Alzheimer’s Dementia

Researched by:

  • Kimberly Eyer ID
    Kimberly Eyer

    User avatarKimberly Eyer, a Registered Nurse with 30 years of nursing experience across diverse settings, including Home Health, ICU, Operating Room Nursing, and Research. Her roles have encompassed Operating Room Nurse, RN First Assistant, and Acting Director of a Same Day Surgery Center. Her specialty areas include Adult Cardiac Surgery, Congenital Cardiac Surgery, Vascular Surgery, and Neurosurgery.

  • Karen Pendergrass ID
    Karen Pendergrass

    User avatarKaren Pendergrass is a microbiome researcher specializing in microbiome-targeted interventions (MBTIs). She systematically analyzes scientific literature to identify microbial patterns, develop hypotheses, and validate interventions. As the founder of the Microbiome Signatures Database, she bridges microbiome research with clinical practice. In 2012, based on her own investigative research, she became the first documented case of FMT for Celiac Disease—four years before the first published case study.

Fact-checked by:

  • Kimberly Eyer ID
    Kimberly Eyer

    User avatarKimberly Eyer, a Registered Nurse with 30 years of nursing experience across diverse settings, including Home Health, ICU, Operating Room Nursing, and Research. Her roles have encompassed Operating Room Nurse, RN First Assistant, and Acting Director of a Same Day Surgery Center. Her specialty areas include Adult Cardiac Surgery, Congenital Cardiac Surgery, Vascular Surgery, and Neurosurgery.

May 18, 2025

Alzheimer’s disease (D) is a progressive neurodegenerative disorder characterized by amyloid-beta (Aβ) plaques, neurofibrillary tangles, neuroinflammation, and metabolic dysfunction, ultimately leading to cognitive decline and dementia. Emerging research highlights the microbiota-gut-brain axis as a crucial factor in D pathogenesis, with gut dysbiosis contributing to neuroinflammation, immune dysregulation, and blood-brain barrier permeability. Microbial metabolites, such as […]

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Researched by:

  • Kimberly Eyer ID
    Kimberly Eyer

    User avatarKimberly Eyer, a Registered Nurse with 30 years of nursing experience across diverse settings, including Home Health, ICU, Operating Room Nursing, and Research. Her roles have encompassed Operating Room Nurse, RN First Assistant, and Acting Director of a Same Day Surgery Center. Her specialty areas include Adult Cardiac Surgery, Congenital Cardiac Surgery, Vascular Surgery, and Neurosurgery.

  • Karen Pendergrass ID
    Karen Pendergrass

    User avatarKaren Pendergrass is a microbiome researcher specializing in microbiome-targeted interventions (MBTIs). She systematically analyzes scientific literature to identify microbial patterns, develop hypotheses, and validate interventions. As the founder of the Microbiome Signatures Database, she bridges microbiome research with clinical practice. In 2012, based on her own investigative research, she became the first documented case of FMT for Celiac Disease—four years before the first published case study.

Fact-checked by:

  • Kimberly Eyer ID
    Kimberly Eyer

    User avatarKimberly Eyer, a Registered Nurse with 30 years of nursing experience across diverse settings, including Home Health, ICU, Operating Room Nursing, and Research. Her roles have encompassed Operating Room Nurse, RN First Assistant, and Acting Director of a Same Day Surgery Center. Her specialty areas include Adult Cardiac Surgery, Congenital Cardiac Surgery, Vascular Surgery, and Neurosurgery.

Last Updated: February 1, 2025

Microbiome Signatures identifies and validates condition-specific microbiome shifts and interventions to accelerate clinical translation. Our multidisciplinary team supports clinicians, researchers, and innovators in turning microbiome science into actionable medicine.

Karen Pendergrass

Karen Pendergrass is a microbiome researcher specializing in microbiome-targeted interventions (MBTIs). She systematically analyzes scientific literature to identify microbial patterns, develop hypotheses, and validate interventions. As the founder of the Microbiome Signatures Database, she bridges microbiome research with clinical practice. In 2012, based on her own investigative research, she became the first documented case of FMT for Celiac Disease—four years before the first published case study.

Overview

Alzheimer’s disease (AD) is a progressive neurodegenerative disorder characterized by amyloid-beta (Aβ) plaques, neurofibrillary tangles, neuroinflammation, and metabolic dysfunction, ultimately leading to cognitive decline and dementia. Emerging research highlights the microbiota-gut-brain axis as a crucial factor in AD pathogenesis, with gut dysbiosis contributing to neuroinflammation, immune dysregulation, and blood-brain barrier permeability. Microbial metabolites, such as short-chain fatty acids and amyloid-like proteins, can influence neurodegeneration, either exacerbating or mitigating disease progression. These findings position the microbiome as a key target for potential interventions, including dietary modifications, probiotics, and fecal microbiota transplantation (FMT), while salivary microbiome analysis presents a promising avenue for non-invasive AD diagnostics. Understanding and standardizing microbiome signatures may provide critical insights into disease mechanisms and open new pathways for early detection and therapeutic strategies.

Microbiome Signature: Alzheimer’s Dementia

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Metallomic analysis of brain tissues distinguishes between cases of dementia with Lewy bodies, Alzheimer’s disease, and Parkinson’s disease dementia
June 26, 2024
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Metallomic Signatures
Metallomic Signatures

Did you know?
Metallomic signatures can reveal hidden drivers of disease by mapping how trace metals like nickel, iron, and cadmium shape microbial behavior and immune responses. These signatures not only help identify toxic exposures but also spotlight metal-dependent pathogens, offering new targets for precision-guided therapies.

Dementia with Lewy bodies (DLB) brains show widespread copper depletion and region-specific sodium, manganese, iron, and selenium alterations. While copper loss is common to AD and PDD, DLB presents a distinct metallomic fingerprint, enabling disease differentiation via PCA. Metallomic profiling may aid in diagnosing overlapping dementias and reveals unique pathophysiological signatures.

What was studied?

This original research study investigated whether the metallomic profile of dementia with Lewy bodies (DLB) differs from that of Alzheimer’s disease (AD) and Parkinson’s disease dementia (PDD). The study sought to determine if post-mortem changes in elemental concentrations—particularly in essential metals—could help differentiate these often-overlapping neurodegenerative conditions. Using ICP-MS (Inductively Coupled Plasma–Mass Spectrometry), the authors quantified concentrations of nine elements (Na, Mg, K, Ca, Mn, Fe, Cu, Zn, and Se) across 10 brain regions from DLB patients and age-/sex-matched controls. These findings were directly compared to previously published metallomic profiles for AD and PDD, produced using identical methodologies. Multivariate analyses (PCA and PLS-DA) were employed to assess the potential for disease discrimination based on metal signatures.

Who was studied?

The study analyzed post-mortem brain tissue from 23 DLB patients and 20 controls, collected across ten distinct brain regions. Comparative analyses included prior datasets from similarly matched AD and PDD patient cohorts.

What were the most important findings?

n this study, region-specific metallomic profiling revealed distinct trace element alterations in Dementia with Lewy Bodies (DLB). Copper (Cu) levels were consistently decreased in five of ten DLB brain regions, including the cingulate gyrus (CG), middle temporal gyrus (MTG), primary visual cortex (PVC), substantia nigra (SN), and putamen (PUT), suggesting a widespread Cu deficiency. Sodium (Na) was elevated in four regions—medulla (MED), cerebellum (CB), MTG, and CG—while more localized changes were observed for other metals. Iron (Fe) levels were increased in the motor cortex (MCX) and CG, whereas manganese (Mn) was decreased in both the PVC and MED. Calcium (Ca) was specifically reduced in the hippocampus, and selenium (Se) was also decreased in the PVC. No significant differences in magnesium, potassium, or zinc levels were observed between DLB and control brains. Multivariate analyses, including Principal Component Analysis (PCA) and Partial Least Squares-Discriminant Analysis (PLS-DA), demonstrated that DLB could be distinctly separated from Alzheimer’s disease (AD) and Parkinson’s disease dementia (PDD) based on metallomic signatures. Specifically, CG, MTG, and PVC profiles enabled discrimination between DLB and AD, while the PVC alone differentiated DLB from PDD. Notably, copper depletion emerged as the only common alteration across DLB, AD, and PDD, underscoring its potential central role in the pathogenesis of neurodegenerative diseases. The authors propose that these metallomic fingerprints may reflect disease-specific mechanisms, including variations in oxidative stress, protein aggregation, and mitochondrial dysfunction.

What are the greatest implications of this study?

This study provides compelling evidence that distinct metallomic signatures exist across DLB, AD, and PDD, despite shared pathology such as copper depletion. It strengthens the emerging concept that trace metal dysregulation is disease-specific, rather than a general byproduct of neurodegeneration. The findings support the idea that metallomic profiling—potentially via cerebrospinal fluid or advanced imaging in living patients—could improve differential diagnosis of dementias with overlapping clinical features. Furthermore, the study reinforces the hypothesis that metal dyshomeostasis, particularly copper depletion, may be a contributing pathogenic mechanism, impairing antioxidant defenses and mitochondrial function. These findings could inform new diagnostic tools and therapeutic targets.

Neuromicrobiology, an Emerging Neurometabolic Facet of the Gut Microbiome?
January 17, 2023
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Brain Health
Brain Health

Did you know?
The gut microbiome produces over 90% of the body’s serotonin, a key neurotransmitter that regulates mood, sleep, and cognition.

The paper reviews neuromicrobiology, examining how the gut microbiome influences brain health and cognitive function through neuroactive metabolites like GABA, serotonin, and dopamine, focusing on their biosynthesis, transport, and impact on the gut-brain axis and mental health.

What Was Reviewed?

The paper reviews the emerging field of neuromicrobiology, which explores the interactions between the gut microbiome and the brain, particularly focusing on how gut microbiota produce neuroactive metabolites that influence cognitive function and brain health. It addresses the biosynthesis, absorption, and transport of these neuroactive metabolites, including neurotransmitters such as γ-aminobutyric acid (GABA), serotonin, dopamine, and others. The review also discusses how these compounds interact with the gut-brain axis and their implications for mental health and neurological disorders.

Who Was Reviewed?

The review synthesizes research across multiple studies involving both human and animal models. It examines the gut microbiota's role in producing neuroactive compounds and their potential effects on the central nervous system (CNS). The paper does not focus on a specific population but rather on a broad range of studies that include both healthy and diseased subjects to understand the underlying mechanisms of gut-brain communication via microbial metabolites.

What Were the Most Important Findings of This Review?

Diversity of Neuroactive Metabolites:

The review highlights the diversity of neuroactive metabolites produced by the gut microbiome, including neurotransmitters like GABA, serotonin, dopamine, and their precursors. These metabolites are synthesized by a variety of gut bacteria, and their production is influenced by factors such as diet, genetics, and environmental conditions.


Mechanisms of Interaction with the Brain:

The paper details the pathways through which these neuroactive metabolites interact with the brain, emphasizing the "bottom-up" pathway of the gut-brain axis. This includes the direct signaling of neurotransmitters via the vagus nerve, modulation of the immune system, and the transport of metabolites across the blood-brain barrier (BBB) via transport proteins or secreted microbial extracellular vesicles (MEVs).


Impact on Mental Health and Neurological Disorders:

The review discusses how dysbiosis (an imbalance in gut microbiota) is linked to various mental health disorders, including depression, anxiety, and neurodegenerative diseases like Alzheimer's and Parkinson's. It suggests that microbial metabolites could play a significant role in the pathophysiology of these conditions, offering potential targets for therapeutic interventions.


Microbiota-Targeted Interventions (MBTIs):

The paper underscores the potential of microbiome-targeted interventions (MBTIs), such as prebiotics, probiotics, synbiotics, and postbiotics, to modulate gut-brain interactions. However, it also notes that the precise mechanisms underlying these interventions are not fully understood, which limits their current therapeutic application.


Challenges and Future Directions:

A major theme is the complexity and challenges of translating current findings into clinical practice. The review identifies gaps in understanding how microbial neuroactive metabolites specifically influence brain function and calls for more mechanistic studies to establish causality and therapeutic potential.

What Are the Greatest Implications of This Review?

Advancement of Neuromicrobiology:

The review positions neuromicrobiology as a crucial field for understanding the gut-brain axis and its impact on brain health. It suggests that advances in this area could lead to novel approaches for preventing and treating neurological and psychiatric disorders by targeting the gut microbiome.


Potential for Novel Therapeutics:

The insights into microbial production of neuroactive compounds open up possibilities for developing new microbiota-targeted therapies. These could include specific probiotics engineered to produce neurotransmitters, or prebiotic diets designed to enhance the production of beneficial metabolites, which could be tailored to individual patient needs based on their gut microbiome composition.


Integration of Multi-Omics Approaches:

The paper calls for the integration of metagenomic, metabolomic, and transcriptomic data to better understand the microbiome-gut-brain axis. This could enable a more comprehensive understanding of how gut microbes influence brain health and lead to the identification of biomarkers for disease or targets for intervention.


Need for Mechanistic Research:

The "Neuromicrobiology, an Emerging Neurometabolic Facet of the Gut Microbiome?" review emphasizes the need to move beyond correlation studies and towards mechanistic research that clarifies how specific gut microbes and their metabolites influence brain function. This will be critical for developing evidence-based therapeutic applications and understanding individual variability in response to microbiome-targeted interventions.


Implications for Public Health:

By highlighting the role of the gut microbiome in brain health, the review suggests that dietary and lifestyle interventions targeting the gut microbiome could become a key component of public health strategies for preventing cognitive decline and mental health disorders.

Image modified from the original "Neuromicrobiology, an emerging neurometabolic facet of the gut microbiome?" review paper. Figure 4: The pathways through which gut microbiota-derived neuroactive compounds reach the brain—indirect transportation via modulation of host neurotransmitter biosynthesis, microbial extracellular vesicle (MEV) transportation, and direct transport—highlight the complex interactions between the gut and the brain. These mechanisms provide multiple routes through which the gut microbiome can impact brain function and behavior, emphasizing the importance of the gut-brain axis in health and disease.
Alzheimer's Disease Microbiome Is Associated with Dysregulation of the Anti-Inflammatory P-Glycoprotein Pathway

The microbiota-gut-brain axis is a bidirectional communication system that is poorly understood. Alzheimer's disease (AD), the most common cause of dementia, has long been associated with bacterial infections and inflammation-causing immunosenescence. Recent studies examining the intestinal microbiota of AD patients revealed that their microbiome differs from that of subjects without dementia. In this work, we prospectively enrolled 108 nursing home elders and followed each for up to 5 months, collecting longitudinal stool samples from which we performed metagenomic sequencing and in vitro T84 intestinal epithelial cell functional assays for P-glycoprotein (P-gp) expression, a critical mediator of intestinal homeostasis. Our analysis identified clinical parameters as well as numerous microbial taxa and functional genes that act as predictors of AD dementia in comparison to elders without dementia or with other dementia types. We further demonstrate that stool samples from elders with AD can induce lower P-gp expression levels in vitro those samples from elders without dementia or with other dementia types. We also paired functional studies with machine learning approaches to identify bacterial species differentiating the microbiome of AD elders from that of elders without dementia, which in turn are accurate predictors of the loss of dysregulation of the P-gp pathway. We observed that the microbiome of AD elders shows a lower proportion and prevalence of bacteria with the potential to synthesize butyrate, as well as higher abundances of taxa that are known to cause proinflammatory states. Therefore, a potential nexus between the intestinal microbiome and AD is the modulation of intestinal homeostasis by increases in inflammatory, and decreases in anti-inflammatory, microbial metabolism.IMPORTANCE Studies of the intestinal microbiome and AD have demonstrated associations with microbiome composition at the genus level among matched cohorts. We move this body of literature forward by more deeply investigating microbiome composition via metagenomics and by comparing AD patients against those without dementia and with other dementia types. We also exploit machine learning approaches that combine both metagenomic and clinical data. Finally, our functional studies using stool samples from elders demonstrate how the c microbiome of AD elders can affect intestinal health via dysregulation of the P-glycoprotein pathway. P-glycoprotein dysregulation contributes directly to inflammatory disorders of the intestine. Since AD has been long thought to be linked to chronic bacterial infections as a possible etiology, our findings therefore fill a gap in knowledge in the field of AD research by identifying a nexus between the microbiome, loss of intestinal homeostasis, and inflammation that may underlie this neurodegenerative disorder.

APOE-ε4 Carrier Status and Gut Microbiota Dysbiosis in Patients With Alzheimer Disease

BACKGROUND: Alternations in gut microbiota and a number of genes have been implicated as risk factors for the development of Alzheimer disease (AD). However, the interactions between the altered bacteria and risk genetic variants remain unclear. OBJECTIVE: We aimed to explore associations of the risk genetic variants with altered gut bacteria in the onset of AD. METHODS: We collected baseline data and stool and blood samples from 30 AD patients and 47 healthy controls in a case-control study. The rs42358/rs4512 (ApoE), rs3851179 (PICALM), rs744373 (BIN1), rs9331888 (CLU), rs670139 (MS4A4E), rs3764650 (ABCA7), rs3865444 (CD33), rs9349407 (CD2AP), rs11771145 (EPHA1), and rs3818361/rs6656401 (CR1) were sequenced, and microbiota composition was characterized using 16S rRNA gene sequencing. The associations of the altered gut bacteria with the risk genetics were analyzed. RESULTS: Apolipoprotein ε4 allele and rs744373 were risk loci for the AD among 12 genetic variants. Phylum Proteobacteria; orders Enterobacteriales, Deltaproteobacteria, and Desulfovibrionales; families Enterobacteriaceae and Desulfovibrionaceae; and genera Escherichia-Shigella, Ruminococcaceae_UCG_002, Shuttleworthia, Anaerofustis, Morganelia, Finegoldia, and Anaerotruncus were increased in AD subjects, whereas family Enterococcaceae and genera Megamonas, Enterococcus, and Anaerostipes were more abundant in controls (P <0.05). Among the altered microbiota, APOE ε4 allele was positively associated with pathogens: Proteobacteria. CONCLUSION: The interaction of APOE ε4 gene and the AD-promoting pathogens might be an important factor requiring for the promotion of AD. Targeting to microbiota might be an effective therapeutic strategy for AD susceptible to APOE ε4 allele. This needs further investigation.

Altered microbiomes distinguish Alzheimer's disease from amnestic mild cognitive impairment and health in a Chinese cohort

OBJECTIVE: (Background): Alzheimer's disease (AD), clinically characterized by the progressive neurodegenerative condition and cognitive impairment, is one of the main causes of disability in elder people worldwide. Recently, several animal studies indicated that the 'gut-brain' axis might contribute to the amyloid deposition of AD. However, data about gut dysbiosis in human AD remains scarce in the literature, especially including the whole process of AD. In this prospective and cross-sectional study, we aimed at identifying differences in microbiome between patients with AD (Pre-onset stage amnestic mild cognitive impairment, aMCI; and AD) and the normal cognition healthy controls (HC). Additionally, the potential association between IM and clinical characteristics of AD was evaluated. METHODS: A total of 97 subjects (33 AD, 32 aMCI, and 32 HC) were recruited in the study. The composition of gut bacterial communities was determined by 16S ribosomal RNA Miseq sequencing. In addition, Phylogenetic Investigation of Communities by Reconstruction of Unobserved States (PICRUSt) was used to predict function shift of intestinal microbiota. The Mini-Mental State Examination (MMSE), Montreal Cognitive Assessment (MoCA) or Clinical Dementia Rating (CDR) scores were used to evaluate the severity of cognitive impairment in patients. RESULTS: The fecal microbial diversity was decreased in AD patients compared with aMCI patients and HC. And the microbial composition was distinct among aMCI, AD and healthy control groups. Among bacterial taxa, the proportion of phylum Firmicutes was significantly reduced (P = 0.008), whereas Proteobacteria (P = 0.024) was highly enriched in the AD compared with HC. In addition, similar alterations were observed at the order, class and family levels of these two phyla. And Gammaproteobacteria, Enterobacteriales and Enterobacteriaceae showed a progressive enriched prevalence from HC to aMCI and AD patients. Further, a significant correlation was observed between the clinical severity scores of AD patients and the abundance of altered microbiomes. Moreover, the KEGG results showed the increased modules related to glycan biosynthesis and metabolism in AD and aMCI patients and decreased pathways related to immune system in AD patients. Importantly, the discriminating models based on predominant microbiota could effectively distinguish aMCI and AD from HC (AUC = 0.890, 0.940, respectively), and also AD from aMCI (AUC = 0.925). Notably, the models based on the abundance of family Enterobacteriaceae could distinguish AD from both aMCI (AUC = 0.688) and HC (AUC = 0.698). CONCLUSIONS: Distinct microbial communities, especially enriched Enterobacteriaceae, were associated with patients with AD when compared with predementia stage aMCI and healthy subjects. These novel findings will give new clues to understand the disease and provide new therapeutic target for intervention or a marker for this disease.

Analysis of Salivary Microbiome in Patients with Alzheimer's Disease

Recent studies found that poor oral hygiene was associated with increased risk of dementia, and the number of oral bacteria significantly increased in the brain tissues of patients with Alzheimer's disease (AD), suggesting that the oral microbiota may play an important role in the pathogenesis of AD. However, the actual composition of oral bacteria communities in patients with AD and whether these oral bacteria are associated with disease severity remain largely unknown. Also, the APOEɛ4 polymorphism is a strong risk factor for sporadic AD, and it would be pertinent to see if the bacterial flora was different in those patients who were APOEɛ4 positive. A total of 78 subjects were recruited in this study, including 39 patients with AD and 39 healthy controls. Saliva was collected from each subject. 16S ribosomal RNA (16S rRNA) sequencing was conducted to analyze the salivary microbiota, and Sanger sequencing was performed to analyze the APOE genotype. There was a significantly lower richness and diversity of saliva microbiota detected in AD patients than healthy controls. The relative abundance of Moraxella, Leptotrichia, and Sphaerochaeta in the saliva of AD patients greatly increased, whereas that of Rothia was significantly reduced. Compared with APOEɛ4 (-) patients, the level of Abiotrophia and Desulfomicrobium was comparatively abundant, while Actinobacillus and Actinomyces decreased significantly in patients carrying the APOEɛ4. No bacteria were found to be associated with the severity of AD. This is the first study to analyze the salivary microorganisms in patients with AD, and we discovered that the composition of salivary microbiome was altered in AD, providing further support for the role of the oral microbiome in AD development.

Disturbed microbial ecology in Alzheimer's disease: evidence from the gut microbiota and fecal metabolome

BACKGROUND: Gut microbiota (GMB) alteration has been reported to influence the Alzheimer's disease (AD) pathogenesis through immune, endocrine, and metabolic pathways. This study aims to investigate metabolic output of the dysbiosis of GMB in AD pathogenesis. In this study, the fecal microbiota and metabolome from 21 AD participants and 44 cognitively normal control participants were measured. Untargeted GMB taxa was analyzed through 16S ribosomal RNA gene profiling based on next-generation sequencing and fecal metabolites were quantified by using ultrahigh performance liquid chromatography-mass spectrometry (UPLC-MS). RESULTS: Our analysis revealed that AD was characterized by 15 altered gut bacterial genera, of which 46.7% (7/15 general) was significantly associated with a series of metabolite markers. The predicted metabolic profile of altered gut microbial composition included steroid hormone biosynthesis, N-Acyl amino acid metabolism and piperidine metabolism. Moreover, a combination of 2 gut bacterial genera (Faecalibacterium and Pseudomonas) and 4 metabolites (N-Docosahexaenoyl GABA, 19-Oxoandrost-4-ene-3,17-dione, Trigofoenoside F and 22-Angeloylbarringtogenol C) was able to discriminate AD from NC with AUC of 0.955 in these 65 subjects. CONCLUSIONS: These findings demonstrate that gut microbial alterations and related metabolic output changes may be associated with pathogenesis of AD, and suggest that fecal markers might be used as a non-invasive examination to assist screening and diagnosis of AD.

Gut Microbiome Alterations Precede Cerebral Amyloidosis and Microglial Pathology in a Mouse Model of Alzheimer's Disease

Emerging evidence suggests that the gut microbiome actively regulates cognitive functions and that gut microbiome imbalance is associated with Alzheimer's disease (AD), the most prevalent neurodegenerative disorder. However, the changes in gut microbiome composition in AD and their association with disease pathology, especially in the early stages, are unclear. Here, we compared the profiles of gut microbiota between APP/PS1 transgenic mice (an AD mouse model) and their wild-type littermates at different ages by amplicon-based sequencing of 16S ribosomal RNA genes. Microbiota composition started diverging between the APP/PS1 and wild-type mice at young ages (i.e., 1-3 months), before obvious amyloid deposition and plaque-localized microglial activation in the cerebral cortex in APP/PS1 mice. At later ages (i.e., 6 and 9 months), there were distinct changes in the abundance of inflammation-related bacterial taxa including Escherichia-Shigella, Desulfovibrio, Akkermansia, and Blautia in APP/PS1 mice. These findings suggest that gut microbiota alterations precede the development of key pathological features of AD, including amyloidosis and plaque-localized neuroinflammation. Thus, the investigation of gut microbiota might provide new avenues for developing diagnostic biomarkers and therapeutic targets for AD.

Gut Microbiome Features of Chinese Patients Newly Diagnosed with Alzheimer's Disease or Mild Cognitive Impairment

BACKGROUND: Patients with Alzheimer's disease (AD) have gut microbiome alterations compared with healthy controls. However, previous studies often assess AD patients who have been on medications or other interventions for the disease. Also, simultaneous determination of gut microbiome in patients with mild cognitive impairment (MCI) or AD in a study is rare. OBJECTIVE: To determine whether there was a gut microbiome alteration in patients newly diagnosed with AD or MCI and whether the degree of gut microbiome alteration was more severe in patients with AD than patients with MCI. METHODS: Fecal samples of 18 patients with AD, 20 patients with MCI, and 18 age-matched healthy controls were collected in the morning for 16S ribosomal RNA sequencing. No patient had medications or interventions for AD or MCI before the samples were collected. RESULTS: Although there was no difference in the microbial α-diversity among the three groups, patients with AD or MCI had increased β-diversity compared with healthy controls. Patients with AD had decreased Bacteroides, Lachnospira, and Ruminiclostridium_9 and increased Prevotella at the genus level compared with healthy controls. The changing direction of these genera in patients with MCI was the same as patients with AD. However, Lachnospira was the only genus whose abundance in patients with MCI was statistically significantly lower than healthy controls. Bacteroides, Lachnospira, and Ruminiclostridium_9 were positively associated with better cognitive functions whereas Prevotella was on the contrary when subjects of all three groups were considered. The negative correlation of Prevotella with cognitive functions remained among patients with MCI. CONCLUSION: Patients newly diagnosed with AD or MCI have gut dysbiosis that includes the decrease of potentially protective microbiome, such as Bacteroides, and the increase of microbiome that can promote inflammation, such as Prevotella. Our results support a novel idea that the degree of gut dysbiosis is worsened with the disease stage from MCI to AD.

Gut Microbiota is Altered in Patients with Alzheimer's Disease

Previous studies suggest that gut microbiota is associated with neuropsychiatric disorders, such as Parkinson's disease, amyotrophic lateral sclerosis, and depression. However, whether the composition and diversity of gut microbiota is altered in patients with Alzheimer's disease (AD) remains largely unknown. In the present study, we collected fecal samples from 43 AD patients and 43 age- and gender-matched cognitively normal controls. 16S ribosomal RNA sequencing technique was used to analyze the microbiota composition in feces. The composition of gut microbiota was different between the two groups. Several bacteria taxa in AD patients were different from those in controls at taxonomic levels, such as Bacteroides, Actinobacteria, Ruminococcus, Lachnospiraceae, and Selenomonadales. Our findings suggest that gut microbiota is altered in AD patients and may be involved in the pathogenesis of AD.

Gut microbiome alterations in Alzheimer's disease

Alzheimer's disease (AD) is the most common form of dementia. However, the etiopathogenesis of this devastating disease is not fully understood. Recent studies in rodents suggest that alterations in the gut microbiome may contribute to amyloid deposition, yet the microbial communities associated with AD have not been characterized in humans. Towards this end, we characterized the bacterial taxonomic composition of fecal samples from participants with and without a diagnosis of dementia due to AD. Our analyses revealed that the gut microbiome of AD participants has decreased microbial diversity and is compositionally distinct from control age- and sex-matched individuals. We identified phylum- through genus-wide differences in bacterial abundance including decreased Firmicutes, increased Bacteroidetes, and decreased Bifidobacterium in the microbiome of AD participants. Furthermore, we observed correlations between levels of differentially abundant genera and cerebrospinal fluid (CSF) biomarkers of AD. These findings add AD to the growing list of diseases associated with gut microbial alterations, as well as suggest that gut bacterial communities may be a target for therapeutic intervention.

Gut microbiome characteristics in subjective cognitive decline, mild cognitive impairment and Alzheimer's disease: a systematic review and meta-analysis

BACKGROUND AND PURPOSE: The gut microbiome has been reported to be closely related to Alzheimer's disease (AD) progression. Here, a comprehensive meta-analysis of gut microbial characteristics in AD, mild cognitive impairment (MCI) and subjective cognitive decline (SCD) was performed to compare gut microbial alterations at each stage. METHODS: A total of 10 databases (CNKI, WanFang, VIP, SinoMed, WOS, PubMed, Embase, Cochrane Library, PsycINFO and Void) were searched and 34 case-control studies were included. α and β diversity and the relative abundance of gut microbiota were analysed as outcome indices. Data analysis was performed using Review Manager (5.4.1) and R. RESULTS: Chao1 and Shannon index levels in AD were significantly lower compared with healthy controls (HCs), and the Chao1 index was significantly lower in MCI compared with HCs. There was a significant difference in β diversity of gut microbiomes in patients (SCD, MCI, AD) compared with HCs. The relative abundance of Firmicutes at the phylum level was significantly lower in patients with AD and MCI than HCs. However, the relative abundance of Bacteroidetes at the phylum level was significantly higher in patients with MCI than HCs. There was an increasing trend for Enterobacteriaceae and a decreasing trend for Ruminococcaceae, Lachnospiraceae and Lactobacillus during AD; Lactobacillus showed a decreasing trend early in SCD. CONCLUSION: Our results indicated that there were gut microbiological abnormalities in AD, even as early as the SCD stage. The dynamic, consistent changes in gut microbes with the disease process showed that they might serve as potential biomarkers for early identification and diagnosis of AD.

Gut microbiota regulate Alzheimer's disease pathologies and cognitive disorders via PUFA-associated neuroinflammation

OBJECTIVE: This study is to investigate the role of gut dysbiosis in triggering inflammation in the brain and its contribution to Alzheimer's disease (AD) pathogenesis. DESIGN: We analysed the gut microbiota composition of 3×Tg mice in an age-dependent manner. We generated germ-free 3×Tg mice and recolonisation of germ-free 3×Tg mice with fecal samples from both patients with AD and age-matched healthy donors. RESULTS: Microbial 16S rRNA sequencing revealed Bacteroides enrichment. We found a prominent reduction of cerebral amyloid-β plaques and neurofibrillary tangles pathology in germ-free 3×Tg mice as compared with specific-pathogen-free mice. And hippocampal RNAseq showed that inflammatory pathway and insulin/IGF-1 signalling in 3×Tg mice brain are aberrantly altered in the absence of gut microbiota. Poly-unsaturated fatty acid metabolites identified by metabolomic analysis, and their oxidative enzymes were selectively elevated, corresponding with microglia activation and inflammation. AD patients' gut microbiome exacerbated AD pathologies in 3×Tg mice, associated with C/EBPβ/asparagine endopeptidase pathway activation and cognitive dysfunctions compared with healthy donors' microbiota transplants. CONCLUSIONS: These findings support that a complex gut microbiome is required for behavioural defects, microglia activation and AD pathologies, the gut microbiome contributes to pathologies in an AD mouse model and that dysbiosis of the human microbiome might be a risk factor for AD.

Injection of amyloid-β to lateral ventricle induces gut microbiota dysbiosis in association with inhibition of cholinergic anti-inflammatory pathways in Alzheimer's disease

BACKGROUND: Alzheimer's disease (AD) is the most common neurodegenerative disease and its pathogenesis is still unclear. There is dysbiosis of gut microbiota in AD patients. More importantly, dysbiosis of the gut microbiota has been observed not only in AD patients, but also in patients with mild cognitive impairment (MCI). However, the mechanism of gut microbiota dysbiosis in AD is poorly understood. Cholinergic anti-inflammatory pathway is an important pathway for the central nervous system (CNS) regulation of peripheral immune homeostasis, especially in the gut. Therefore, we speculated that dysfunction of cholinergic anti-inflammatory pathway is a potential pathway for dysbiosis of the gut microbiota in AD. METHODS: In this study, we constructed AD model mice by injecting Aβ1-42 into the lateral ventricle, and detected the cognitive level of mice by the Morris water maze test. In addition, 16S rDNA high-throughput analysis was used to detect the gut microbiota abundance of each group at baseline, 2 weeks and 4 weeks after surgery. Furthermore, immunofluorescence and western blot were used to detect alteration of intestinal structure of mice, cholinergic anti-inflammatory pathway, and APP process of brain and colon in each group. RESULTS: Aβ1-42 i.c.v induced cognitive impairment and neuron damage in the brain of  mice. At the same time, Aβ1-42 i.c.v induced alteration of gut microbiota at 4 weeks after surgery, while there was no difference at the baseline and 2 weeks after surgery. In addition, changes in colon structure and increased levels of pro-inflammatory factors were detected in Aβ1-42 treatment group, accompanied by inhibition of cholinergic anti-inflammatory pathways. Amyloidogenic pathways in both the brain and colon were accelerated in Aβ1-42 treatment group. CONCLUSIONS: The present findings suggested that Aβ in the CNS can induce gut microbiota dysbiosis, alter intestinal structure and accelerate the amyloidogenic pathways, which were related to inhibiting cholinergic anti-inflammatory pathways.

Mild cognitive impairment has similar alterations as Alzheimer's disease in gut microbiota

OBJECTIVE: Gut microbiota changes before the onset of Alzheimer's disease (AD) and the alterations could be detected in the stage of mild cognitive impairment (MCI). The findings might offer diagnostic biomarkers before the onset of dementia. BACKGROUND: AD is the most common cause of dementia, and MCI is the predementia state. Recent studies suggest the alterations in the gut microbial communities associated with AD, whereas the microbiota in MCI before the onset of dementia has not been discovered and characterized in humans. NEW/UPDATED HYPOTHESIS: We hypothesize that the dysbiosis happens in the MCI stage. Patients with AD and MCI have decreased microbial diversity, and changes in gut microbiota could be detected for early detection of AD. In our preliminary study, we identified differences between AD and normal controls in 11 genera from the feces and 11 genera from the blood. No difference in genera between AD and MCI was detected. Using the diagnostic model from fecal samples with all different genera input, 93% (28 in 30) of patients with MCI could be identified correctly. MAJOR CHALLENGES FOR THE HYPOTHESIS: The diagnosis of MCI and AD in the study was based on symptoms and neuroimaging, and AD biomarkers should be included for precise diagnosis in further validating studies. Besides, as the microbiota changes longitudinally, their relationship with the progress of dementia needs to be studied in the prospective studies. LINKAGE TO OTHER MAJOR THEORIES: Escherichia was observed increased at genus level in both fecal and blood samples from AD and MCI. For AD biomarker, postmortem brain tissue from patients with AD showed lipopolysaccharides and gram-negative Escherichia coli fragments colocalize with amyloid plaque. In this way, the amyloid pathogenesis for AD would be triggered during MCI by gut microbiota shifting. Besides, systemic inflammatory reactions caused by compounds secreted by bacteria may impair the blood-brain barrier and promote neuroinflammation and/or neurodegeneration. Furthermore, abnormal metabolites caused by microbial gene functions have an impact on neurodegeneration.

Modulation of the Gut Microbiota in Memory Impairment and Alzheimer's Disease via the Inhibition of the Parasympathetic Nervous System

The gut microbiota has been demonstrated to play a critical role in maintaining cognitive function via the gut-brain axis, which may be related to the parasympathetic nervous system (PNS). However, the exact mechanism remains to be determined. We investigated that patients with mild cognitive impairment (MCI) and Alzheimer's disease (AD) could exhibit an altered gut microbiota through the suppression of the PNS, compared to the healthy individuals, using the combined gut microbiota data from previous human studies. The hypothesis was validated in rats to suppress the PNS by scopolamine injections. The human fecal bacterial FASTA/Q files were selected and combined from four different AD studies (n = 410). All rats had a high-fat diet and treatments for six weeks. The MD rats had memory impairment by scopolamine injection (2 mg/kg body weight; MD, Control) or no memory impairment by saline injection. The scopolamine-injected rats had a donepezil intake as the positive group. In the optimal model generated from the XGboost analysis, Blautia luti, Pseudomonas mucidoiens, Escherichia marmotae, and Gemmiger formicillis showed a positive correlation with MCI while Escherichia fergusonii, Mycobacterium neglectum, and Lawsonibacter asaccharolyticus were positively correlated with AD in the participants with enterotype Bacteroides (ET-B, n = 369). The predominant bacteria in the AD group were negatively associated in the networking analysis with the bacteria in the healthy group of ET-B participants. From the animal study, the relative abundance of Bacteroides and Bilophilia was lower, and that of Escherichia, Blautia, and Clostridium was higher in the scopolamine-induced memory deficit (MD) group than in the normal group. These results suggest that MCI was associated with the PNS suppression and could progress to AD by exacerbating the gut dysbiosis. MCI increased Clostridium and Blautia, and its progression to AD elevated Escherichia and Pseudomonas. Therefore, the modulation of the PNS might be linked to an altered gut microbiota and brain function, potentially through the gut-brain axis.

Profiles of subgingival microbiomes and gingival crevicular metabolic signatures in patients with amnestic mild cognitive impairment and Alzheimer's disease

BACKGROUND: The relationship between periodontitis and Alzheimer's disease (AD) has attracted more attention recently, whereas profiles of subgingival microbiomes and gingival crevicular fluid (GCF) metabolic signatures in AD patients have rarely been characterized; thus, little evidence exists to support the oral-brain axis hypothesis. Therefore, our study aimed to characterize both the microbial community of subgingival plaque and the metabolomic profiles of GCF in patients with AD and amnestic mild cognitive impairment (aMCI) for the first time. METHODS: This was a cross-sectional study. Clinical examinations were performed on all participants. The microbial community of subgingival plaque and the metabolomic profiles of GCF were characterized using the 16S ribosomal RNA (rRNA) gene high-throughput sequencing and liquid chromatography linked to tandem mass spectrometry (LC-MS/MS) analysis, respectively. RESULTS: Thirty-two patients with AD, 32 patients with aMCI, and 32 cognitively normal people were enrolled. The severity of periodontitis was significantly increased in AD patients compared with aMCI patients and cognitively normal people. The 16S rRNA gene sequencing results showed that the relative abundances of 16 species in subgingival plaque were significantly correlated with cognitive function, and LC-MS/MS analysis identified a total of 165 differentially abundant metabolites in GCF. Moreover, multiomics Data Integration Analysis for Biomarker discovery using Latent cOmponents (DIABLO) analysis revealed that 19 differentially abundant metabolites were significantly correlated with Veillonella parvula, Dialister pneumosintes, Leptotrichia buccalis, Pseudoleptotrichia goodfellowii, and Actinomyces massiliensis, in which galactinol, sn-glycerol 3-phosphoethanolamine, D-mannitol, 1 h-indole-1-pentanoic acid, 3-(1-naphthalenylcarbonyl)- and L-iditol yielded satisfactory accuracy for the predictive diagnosis of AD progression. CONCLUSIONS: This is the first combined subgingival microbiome and GCF metabolome study in patients with AD and aMCI, which revealed that periodontal microbial dysbiosis and metabolic disorders may be involved in the etiology and progression of AD, and the differential abundance of the microbiota and metabolites may be useful as potential markers for AD in the future.

Metallomic Signatures

A metallomic signature is the condition-specific profile of trace metals and metal-binding molecules that reflects disrupted metal homeostasis.

Brain Health

Brain health encompasses the overall functioning and well-being of the brain, including cognitive function, emotional and psychological well-being, neurological integrity, behavioral health, neurodevelopmental health, age-related brain health, and brain resilience and plasticity.

Brain Health

Brain health encompasses the overall functioning and well-being of the brain, including cognitive function, emotional and psychological well-being, neurological integrity, behavioral health, neurodevelopmental health, age-related brain health, and brain resilience and plasticity.

Microbiome-Targeted Interventions (MBTIs)

Microbiome Targeted Interventions (MBTIs) are cutting-edge treatments that utilize information from Microbiome Signatures to modulate the microbiome, revolutionizing medicine with unparalleled precision and impact.

Brain Health

Brain health encompasses the overall functioning and well-being of the brain, including cognitive function, emotional and psychological well-being, neurological integrity, behavioral health, neurodevelopmental health, age-related brain health, and brain resilience and plasticity.

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