile acid pool, suggesting reduced gut motility No analysis of long-term efficacy; no targeted metabolomics performed KD and low-fat diets may have neuroprotective effects in AD by increasing levels of ketone bodies and reducing inflammation; relatively safe, easy to follow, and cheap, which makes them attractive as potential lifestyle interventions for AD. Further research is needed to confirm the long-term efficacy and safety of these intervention strategies and to investigate their underlying mechanisms. Further deeper lipid metabolomic analysis and ketogenesis pathways should be considered in future studies Dilmore et al. [44] (2023) 
US cohort of 20 patients with MCI or CN MCI group: sex female = 6 (66.7%) MMKD 6-week washout period 
CN group: n = 11 Alternative diet 
MCI group: n = 9 
Randomized, double-blind, controlled trial NA Age, years ±SD Selenium N/A 12 consecutive weeks PB and selenium co-supplementation: ↑ improvement in MMSE score and ↓ in serum triglycerides, VLDL, LDL, total-/HDL-cholesterol compared with only selenium and placebo No microbiome analysis before and after treatments; no analysis of underlying mechanisms (metabolome and microbiome), gut-brain axis modulation; no brain imaging evaluation; no analysis of long-term efficacy. PB strain used in the study was not well-characterized PB and selenium co-supplementation may have anti-inflammatory effects that could contribute to slowing the progression of AD; they may have neuroprotective effects by promoting neuronal survival and regeneration, reducing inflammation, and improving metabolic health; beneficial effects on insulin sensitivity and Aβ levels, which could help protect the brain from damage and may have the potential to target the underlying genetic causes of AD Tamtaji et al. [30] (2019) 
Iran cohort of 79 patients PBO group = 78.5±8.0 PB + selenium Selenium supplementation: ↓ hs-CRP, insulin, HOMA-IR, LDL-cholesterol and total-/HDL-cholesterol ratio compared with the placebo and ↑ total GSH and QUICKI compared with the PBO 
PBO group: n = 26 Selenium group: 78.8±10.2 
Selenium group: n = 26 PB + selenium group: 76.2±8.1 
PB + selenium group: n = 27 
StudySexAgeInterventionsDrug treatmentsDurationResultsMissing pointsRelevanceReference
Observational study Tertile 1 group: males = 26% Age, mean, years MIND Hypertensive medication use (%) 12 months (follow-up after 4.5 years) High adherence to MD and DASH diets may reduce AD risk and moderate to high adherence to the MIND diet may also decrease AD risk Longer follow-up period; Measurement of blood levels of nutrients and biomarkers; investigation of underlying mechanisms (e.g., reducing inflammation, oxidative stress, or amyloid-beta plaque formation); no analysis on gut microbial changes or metabolomics Preliminary evidence that the MIND diet may be a promising way to reduce the AD risk; the combination of the beneficial components of the Mediterranean and DASH diets may be particularly effective at protecting against AD Morriset al. [32] (2015) 
US cohort of 923 participants Tertile 2 group: males = 25% Tertile 1 group = 81.7 DASH Tertile 1 = 57 No causal relationship between the MIND diet and reduced risk of cognitive decline. Other factors, such physical exercises, cognitive training and socio-economic status, may have a contributed to the study’s findings 
Tertile 3 group: males = 22% Tertile 2 group = 81.4 MD Tertile 2 = 53 
Tertile 3 group = 80.4 Tertile 3 = 53 
Randomized controlled trial Intervention group: females = 45% Age, years 100–20% of daily energy from proteins N/A 2 years Benefits on cognition, even in people with genetic susceptibility to AD Targeted mainly healthy elderly people (often volunteers); no discovery of underlying mechanisms; no information about other medication; no long-term follow-up after end of intervention; outcome assessments not blinded, no intention-to-treat analyses, or cognitive training effects assessed only on the trained tasks; no assessment for AD markers; no analysis on gut microbial changes or metabolomics Multidomain intervention can improve cognitive function in at-risk elderly people; combination of diet, exercise, cognitive training, and vascular risk monitoring may be an effective way to prevent cognitive decline; foundation for further research on the use of multidomain interventions for the prevention of cognitive decline. However, it is not possible to establish a causal relationship between the FINGER intervention diet and cognitive declines. Other factors, such genetics, underlying health conditions, age, sex, and socio-economic status, may have contributed to the study findings. The study was conducted on elderly people, so the findings may not be applicable to younger people Ngandu et al. [34] (2015) 
Finnish cohort of 1,190 patients Control group: females = 47% Intervention group = 69·5 (4·6) 25–25% daily of energy from fat: <10% from saturated plus trans fatty acids, 10–20 from monosaturated fatty acids, and 5–10% from polyunsaturated fatty acids (including 2·5-3 g/day of omega-3 fatty acids-) The FINGER intervention may help slow the rate of cognitive decline but it cannot prevent dementia 
Intervention group: n = 591 Control group = 69·2 (4·7) 45–55% daily energy from carbohydrates (<10% from refined sugar), 25–35% g/day of dietary fibre, less than 5 g/day of salt, and less than 5% daily energy from alcohol 
Control group: n = 599 
Randomized, double-blind, controlled trial Males Age (years), mean (SD), median (range) Active Group: 125 mL/day of Medical Food Souvenaid (consisting of docosahexaenoic acid, eicosapentaenoic acid, uridine monophosphate, choline, vitamins B12, B6, C, E, and folic acid, phospholipids, and selenium AD Medication (see details in Soininen 2017) 24 months No significant effect on the NTB primary endpoint in prodromal AD. Cognitive decline much ↓ than expected and decline in the control group was ↓ then the pre-study estimates of −0·4 during 24 months No investigation of underlying mechanisms; no measurement of blood levels of nutrients and biomarkers; no analysis on gut microbial changes or metabolomics Preliminary evidence that a multi-nutrient supplement may not be an effective treatment for prodromal AD; it suggests that larger, longer term trials are needed to confirm these findings and to determine the optimal dose and duration of Medical Food Souvenaid intake for preventing cognitive decline Soininen et al. [36] (2017) 
Finnish, German, Dutch, and Swedish cohort of 311 patients Control group = 73 (46%) Control group = 70·7 (6·2), 71 (52–84) Control group: 125 mL/day of control drink 
Control group: n = 158 Active group = 81 (53%) Active group = 71·3 (7·0), 72 (50–86) 
Active group: n = 153 Females 
Control group = 85 (54%) 
Active group = 72 (47%) 
Randomized controlled trial Female (%) Age, years Multidomain intervention plus omega-3 polyunsaturated fatty acids N/A 36 months No significant differences in 3-year cognitive decline between any of the three intervention groups and the PBO group No investigation of the underlying mechanisms; no measurement of participants’ blood level of omega-3 polyunsaturated fatty acids Preliminary evidence that a multidomain intervention combined with omega-3 supplementation may not be an effective treatment for prodromal AD; it suggests that larger, longer term trials are needed to confirm these findings. An effective multidomain intervention strategy to prevent or delay cognitive impairment and the target population remains to be determined Andrieu et al. [37] (2017) 
French and Monegasque Cohort of 1,525 patients Overall: females = 978 (64%) Overall = 75·3 (4·4) Multidomain intervention plus placebo 
Multidomain plus polyunsaturated Multidomain plus polyunsaturated Multidomain plus polyunsaturated fatty acids = 75·4 (4·4) Omega-3 polyunsaturated fatty acids 
 fatty acids group: n = 374 fatty acids group: females = 229 (61%) Multidomain plus PBO = 75·0 (4·1) 
Multidomain plus PBO group: n = 390 Multidomain plus PBO group: females = 245 (64%) Polyunsaturated fatty acids = 75·6 (4·7) 
Polyunsaturated fatty acids group: n = 381 Polyunsaturated fatty acids group: females = 245 (64%) PBO = 75·1 (4·3) 
PBO group: n = 380 PBO group: females = 252 (66%) 
Systematic-Review Refer to Canhada et al. [35Refer to Canhada et al. [35Omega-3 fatty acids N/A  Most of the studies did not find statistically significant results for omega-3 fatty acids supplementation compared to PBO, some did show some benefit but only in a few cognitive assessment scales. Effects of omega-3 fatty acids appear to be most effectively demonstrated in patients with very mild AD Relatively small number of studies considered; different doses and types of omega-3 fatty acids which makes it difficult to compare the results; studies have different follow-up periods, from 6 months to 2 years Larger trials are needed to confirm findings; further research with larger trials with more consistent dosing, types, and follow-up are needed; Omega-3 fatty acids may be beneficial in disease onset when there is a slight impairment of brain function Canhada et al. [38] (2018) 
Meta-analysis of 7 studies 
Observational Study Ratio (male/female): 2/3 Age, years, mean±SD Dietary supplement: 1-month of 60-40 MCT oil (1-month supplementation of 30 g MCT oil (60% C10 + 40% C8)/day) N/A 1 month Brain ketone consumption doubled on both types of MCT supplement. Relationship between plasma ketones and brain ketone uptake was the same as in healthy young adults and types of kMCT increased total brain energy metabolism by increasing ketone supply without affecting brain glucose utilization Number of participants relatively small; assessment for AD markers (only MRI and PET, not, plasma, and CSF); no comparison with other interventions such as physical exercise and cognitive training The study provides preliminary evidence that kMCT diet improve brain energy metabolism, oxygen level and brain activity in AD people. Further large and long-term studies are required to confirm the results of the study. It is necessary to clarify the mechanisms through which the intake of kMCT could exert its beneficial effects in AD. Croteau et al. [39] (2018) 
Canadian cohort of 20 participants 73.5±7.1 years Dietary Supplement: 1 month of C8 kMCT oil. 1-month supplementation of 30 g MCT oil (100% C8)/day (1 month of C8 MCT oil) 
Randomized controlled trial NA Mean age (SD) = 74.7 (SD = 6.7) Emulsified MCTs N/A NA Significant ↑ in levels of β-OHB were observed 90 min after treatment when cognitive tests were administered; β-OHB elevations were moderated by APOE genotype; for ε4+ subjects, β-OHB levels continued to rise between the 90- and 120-min blood draws in the treatment condition, while the β-OHB levels of ε4− subjects held constant. On cognitive testing, MCT treatment facilitated performance on the ADAS-cog for ε4− subjects, but not for ε4+ subjects More detailed cognitive testing; longer follow-up; more rigorous statistical analyses; β-OHB supplementation's effects on cognitive domains were not assessed; no assessment of effects of β-OHB on memory-impaired adults with different conditions; no analysis on the impact of β-OHB supplementation on long-term cognitive function The administration of β-OHB could potentially serve as a promising therapeutic intervention for individuals experiencing cognitive impairment Reger et al. [40] (2004) 
US cohort of 20 patients with probable Emulsified long-chain triglycerides as a PBO However, the findings are still preliminary. Larger, longer term studies are needed to confirm the study findings and it is necessary to clarify the mechanism by which β-OHB supplementation could exert its beneficial effects for cognitive impairment 
AD 
Randomized crossover clinical trial Ketogenic-usual diet group: males = 10 (77%) Age (years), SD, range MKD Ketogenic-usual diet group: Donepezil 4 (31%), Beta Blocker 4 (31%), Statin 2 (15%), No medication at all 3 (23%) Two 12-week treatment periods separated by a 10-week washout period Patients on the KD ↑ their mean within-individual ADCS-ADL and QOL-AD scores compared with the usual diet Limited cognitive tests; more comprehensive cognitive testing, longer follow-up compared to the other studies; no examination of the effects of MKD on specific cognitive domains, such as working memory, long-term memory, or executive function; no examination of the effects of MKD on different stages of AD, such as mild, moderate, or severe; no examination of the effects of MKD on biomarkers of AD; lack of non-AD controls It suggests that MKD may be a promising treatment for AD but the small cohort size makes it difficult to generalize the findings to a larger population and the short duration of the study does not allow for the evaluation of the long-term effects of the MKD. Future studies should investigate the efficacy of more practical and tolerable forms of the MKD (without side effects, such as fatigue, constipation, and nausea) Phillips et al. [42] (2021) 
New Zealanders cohort of 26 patients Usual-KD group: males = 6 (46%) All patients group = 69.8±6.0 (range, 57–79) Usual diet supplemented with low-fat healthy-eating guidelines Usual-KD group: donepezil 4 (31%), beta blocker 1 (8%), Statin 2 (15%), no medication at all 4 (31%) 
Ketogenic-usual diet group: n = 13  Ketogenic-usual diet group = 68.0±5.4 (range, 57–77) 
Usual-ketogenic diet group: n = 13  Usual-ketogenic diet group = 71.7±6.2 (range, 61–79) 
Observational Study with control group Ratio males/females = 11/9 Age, years ±SD Ketogenic formula (Ketonformula®) containing 20 g of MTCs) N/A 12 weeks The first trial: no significant difference in any cognitive test results between the administrations of the KD and PO formulae No examination of the effects of ketogenic meals on specific cognitive domains; no analysis of the effects of ketogenic meals on different types of elderly adults (with or without CI); no examination of long-term effects of the ketogenic meals on cognitive function; no healthy individuals on the same diets Ketogenic meals may be a promising treatment for cognitive impairment but the small sample size makes it difficult to generalize the findings to a larger population and the single-meal intervention does not allow for the evaluation of the long-term effects of the ketogenic meals on cognitive function. The absence of a placebo-control group makes it difficult to establish a causal relationship between the ketogenic meal and the observed benefits. Future studies should investigate the efficacy of more practical and tolerable forms of the ketogenic meal (without side effects) Ota et al. [43] (2019) 
Japanese cohort of 20 patients with AD 73.4±6.0 Isocaloric PBO formula without MCTs 8 weeks: patients showed significant improvement in their immediate and delayed logical memory tests compared to their baseline scores 
12 weeks: significant improvements in the digit-symbol coding test and immediate logical memory test compared to the baseline 
Randomized, single-blinded, placebo-controlled trial Folate and vitamin B12 group: males = 30 (50.00%) Age, years ±SD Folic acid 1.2 mg/d + vitamin B12 50 μg/d All participants were on dementia medication as a basic routine therapy 6 months Folic acid plus vitamin B12 supplementation had a beneficial effect on the MoCA total scores, naming scores, orientation scores, and ADAS-Cog domain score of attention, as compared to those of the control subjects. Supplementation significantly ↑ plasma SAM and SAM/SAH, and significantly ↓ the levels of serum Hcy, plasma SAH and serum TNFα compared to the control subjects No individual personalized dosage; no long-term efficacy reported; no nutritional status assessment; no brain imaging evaluation; no subgroup analysis; generalizability; no evaluation of methylation levels of inflammatory markers Supplementation with folic acid and vitamin B12 improved cognitive performance and reduced inflammation in AD patients; B vitamins may have a neuroprotective role in AD by reducing homocysteine levels and promoting SAM synthesis; nutrient intervention with folic acid and vitamin B12 could offer a non-pharmacological strategy to slow cognitive decline and alleviate inflammatory burden in AD patients. However, larger and longer term studies are needed to confirm these findings and address the limitations of the current study Chen et al. [45] (2021) 
Chinese cohort of 101 patients PBO group: males = 26 (43.33%) Folate and vitB12 group 68.58±7.29 PBO 
Folate and vitamin B12 group: n = 51 PBO group 68.02±8.34 
PBO group: n = 50 
Randomized controlled trial CN group: sex female = 9 (81.8%) Age, years (SD) CN group = 64.9 (7.9) Low-fat AHA diet N/A 6 weeks Participants with MCI on the MMKD had ↓ levels of GABA-producing microbes Alistipes sp.CAG:514 and GABA, and ↑ levels of GABA-regulating microbes Akkermansia muciniphila. MCI individuals with curcumin in their diet had ↓ levels of bile salt hydrolase-containing microbes and an altered bile acid pool, suggesting reduced gut motility No analysis of long-term efficacy; no targeted metabolomics performed KD and low-fat diets may have neuroprotective effects in AD by increasing levels of ketone bodies and reducing inflammation; relatively safe, easy to follow, and cheap, which makes them attractive as potential lifestyle interventions for AD. Further research is needed to confirm the long-term efficacy and safety of these intervention strategies and to investigate their underlying mechanisms. Further deeper lipid metabolomic analysis and ketogenesis pathways should be considered in future studies Dilmore et al. [44] (2023) 
US cohort of 20 patients with MCI or CN MCI group: sex female = 6 (66.7%) MMKD 6-week washout period 
CN group: n = 11 Alternative diet 
MCI group: n = 9 
Randomized, double-blind, controlled trial NA Age, years ±SD Selenium N/A 12 consecutive weeks PB and selenium co-supplementation: ↑ improvement in MMSE score and ↓ in serum triglycerides, VLDL, LDL, total-/HDL-cholesterol compared with only selenium and placebo No microbiome analysis before and after treatments; no analysis of underlying mechanisms (metabolome and microbiome), gut-brain axis modulation; no brain imaging evaluation; no analysis of long-term efficacy. PB strain used in the study was not well-characterized PB and selenium co-supplementation may have anti-inflammatory effects that could contribute to slowing the progression of AD; they may have neuroprotective effects by promoting neuronal survival and regeneration, reducing inflammation, and improving metabolic health; beneficial effects on insulin sensitivity and Aβ levels, which could help protect the brain from damage and may have the potential to target the underlying genetic causes of AD Tamtaji et al. [30] (2019) 
Iran cohort of 79 patients PBO group = 78.5±8.0 PB + selenium Selenium supplementation: ↓ hs-CRP, insulin, HOMA-IR, LDL-cholesterol and total-/HDL-cholesterol ratio compared with the placebo and ↑ total GSH and QUICKI compared with the PBO 
PBO group: n = 26 Selenium group: 78.8±10.2 
Selenium group: n = 26 PB + selenium group: 76.2±8.1 
PB + selenium group: n = 27 

AD, Alzheimer’s disease; ADAS-Cog, Alzheimer’s Disease Assessment Scale cognitive subscale; ADCS-ADL, Alzheimer’s Disease Cooperative Study – Activities of Daily Living; AHA, American Heart Association; APOE, apolipoprotein E; CN, Cognitively Normal; DASH, Dietary Approaches to Stop Hypertension; β-OHB, β-hydroxybutyrate; KD, Ketogenic Diet; kMCT, keto-medium chain triglycerides; GSH, glutathione; Hcy, homocysteine; HDL, hjigh-density lipoproteins; hs-CRP, high serum sensitivity C-reactive protein; LDL, low density lipoproteins; MCI, mild cognitive impairment; MD, Mediterranean diet; MIND, Mediterranean-DASH Intervention for Neurodegenerative Delay; MKD, Modified Ketogenic Diet; MMKD, High-fat modified Mediterranean KD; MoCA, Montreal Cognitive Assessment; MTCs, medium-chain triglycerides; PB, probiotic; PBO, Placebo; QOL-AD, Quality-of-Life in Alzheimer’s Disease; QUICKI, Quantitative Insulin Sensitivity Check Index; SAH, S-Adenosyl-l-homocysteine; SAS, S-adenosylmethionine; VLDL, very low density lipoproteins.

In a volunteer study, food frequency questionnaires were completed by 1,306 eligible participants of the Rush Memory and Aging Project (MAP) living in retirement communities and senior public housing in the Chicago area from 2004 to February 2013. Over the course of the study, 1,068 participants completed the food frequency questionnaires, of whom 923 had at least two neuropsychological assessments and were clinically free of AD at baseline. The study showed that high adherence to the Mediterranean and DASH (Dietary Approaches to Stop Hypertension) diets may reduce the risk of AD. Moderate to high adherence to the Mediterranean-DASH Intervention for Neurodegenerative Delay (MIND) diet may also reduce the risk of AD [32].

The Finnish Geriatric Intervention Study to Prevent Cognitive Impairment and Disability (FINGER) [33, 42] is a multicentre, randomised intervention study that started in 2009 and enrolled 1,200 people aged 60–77 years with an increased risk of dementia. Participants received individual and group sessions on dietary advice, exercise, cognitive training, and monitoring and maintenance of metabolic and vascular risk factors. The study showed cognitive benefits, even in people with a genetic susceptibility to AD. The FINGER trial was developed within the global FINGERS network, which will involve more than 25 countries by 2020. The aim of the network was to adapt, test and optimise the FINGER model in different geographical, cultural, and economic settings to understand how different interventions combined with the medical food Souvenaid (Nutricia; Zoetermeer, the Netherlands) might affect clinical dementia. The Souvenaid food contains a multi-nutrient combination (Fortasyn Connect) as the active component, consisting of docosahexaenoic acid, eicosapentaenoic acid, uridine monophosphate, choline, vitamins B12, B6, C, E, and folic acid, phospholipids, and selenium [43]. These nutrients, which have established biological and neuroprotective properties, have been specifically combined to increase efficacy compared to individual nutrients and are the subject of the LipiDiDiet research consortium, which is investigating the preclinical and clinical effects of nutrition in AD [34]. This study was a 24-month randomised, controlled, double-blind, parallel-group, multicentre trial (11 sites in Finland, Germany, the Netherlands and Sweden) with 12-month double-blind extensions. The study (number NTR1705 in the Dutch Trial Register) enrolled 153 people with prodromal AD, 153 in the active group who received a 125 mL once-daily drink containing Fortasyn Connect and 158 controls. The primary endpoint was the change in score on a neuropsychological test battery (NTB). While the dietary intervention had no significant effect on the primary endpoint of NTB over 2 years in prodromal AD, cognitive decline in this population was much less than expected. There were also group differences in secondary endpoints of disease progression, measuring cognition and function, and hippocampal atrophy.

Other clinical trials using specific dietary supplements to improve cognitive function in older adults with memory problems [44], such as the French MAPT trial [35] of omega-3 fatty acid supplements, showed negative results for cognitive decline over 3 years. These findings suggest that further studies of nutritional approaches with larger sample sizes, longer duration, or a more sensitive primary endpoint in this pre-dementia population are needed to understand whether diet, along with various therapies, could be an effective approach to improve dementia symptoms and have positive outcomes in people with AD.

AD disrupts energy metabolism in the brain, affecting insulin signalling, glucose utilisation and mitochondria. Ketogenic diets, which are high in fat and low in carbohydrates, may enhance energy production from ketones [36, 37]. Clinical trials suggest that the ketogenic diet may have beneficial effects on cognitive improvement, working memory, visual attention, and task switching in non-demented older people [45]. In the first randomised trial (number ACTRN12618001450202) of the ketogenic diet in patients with AD, patients were randomised to a modified ketogenic diet or their usual diet supplemented with low-fat healthy eating guidelines and enrolled in a single-phase, assessor-blinded, two-period crossover trial (two 12-week treatment periods separated by a 10-week washout period). High rates of retention, adherence, and safety were achieved with a 12-week modified ketogenic diet in AD patients [38]. Compared with a usual low-fat diet, patients on the ketogenic diet improved daily function and quality of life.

The same conclusion was reached in another study of a Japanese cohort of 20 patients with mild to moderate Alzheimer's [39]. On different days, these patients underwent neurocognitive tests 120 min after consuming 50 g of a ketogenic formula (Ketonformula®) containing 20 g of medium-chain triglycerides (MCTs) or an isocaloric placebo formula without MCTs. Patients then took 50 g of the ketogenic formula daily for up to 12 weeks and underwent monthly neurocognitive testing. In the first study, there was no significant difference in any of the cognitive test results between the ketogenic and placebo groups. In the subsequent study of chronic use of the ketogenic formula, 16 of the 20 patients completed the 12-week treatment. At 8 weeks after the start of the study, the patients showed significant improvements in their immediate and delayed logical memory tests compared to baseline, and at 12 weeks they showed significant improvements in the digit-symbol encoding test and the immediate logical memory test compared to baseline. In addition, 20 adults with mild cognitive impairment (MCI) or cognitively normal were fed a low-fat American Heart Association diet or a high-fat modified Mediterranean ketogenic diet (MMKD) for 6 weeks, followed by a 6-week washout period, after which they switched to the other diet. Shot-gun metagenomics and metabolomics showed that people with MCI who were fed the MMKD had lower levels of the GABA-producing microbes Alistipes species and GABA, and higher levels of the GABA-regulating microbe Akkermansia muciniphila [41].

Other supplements and vitamins have also been studied in AD to understand their effect on dementia progression. 101 patients clinically diagnosed with probable AD were recruited into a randomised, single-blind, placebo-controlled trial evaluating folic acid, and vitamin B12 supplementation on cognition and inflammation. The results showed a beneficial effect on behavioural scores and blood inflammatory parameters in patients who did not consume a folic acid-enriched diet [40].

Dietary interventions have a long history in the treatment of various diseases. However, studies of the use of diet or dietary supplements as therapeutic strategies do not always assess the downstream effects on gut microbial composition or molecular pathways. It is essential that future studies include these aspects to gain further insight and determine the links between diet, microbiota, and metabolic pathways associated with cognitive decline.

As discussed in previous chapters, a growing body of evidence highlights the important role of the gut microbiota in AD and dementia. However, there are still many unanswered questions in this field that hinder a full understanding of the role of the microbiota at different stages of pathogenesis and its potential to mitigate or delay the progression of AD. A key point in clinical investigations is to translate findings from limited study cohorts into practical strategies that benefit a broader population of patients with AD or other neurological disorders. Outcomes following probiotics, FMT, and dietary interventions are dependent on the metabolic and microbiome profile of the individual, highlighting the importance of personalised approaches [46]. Only a thorough understanding of the underlying mechanisms and microbial interactions will allow the development of targeted dietary or microbial interventions, such as FMT or probiotics that focus on the delivery of microbes, dietary components, or metabolites that can actually mitigate the patient’s cognitive decline. This will pave the way for personalised treatment approaches and minimise the risk of side effects, e.g., by excluding redundant bacteria, without compromising the disease-modifying effects of microbial interventions. In particular, the lack of analysis of the microbiota at different stages of disease development, including early stages prior to clinical symptom manifestation, is a significant gap in current research. Obtaining such data would also provide valuable insights into whether microbiota dysbiosis is a cause or consequence of AD. Furthermore, it is imperative to integrate microbiota analysis with clinical neurological and inflammatory parameters, as well as with detailed information on patients’ lifestyle, including dietary habits (e.g., using detailed and validated food frequency questionnaires), both before and after interventions designed to alter microbiota composition. Although not discussed within the scope of this review, given the early onset of molecular manifestations of AD before the onset of clinical symptoms, it may be interesting to understand how the use or overuse of antibiotics might affect the composition of the gut microbiota and its potential association with early manifestations of AD. In summary, we believe the suggested approaches are essential to characterise disease progression and design novel and effective interventions.

The authors have no conflicts of interest to declare.

F.R. is supported by the following funding systems: Helmut Horten Fundation Grant, Biostime Institute Nutrition and Care (BINC)-Geneva grant, Novartis Grant, FISM-Fondazione Italiana Sclerosi Multipla-Cod.:2020/R-Single/029 and financed or co-financed with the “5 per mille” public funding, JPND Research AD_imprint, and SFB TRR241 B03 of the German Research Foundation.

M.C. is supported by JPND Research AD_imprint. J.B.K. is supported by SFB TRR241 B03 of the German Research Foundation. Supplementary Figure 1 has been created with BioRender.com.

M.C., J.B.K., and F.R. conceived the idea and wrote the manuscript, M.C. and J.B.K. generated tables.

Additional Information

Matteo Ceccon and Johan B. Kantsjö contributed equally to this work.

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