The Gut Microbiome and its Implications for Alzheimer's Disease

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Introduction

Alzheimer’s is a disease that causes dementia, which refers to a state of mental processing/cognitive decline that encompasses a wide variety of symptoms, such as delirium, depression, psychosis, difficulties with sleep, etc [1][2]. Individuals with Alzheimer’s disease gradually experience cognitive impairment, negatively impacting their memory and overall life. Lopez et. al report the following about individuals with Alzheimer’s disease: “There is insidious onset with loss of episodic memory where patients ask questions repeatedly, repeat conversations, and have difficulty remembering details of shared or current events. There is difficulty remembering names of objects and people”[3]. Alzheimer’s disease and the significant cognitive impairment that results continues to affect the individual’s entire body until they can no longer perform basic tasks; ultimately, they die. This is why there is such a need for research relating to both the general development/processes that contribute to the onset of Alzheimer’s disease, as well as potential treatments to prevent or treat the disease.


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Figure 1. Displays the proportions of individuals impacted by Alzheimer's disease. Image produced by the Alzheimers Association in 2019. [1].

Cellular and Molecular Processes that Characterize Development of Alzheimer’s Disease

Information is from the 2019 Alzheimer’s Association Report: Beta-amyloid (Aβ) accumulation is a key factor with respect to the development of Alzheimer’s disease. The presenilin 1 and 2 genes are responsible for the production of presenilins, which comprise the gamma-secretase complex, which is the enzyme complex that is responsible for cleaving the amyloid precursor protein (APP to produce beta-amyloid; thus,“AD[Alzheimer’s disease]-causing mutations… predispose to Aβ deposition, either by increasing Aβ production, increasing the production of the longer more pathological Aβ42 species, or enhancing Aβ aggregation”[4]. When beta-amyloid accumulates in the form of plaques outside the neurons, they interfere with neuron communication, kickstarting cognitive decline and neurodegeneration, and thus causing the development of Alzheimer’s disease. [Picture is from source 4]. One thing that the AD-affected neuron regions all have in common is the presence of tangled filaments. Selkoe states the following about those filaments: “Electron microscopy reveals that most of these fibers consist of pairs of ∼10-nm filaments wound into helices (paired helical filaments or PHF), with a helical period of ∼160 nm”[5]. These fibers are composed of numerous tau filaments that are phosphorylated. Tau is a protein that has an important role with respect to causing the protein tubulin to assemble in microtubules, which play an essential role in cytoskeleton formation, transport, and mitosis. In a normal brain, “Tau is regulated during both normal homeostasis and in stress‐induced responses by an array of posttranslational modifications that includes glycosylation, ubiquitination, glycation, nitration, and oxidation”[6]. In addition, tau can also be regulated by phosphorylation. However, in brains with Alzheimer’s disease, the protein becomes hyperphosphorylated due to a kinase imbalance, causing it to struggle in its role of microtubule formation. In addition, the ubiquitin-proteasome pathway, which plays an important role with respect to the breakdown of tau, can no longer degrade the protein when it is hyperphosphorylated[6].Thus, hyperphosphorylation of tau will cause heavy accumulation of tangled tau filaments, which similar to accumulation of the beta-amyloid protein, can cause severe neuroinflammation, contributing to the development of Alzheimer’s disease.

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Figure 2. Displays the general mechanism through which Aβ42 accumulation leads to onset of Alzheimer's disease. Image produced by Verdile et. al in 2004. [2].


Gut Microbiome and General Relation to Alzheimer’s Disease

The human gut microbiome is home to numerous bacterial species and taxa in general. A research study conducted in 2016 by Cattaneo et. al [7]. involved the measurement of blood cytokine levels as well as the bacterial abundance of the following bacterial species/taxa: “Escherichia/Shigella, Pseudomonas aeruginosa, Eubacterium rectale, Eubacterium hallii, Faecalibacterium prausnitzii, and Bacteroides fragilis”[7]. The first two bacterial taxa were known for their pro-inflammatory activity (inducing inflammation) and the rest were known for their anti-inflammatory activity (fighting against inflammation). Cytokines, important proteins that are part of the innate immune system, are stimulated by excess beta-amyloid production and accumulation (general term for this is amyloidosis). The purpose of their study was to find some correlation between beta-amyloid production and the specific species of bacteria listed above that are commonly found in the human gut microbiome. Through performing amyloid PET scans and bacterial DNA isolation and sequencing on elderly patients with Alzheimer’s disease, the researchers were able to conclude the following:“Interestingly, the abundance of Escherichia/Shigella correlated positively with the levels of IL-1β, CXCL2, and NLRP3, whereas E. rectale correlated negatively with the levels of IL-1β, CXCL2, and NLRP3 and positively with IL-10”[7]. IL-1β, CXCL2, and NLRP3 are cytokines that induce an inflammatory response, whereas the vice versa is true for the cytokine IL-10. The results confirmed the researchers' hypothesis, which was that Escherichia/Shigella bacteria, as they were known for their pro-inflammatory activity, would positive correlate with pro-inflammatory cytokines, which is important as due to the fact that these pro-inflammatory cytokines are already known for their role in the development of AD, these results show that the human gut microbiome definitely has a correlation with AD. Another study [8] conducted by Vogt et. al sought to determine/distinguish factors of the relationship between the human gut microbiome and Alzheimer’s disease, similar to study[7]. Through the study, the researchers determined the following: AD patients had decreased numbers of bacteria belonging to the phyla Firmicutes and Actinobacteria, but also had increased numbers of bacteria belonging to the phyla Bacteroidetes and Proteobacteria. Yet another study conducted by Hopkins and Macfarlane [9] observed differences in human gut microbiome composition between young and elderly individuals. They observed that elderly individuals had lower levels of bacteria from the following phyla: Bifidobacterium and Lactobacillus. These bacteria are especially important, especially considering their role with respect to the production of aminobutyric acid, specifically gamma aminobutyric acid, which has an important role in the maintenance and regulation of the CNS (central nervous system)[9]. Thus, when levels of those particular bacterium decrease, significant cognitive impairment, as well as other symptoms such as depression and anxiety, can occur, demonstrating through that the inevitable changes in an individual's gut microbiome due to age can have significant effects on an individual’s mental state. In general, as age tends to go up, microbial activity and diversity (in the human gut microbiome) decrease, and as a consequence, significant cognitive impairment in the form of Alzheimer’s disease or other neurological disease, can occur (demonstrated by all the research studies discussed above). This is primarily due to the established relationship between the CNS (central nervous system) and gut microbiome, which is technically referred to as the gut-brain axis. Another component of this argument is the blood-brain barrier.


Blood-Brain Barrier/ Gut-Brain Axis

An article by Megur et. al [10] discusses the well-established relationship between the brain and the bacteria represented within the gut microbiome. The article mentions the following strains of bacteria: Escherichia, Lactobacillus, Saccharomyces, and Bacillus. These taxa of bacteria are especially important due to their known involvement with respect to the synthesis of certain amino acids, including, but not limited to, the following: dopamine, histamine, serotonin, and gamma-aminobutyric acid. The three formerly listed amino acids are especially well-known neurotransmitters. The latter, gamma-aminobutyric acid (commonly abbreviated as GABA), is also a crucial neurotransmitter, especially with respect to its application in the case of Alzheimer’s disease. A review article by Li et. al [11] provides more in depth-analysis of GABA and its applications to the conditions underlying Alzheimer’s disease. The article describes GABA as the following: “the principal inhibitory transmitter in mammalian CNS [central nervous system]”[11].This means that GABA takes on a regulatory role through inhibition of neural signal transmissions. Not much is still known yet about the inhibition of GABA production and how it relates to the development of AD, but what we can conclude is that the absence (or especially even overabundance) of GABA-converting microorganisms can result in GABA dysfunction and regulation, potentially having an impact on the signaling and generally neural processes involved in the development of Alzheimer’s disease.

Oral Microbiome and Influence on Alzheimer’s Disease

Similar to the gut microbiome, the human oral cavity is also home to a variety of microbes, composing the oral microbiome. According to source [12], many of the bacteria that compose this microbial community are bacteria that have a tendency to form bacterial biofilms. These biofilms are heavily involved with respect to the maintenance of homeostasis within the oral cavity. Narengaowa et. al state the following, elaborating on the statement above: “The association between biofilms and a healthy gum is characterized by a limited commensal microbiota dominated by members of the phylum Firmicutes, including a diverse group of streptococcal species”[12]. These bacteria also play other significant roles, besides the maintenance of the oral microbiome. Some of those bacteria have significant contributions to the onset of various oral diseases. The following bacteria have been known to contribute to the onset of one disease in particular, periodontitis: P. gingivalis, Tannerella forsythia, and Treponema denticola [13]. Periodontitis (also referred to as periodontal disease) is characterized by oral abscesses that can lead to a variety of physiological conditions, such as the bleeding of gums, and in the case of chronic periodontitis, even tooth loss [14]. A study by Jamarillo et. al sought to characterize even further the microbial community involved with the development of periodontal disease [14]. In this study, the researchers took subgingival (referring to the area below the gums) microbial samples, processed, and then cultured the microbes in anaerobic culture conditions onto plates containing Brucella blood agar medium. They then classified the bacteria using various tests; they results of their microbial isolation, classification, and analysis is summarized in the figure below:

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Figure 3. Displays the proportions of bacteria, cultured from oral samples. Image produced by Jaramillo et. al in 2005. [3].

Also in accordance with study [13], P. gingivalis was a very prominent bacteria in the microbial communities of patients with periodontal disease. The reason why these results are significant is due to the fact that several studies have examined a correlation between periodontal disease and Alzheimer’s disease, mediated by what can be called the oral-brain axis. One study performed by Poole et. al [15] dove into an investigation relating to the following bacteria (already discussed above to have a significant impact with respect to the development of periodontal disease): T. denticola, T. forsythia, and P. gingivalis. The researchers’ goal was to classify and hopefully find these bacteria/ bacterial imprints in the brain tissue of deceased Alzheimer’s patients (samples were taken 12 hours after death). The researchers took an astrocyte cell line (known as SVGp12) and used these cells to culture P. gingivalis. LPS (lipopolysaccharide), although a major component of the cell walls of many bacteria, is also a commonly known endotoxin. Using immunoblotting, researchers were able to conclude that the investigated SVGp12 cell line was able to, and did, absorb the LPS secreted by the P. gingivalis bacteria. The researchers said that this phenomenon was also observed in “4 out of 10 AD [Alzheimer’s disease] cases”[15]. This conclusion was important, as it provided some insight into the possible connections between the oral microbiome and Alzheimer’s disease. What would have been interesting to determine from this study was if researchers noticed any distinct histological/ physiological correlations between the cells exposed to the P. gingivalis bacteria and the cells taken from the brain samples of patients with Alzheimer’s disease- any of those sort of correlations would have helped to reaffirm the statement that the composition of the oral microbiome can have an impact with respect to the onset of Alzheimer’s disease. Narengaowa et. al [12] dives into the more specific physiological impacts that the presence of periodontal disease within an Alzheimer’s patient can have on the development of AD in that respective individual. They state that these bacteria could possibly be responsible for general inflammation through the production of various cytokines (leading to the onset of AD, especially considering how intertwined the oral and cerebral cavities are), or they could cause the development of AD through a more indirect means, such as the allowance of the entry of pathogenic microorganisms. Another interesting study conducted by Ide et. al was successful in establishing more concrete physiological correlations between periodontal disease and Alzheimer’s [16]. The experimental conditions are as follows. The researchers sampled a community of 60 participants (specifically non-smokers) with periodontal disease. The participants were subject to a cognitive assessment, and then afterwards blood sampling was performed to assess the levels of various proinflammatory as well as anti-inflammatory cytokines. The researchers found that there was indeed a correlation between severity of periodontal disease and cognitive decline (demonstrated by the various statistics involving the cognitive tests that the participants were required to take). The researchers were not able to exactly determine why this particular correlation was present, but they were able to come to another interesting conclusion that is also supported by the studies discussed above: for the majority of patients, as the severity of periodontal disease increased, their pro-inflammatory cytokine levels were also accordingly augmented. From all the research studies and journal reviews discussed above, we can most definitely conclude that Alzheimer’s disease is at least being somewhat mediated by microbial interactions in the microbial community that inhabits the oral cavity. One of these bacteria in particular, P. gingivalis, definitely has some role with Alzheimer’s disease mediation, either through the production of endotoxin lipopolysaccharide (which can easily be transported to the CNS/associated structures) or the production of pro-inflammatory cytokines, which are known to have a significant role with respect to the onset of Alzheimer’s disease.


Impact of Race/Ethnicity on Alzheimer’s Disease

According to an article written by Nianogo et. al [17], “Almost two-thirds of US adults with ADRDs [Alzheimer’s disease and related dementias] are women, and compared with older White individuals, older Black individuals are twice as likely to have ADRDs and older Hispanic individuals are 1.5 times as likely”. These statistics demonstrate the presence of an obvious disparity. In the following study conducted by Morris et. al [18], researchers looked at the different biomarkers of Alzheimer’s disease (many of them were discussed above), and conducted a comparison in the prevalence of these markers between African American and white individuals. Researchers performed a spinal tap/puncture on the research participants and from this procedure, obtained their cerebrospinal fluid (CSF). Using an immunosorbent assay, they measured the concentrations of Aβ42, as well as tau. They also performed amyloid-β PET imaging, which helped researchers to have a visual of the amyloid-β plaques present in individuals with Alzheimer’s disease. In addition to the above biomarkers, the researchers also considered the presence of the Apolipoprotein E genotype (commonly abbreviated as APOE), which is commonly considered to be a genetic risk factor/marker for the onset of Alzheimer’s disease. MRI (magnetic resonance imaging) was also performed on the research participants to determine the volumes of their hippocampuses. To qualify for participation in the study, research participants had to at least have one of the biomarkers mentioned above. The results were interesting, and were as follows. Among a sample of African Americans as well as white individuals with a family history of dementia, African Americans had lower hippocampal volumes; what was interesting, however, was that for African Americans and white individuals without a family history of dementia, this trend was not present. There was no significant difference with respect to the amyloid-β concentrations among African Americans and white individuals. However, the researchers were able to determine that African Americans had lower CSF tau concentrations when compared with white individuals. The researchers also stated something interesting: “African American individuals had to score below 19 on the Mini-Mental State Examination to warrant a diagnosis of dementia, whereas white individuals were diagnosed with dementia when scoring less than 21 on the Mini-Mental State Examination”[18]. This was particularly interesting for me, and it made me wonder how much of the disparity (with respect to the racial and ethnic proportions of people that Alzheimer’s disease affects) could be attributed to the inherent and systemic flaws that may be present within diagnosis/testing for Alzheimer’s disease. I also found it interesting how, besides the differing tau concentrations among African Americans and white individuals, there were no other significant differences with respect to the Alzheimer’s disease biomarkers that the researchers tested for, indicating that the obvious disproportionalities between African Americans white people must not fully (or inherently) be biological. Future studies could proceed with consideration of other non-biological factors (at least those inherently related to the human body) such as environmental factors, and how those could perhaps contribute to the racial disparity associated with Alzheimer’s disease. One important thing that this study makes essential to consider is how Alzheimer’s testing (that is solely based on biological marker concentrations) should be adjusted per racial group. However, on the other hand, non-standardization of these biological markers might even lead to more incorrect AD diagnoses.


Conclusion

Alzheimer's disease, the leading cause of dementia, is an awful disorder characterized by cognitive decline, difficulty with respect to communication, as well as other seemingly "normal" skills, etc. Individuals who are subject to Alzheimer's disease often have trouble remembering the names of their loved ones, remembering certain events in the past, or just remembering how to go about life in general. Alzheimer's disease is characterized by several biomarkers, such as tau and Aβ42 accumulation, low CSF (cerebrospinal fluid) levels, etc. These different biomarkers and their general impact with respect to the development of Alzheimer's disease is generally mediated by the human microbiome, especially the gut and oral microbiomes. These microbiomes are home to various taxa of bacteria, which are responsible for the secretion and production of various substances that are responsible for the mediation of AD (Alzheimer's disease) development. Yet, so much still remains unknown about Alzheimer's disease, especially relating to how it affects different groups of people. As discussed in the previous section, there are very obvious disparities with respect to the racial proportions that Alzheimer's disease affects, but not a whole lot is still known about why that disparity exists. Moving forward, there is still so much more research to be done and more knowledge to be gained surrounding this disease.

References

  1. ↑ Lyketsos CG. Neuropsychiatric Symptoms in Dementia: Overview and Measurement Challenges. The journal of prevention of Alzheimer’s disease [Internet. 2015 [cited 2019 Oct 23];2(3):155–6. Available from: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4712963/]
  2. ↑ Geda YE, Schneider LS, Gitlin LN, Miller DS, Smith GS, Bell J, et al. Neuropsychiatric symptoms in Alzheimer’s disease: Past progress and anticipation of the future. Alzheimer’s & Dementia. 2013 Apr 5;9(5):602–8
  3. ↑ Soria Lopez JA, González HM, Léger GC. Alzheimer’s disease. Handbook of Clinical Neurology [Internet. 2019;167:231–55. Available from: https://www.sciencedirect.com/science/article/abs/pii/B9780128047668000133?via%3Dihub]
  4. ↑ Verdile G. The role of beta amyloid in Alzheimer?s disease: still a cause of everything or the only one who got caught? Pharmacological Research. 2004 Oct;50(4):397–409
  5. ↑ Selkoe DJ. Alzheimer’s Disease: Genes, Proteins, and Therapy. Physiological Reviews [Internet. 2001 Apr 1;81(2):741–66. Available from: https://doi.org/10.1152/physrev.2001.81.2.741]
  6. ↑ 6.0 6.1 Medeiros R, Baglietto-Vargas D, LaFerla FM. The Role of Tau in Alzheimer’s Disease and Related Disorders. CNS Neuroscience & Therapeutics. 2010 Jun 14;17(5):514–24
  7. ↑ 7.0 7.1 7.2 7.3 Cattaneo A, Cattane N, Galluzzi S, Provasi S, Lopizzo N, Festari C, et al. Association of brain amyloidosis with pro-inflammatory gut bacterial taxa and peripheral inflammation markers in cognitively impaired elderly. Neurobiology of Aging. 2017 Jan;49:60–8.
  8. ↑ [https://www.nature.com/articles/s41598-017-13601-y Vogt NM, Kerby RL, Dill-McFarland KA, Harding SJ, Merluzzi AP, Johnson SC, et al. Gut microbiome alterations in Alzheimer’s disease. Scientific Reports. 2017 Oct 19;7(1).
  9. ↑ 9.0 9.1 Hopkins MJ, MacFarlane GT. Changes in predominant bacterial populations in human faeces with age and with Clostridium difficile infection. Journal of Medical Microbiology. 2002 May 1;51(5):448–54
  10. ↑ Megur A, Baltriukienė D, Bukelskienė V, Burokas A. The Microbiota–Gut–Brain Axis and Alzheimer’s Disease: Neuroinflammation Is to Blame? Nutrients. 2020 Dec 24;13(1):37
  11. ↑ 11.0 11.1 Li Y, Sun H, Chen Z, Xu H, Bu G, Zheng H. Implications of GABAergic Neurotransmission in Alzheimer’s Disease. Frontiers in Aging Neuroscience. 2016 Feb 23;8
  12. ↑ 12.0 12.1 12.2 [https://www.frontiersin.org/journals/cellular-neuroscience/articles/10.3389/fncel.2021.633735/full Narengaowa, Kong W, Lan F, Awan UF, Qing H, Ni J. The Oral-Gut-Brain AXIS: The Influence of Microbes in Alzheimer’s Disease. Frontiers in Cellular Neuroscience. 2021 Apr 14;15]
  13. ↑ 13.0 13.1 Periodontal microbial ecology: EBSCOhost [Internet. Ebscohost.com. 2025 [cited 2025 Apr 14]. Available from: https://web.p.ebscohost.com/ehost/detail/detail?vid=0&sid=516623db-318a-488c-b41c-487c7573fa99%40redis&bdata=JnNpdGU9ZWhvc3QtbGl2ZQ%3d%3d#db=a9h&AN=16792702]
  14. ↑ 14.0 14.1 Jaramillo A, Arce RM, Herrera D, Betancourth M, Botero JE, Contreras A. Clinical and microbiological characterization of periodontal abscesses. Journal of Clinical Periodontology. 2005 Dec;32(12):1213–8.
  15. ↑ 15.0 15.1 Poole S, Singhrao SK, Kesavalu L, Curtis MA, Crean S. Determining the Presence of Periodontopathic Virulence Factors in Short-Term Postmortem Alzheimer’s Disease Brain Tissue. Journal of Alzheimer’s Disease [Internet. 2013 Aug 5;36(4):665–77. Available from: https://content.iospress.com/articles/journal-of-alzheimers-disease/jad12191]
  16. ↑ Ide M, Harris M, Stevens A, Sussams R, Hopkins V, Culliford D, et al. Periodontitis and Cognitive Decline in Alzheimer’s Disease. Garg P, editor. PLOS ONE. 2016 Mar 10;11(3):e0151081
  17. ↑ Nianogo RA, Rosenwohl-Mack A, Yaffe K, Carrasco A, Hoffmann CM, Barnes DE. Risk Factors Associated With Alzheimer Disease and Related Dementias by Sex and Race and Ethnicity in the US. JAMA Neurology. 2022 May 9;79(6)
  18. ↑ 18.0 18.1 Morris JC, Schindler SE, McCue LM, Moulder KL, Benzinger TLS, Cruchaga C, et al. Assessment of Racial Disparities in Biomarkers for Alzheimer Disease. JAMA Neurology. 2019 Mar 1;76(3):264.



Authored by Natasha Jose for BIOL 238 Microbiology, taught by Joan Slonczewski,at Kenyon College,2025

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