Introduction
Alzheimer’s disease (AD) is a progressive neurodegenerative disorder that is characterized by loss of memory, cognitive and behavioral skills, and many neuropsychiatric comorbidities, such as depression and sleep disorders. AD is only one form of dementia, or cognitive decline that interferes with daily life, affecting the lives of nearly 50 million people globally based on data from the Alzheimer’s Association. Alzheimer’s is most prevalent in individuals aged 65 years old and above. Contrary to what most people would think, AD’s earliest signs and clinical manifestations are psychiatric and neurological, with increased anxiety and irritability being the most common symptoms observed by close relatives of AD patients. Most AD diagnoses occur during mild stages of the disease, using clinical neuropsychiatric assessments and brain imaging techniques. Magnetic resonance and computed tomographic technologies are used to detect and quantify brain atrophy, particularly in the hippocampus and entorhinal cortex, which are the earliest sites of damage that affect memory formation. Additionally, the cerebrospinal fluid of AD patients is the site of many lipid and protein biomarkers that are used for early diagnosis. In particular, vascular growth factor peptides are being the most widely studied. As the disease progresses, AD patients will become unable to perform simple motor functions, recognize their families, and communicate with them. Hallucinations and impulsive behavior are common during those stages. Therefore, the high prevalence of AD and its profound impact on the quality of life of affected individuals and their caregivers demands our immediate attention.
Alzheimer’s Disease Fact Sheet, 2023
Pathophysiology
Studies of AD have predominantly focused on two major pathologies: amyloid plaque formation, Tau protein aggregations and inflammation and microglial dysfunction (Ana et al., 2023 and Kinney et al., 2018).
Amyloid Plaque Formation
The amyloid precursor protein (APP) is a membrane protein found in the somatodendritic and axonal regions of neuronal cells. In a pathogenic amyloidogenic pathway, this protein is cleaved to form Aβ peptides, which can self-aggregate into plaques. The accumulation of these structures has been shown to hinder synaptic transmission, induce inflammation and oxidative stress, and alter membrane permeability and mitochondrial function in neurons, which explains their toxicity in AD and their effects on cognitive function.
Tau Protein Aggregates
Another hallmark pathology of AD is the formation of neurofibrillary tangles that contain aggregates of Tau protein within neurons. Tau proteins are predominantly found in neuronal axons where they associate with microtubules and regular axonal transport. The function of Tau is regulated post-translationally through phosphorylation. In Alzheimer’s, Tau proteins undergo a conformational change that increases their susceptibility to phosphorylation, which in turn decreases their affinity to microtubules. As the proteins’ biological activity is hindered, they aggregate and form neurofibrillary tangles. As a result, axonal transport is inhibited which affects synaptic activity and leads to cell death.
Inflammation and microglial dysfunction
A third rail in AD pathogenesis has been centered around dysfunctions of the immune system in AD-affected brains. Microglia are immune cells that reside in the central nervous system. It has been shown that Aβ accumulation in AD patients activates microglia. These activated microglia can phagocytose the plaques. However, prolonged microglial activation triggers chronic inflammation in the brain, which damages the neurons and decreases phagocytic efficiency. Microglia will continue to secrete pro-inflammatory cytokines and neurotoxins without clearing plaque accumulation, which intensifies neurodegeneration (Kinney et al., 2018).
Risk factors
The fact that AD mainly affects older people has led scientists to investigate the age-related changes in the brain that might lead to the onset and progression of the disease. The most commonly studied factors are brain atrophy, inflammation, blood vessel damage, and mitochondrial dysfunction. These can be described as the result of the accumulation of genetic and environmental factors over time.
Genetics
Today, we know of 80 genes that are associated with Alzheimer’s disease. Of those genes, three are known to cause AD and are involved in APP breakdown: Amyloid precursor protein (APP) on chromosome 21, Presenilin 1 (PSEN1) on chromosome 14, and Presenilin 2 (PSEN2) on chromosome 1. Anyone with a specific variant of these genes will most likely develop AD before the age of 65. Moreover, an isoform of apolipoprotein E, APOE ε4, has been linked to an increased risk of late-onset Alzheimer’s disease, after the age of 65. APOE is intricately involved in the three pathologies of AD. The APOE 4 allele decreases the efficiency of clearance of amyloid plaques, increases neurotoxicity by interfering with the mitochondrial metabolism of lipidsand inducing oxidative stress, and modulates the microglial neuroinflammatory milieu involved in disease progression.
Environmental
Vascular conditions, like hypertension, heart disease, and metabolic diseases, like obesity and diabetes, have been associated with AD. Managing these chronic illnesses can greatly help in reducing the risks of developing AD. Eating healthy, exercising, and stimulating the brain cognitively and socially are the best ways to maintain healthy aging.
Current treatment
There is currently no cure for AD. Non-steroidal anti-inflammatory drugs may be administered to decrease neuroinflammation. Antidepressants are used to manage anxiety, sleeplessness, and psychotic behavior. Future treatments include anti-amyloid and anti-tau antibodies and brain wave oscillations to stimulate neurocommunication (Weller & Budson, 2018).
The gut microbiome and Alzheimer’s disease
The gut-brain axis refers to the neural, endocrine, and metabolic signaling pathways that link the gastrointestinal tract to the brain. Research suggests that the gut microbiome plays a pivotal role in the development of AD. An interesting study shows that fecal microbiota transplantation from AD-affected humans to microbiota-depleted mouse models decreases neurogenesis in healthy controls (Grabrucker et al., 2023). The exact mechanisms of this interaction are heavily studied. One explanation proposes that bacterial amyloids (such as E.coli curli) in the gut, though different in amino acid sequences from those in the central nervous system (CNS), may enhance the immune response to amyloid plaques in the brain of AD patients. The bacterial amyloids also act as prions that trigger beta-sheet conformational changes in Aβ peptides in the brain.
Another key finding shows that AD patients have increased levels of bacterial products, particularly lipopolysaccharides (LPS), in the plasma and the brain. LPS triggers the microglia through Toll-like receptor (TLR) activation, exacerbating neuroinflammation (Kowalski & Mulak, 2019). Aging-mediated microbiome dysbiosis also favors the development of pro-inflammatory bacteria. This effect, combined with the small bacterial overgrowth observed in AD patients, enhances the permeability of the gastrointestinal tract and destroys the blood-brain barrier (BBB), which exposes the brain to pathogenic bacteria and toxins in the blood. Important brain metabolites are produced in the gut and may be affected by dysbiosis. For instance, differences in gut microbiota populations in AD patients may influence tryptophan and serotonin synthesis which affects the levels of dopamine, norepinephrine, and brain-derived neurotrophic factor. Even more, microbial dysbiosis may alter the production of short-chain fatty acids, including butyrate, propionate, and acetate, which regulate immune responses in the body.
Studies report a decrease in butyrate-producing bacteria in AD, which leads to T-cell imbalances and bacterial translocation from the gut. Finally, intestinal dysbiosis can also contribute to the increase of harmful microbial metabolites which increase amyloid formation and oxidative stress in the brain (Varesi et al., 2022). Hence, the composition and activity of the intestinal microbiome are key factors in the development of Alzheimer’s disease, mainly through affecting neuroinflammation, amyloid formation in the brain, and the permeability of the intestinal mucosa and the blood-brain barrier.
Implications of gut microbiota dysbiosis in prevention and treatment
The interplay between the gut microbiome and the brain leads us to discuss the therapeutic implications of AD treatment. There are three potential strategies for targeting dysbiosis of the gut microbiome of AD patients. Antibiotics and other pharmaceutical compounds may be administered to alter composition over time, though their safety and efficacy have not been extensively tested. Another mechanism is to remodel gut microbes by fecal microbiota transplantation from healthy donors. The benefits and risks of such procedures need to be carefully examined by donor screening (Zhu et al., 2020). Finally, dietary changes that promote anti-inflammatory bacterial growth and maintain beneficial microbial composition reduce the risk of the development of Alzheimer’s. It is recommended to reduce the intake of pastries, sweets, red meat, fried foods, cheese, butter, and margarine and increase the consumption of prebiotics, whole grains, leafy vegetables, berries, nuts, beans, fish, and olive oil.
In conclusion, the relationship between the gut microbiome and AD is a rapidly evolving field that has the potential to transform our understanding of AD pathogenesis and lead to novel therapeutic strategies. By advancing our knowledge of the gut-brain axis, we may ultimately improve the prevention, diagnosis, and treatment of AD, offering hope for the millions of individuals affected by this disease.
References
Alzheimer’s Disease Fact Sheet. (2023, April 5). National Institute on Aging. https://www.nia.nih.gov/health/alzheimers-and-dementia/alzheimers-disease-fact-sheet#:~:text=Alzheimer’s%20disease%20is%20a%20brain,carry%20out%20the%20simplest%20tasks
Ana, R. M., José, B. D., Fernando, R., & Silva, R. (2023). Alzheimer’s disease: Insights and new prospects in disease pathophysiology, biomarkers and disease-modifying drugs. Biochemical Pharmacology, 211, 115522. https://doi.org/10.1016/j.bcp.2023.115522
Grabrucker, S., Marizzoni, M., Silajdžić, E., Lopizzo, N., Mombelli, E., Nicolas, S., Dohm-Hansen, S., Scassellati, C., Moretti, D. V., Rosa, M., Hoffmann, K., Cryan, J. F., O’Leary, O. F., English, J., Lavelle, A., O’Neill, C., Thuret, S., Cattaneo, A., & Nolan, Y. M. (2023). Microbiota from Alzheimer’s patients induce deficits in cognition and hippocampal neurogenesis. Brain, 146(12), 4916–4934. https://doi.org/10.1093/brain/awad303
Kinney, J. W., Bemiller, S. M., Murtishaw, A. S., Leisgang, A. M., Salazar, A., & Lamb, B. T. (2018). Inflammation as a central mechanism in Alzheimer’s disease. Alzheimer’s & Dementia. Translational Research & Clinical Interventions, 4(1), 575–590. https://doi.org/10.1016/j.trci.2018.06.014
Kowalski, K., & Mulak, A. (2019). Brain-Gut-Microbiota axis in Alzheimer’s disease. Journal of Neurogastroenterology and Motility, 25(1), 48–60. https://doi.org/10.5056/jnm18087
Varesi, A., Pierella, E., Romeo, M., Piccini, G. B., Alfano, C., Bjørklund, G., Oppong, A., Ricevuti, G., Esposito, C., Chirumbolo, S., & Pascale, A. (2022). The potential role of gut microbiota in Alzheimer’s disease: From diagnosis to treatment. Nutrients, 14(3), 668. https://doi.org/10.3390/nu14030668
Weller, J., & Budson, A. E. (2018). Current understanding of Alzheimer’s disease diagnosis and treatment. F1000Research, 7, 1161. https://doi.org/10.12688/f1000research.14506.1
Zhu, F., Li, C., Chu, F., Tian, X., & Zhu, J. (2020). Target dysbiosis of gut microbes as a future therapeutic manipulation in Alzheimer’s disease. Frontiers in Aging Neuroscience, 12. https://doi.org/10.3389/fnagi.2020.544235
