One cause of Alzheimer's might be an unhealthy Gut Microbiome, new research shows.

One out of two people at the age of 85 develop Alzheimer’s disease. Alzheimer’s is neurodegenerative disease that starts with short-term memory loss and mood swings, it progresses up to a point where somebody doesn’t recognize his wife or kids anymore and eventually leads to death.

The prevalence of Alzheimer’s is rising. It is predicted that by 2050 about 115 million people will suffer from it, and it is not only because we get older, as more people under 85 develop Alzheimer’s more frequently.

 
alzheimers statistic.jpg
 

However, Alzheimer’s should NOT be part of normal aging, as Dr. Samuel Cohen, researcher for neurodegenerative diseases, explains in his Ted Talk.

Unfortunately, unlike almost every other disease we haven’t made much progress in treating this disease since Alois Alzheimer’s discovered it in 1901.

Most promising drugs fail to work and even previously FDA-approved drugs are not just ineffective but seem to worsen the cognitive decline of patients compared to the placebo. [1, 2]

Dr. Dale Bredesen, author of book “The End of Alzheimer’s” explains, there are at least 36 different factors contributing to the development of Alzheimer’s and finding a drug against all these factors is very unlikely.

However, he also explains that there are different types of Alzheimer’s with three types being the most common forms:

  • Type 1: Inflammatory

  • Type 2: Atrophic

  • Type 3: Toxicity-associated

The Type 1 is characterized by chronic inflammation, meaning that a constantly activated immune system leads to the development of Alzheimer’s. [3]

If you have ever read something about Alzheimer’s Disease you might know that one hallmark of Alzheimer’s is the accumulation of amyloid-ß peptides in the brain. The amyloid-ß prevents the signaling between the neurons when it accumulates outside of the cells and amyloid-ß further induces inflammation which damages the surrounding neurons.

However, amyloid-ß is not the cause of Alzheimer’s but acts much more like a mediator. Scientist think that the formation of amyloid-ß is likely a protective mechanism and is therefore a response to something and is therefore a response to some threat, which further increases inflammation.

I guess the obvious question would be: What is the threat the amyloid-ß tries to protect us from? Many scientist have now evidence that it is microbial. [4, 5]

You might have heard about the Blood-Brain Barrier, which consists of a tight layer of cells that keep everything outside that would somehow threat the brain.

BloodBrainBarrier.jpg

The barrier seems to be more leaky then we thought. Recently, it became clear that certain substances, as well as viruses and bacteria can challenge the integrity of the barrier. [6]

And here is where the microbiome comes in. One molecule that is found on the cell wall of many bacterial species is called lipopolysaccharide, or short LPS. It binds to receptors and initiate the release of pro-inflammatory proteins. However, a healthy gut should prevent bacteria to reach our blood stream and be recognized by immune cells.

But unfortunately, if somebody suffers from something that is commonly known as leaky gut, his or her gut wall became permeable to bacteria and bacterial toxins.

 
Leaky_Gut.png
 

As an example, LPS was used in studies to generate a rat model for Alzheimer’s disease [7], LPS induces anxiety and depressive-like behaviors in mice [8], and there are even new studies connecting LPS to the development of multiple sclerosis. [9]

Additionally, scientist found that patients with Alzheimer’s Disease have on average 3 times higher blood LPS concentrations compared to healthy individuals. [10]

 
Plasma LPS concentrations in Healthy individuals, amyotrophic lateral sclerosis (sALS) and Alzheimer’s (AD) patients [10]

Plasma LPS concentrations in Healthy individuals, amyotrophic lateral sclerosis (sALS) and Alzheimer’s (AD) patients [10]

 

In a 2015 paper, Lebluber and colleagues tested 22 patients with Alzheimer’s disease and found that 3/4 of them had a leaky gut. [11]

Injection of LPS into the blood stream of mice starts the build-up of amyloid plaque and later leads to memory impairment in mice. [12]

LPS also somehow decreases the production of the brain-derived neurotropic factor (BDNF) by 20%, just 7 hours after the injection. BDNF is important for the formation of new neurons and decreases while aging. [13, 14]

Interestingly, Alzheimer’s disease patients have a decreased microbial diversity. [15]

There is one more thing we only recently discovered: Researchers found that microbes can secrete large amounts of amyloids, which might end up in the brain or at least further increase inflammation due to a leaky gut cell wall. [16]

 
Microbial amyloid can engage TLRs on the epithelial surface and prime systemic inflammation through the lymph follicles (Peyer patches) linked to M cells. This priming of the innate immune system via a hematogenous route may cause enhanced response to neuronal amyloids in the brain. Microbial amyloid may also increase production of neuronal amyloids (such as alpha-synuclein) [16]

Microbial amyloid can engage TLRs on the epithelial surface and prime systemic inflammation through the lymph follicles (Peyer patches) linked to M cells. This priming of the innate immune system via a hematogenous route may cause enhanced response to neuronal amyloids in the brain. Microbial amyloid may also increase production of neuronal amyloids (such as alpha-synuclein) [16]

 

Treating Alzheimer’s with Probiotics

Since there is so much evidence that connects the microbiome with the health of the brain, the next step would obviously to test whether an improvement in gut health can prevent or even reverse Alzheimer’s Disease, and this is exactly what a study published in 2016 did.

A randomized double blind control study divided 60 Alzheimer patients into two groups. One group consumed a fermented milk product that contained probiotic bacteria and the other group a placebo milk product. The scientist examined their cognitive function before and after the intervention and found that the probiotic group had a 28% improvement while the other group got worse over the 12 weeks trial period. The probiotic group also showed improvement in many blood markers, including a marker for inflammation. [17]


As I mentioned in the beginning, there are other types of Alzheimer’s Disease that might caused by glucotoxicity, hormonal imbalances or toxins. However, a healthy microbiome can also influence those factors, as it is important for blood sugar control, the production of hormones and for the clearance of potential toxins.

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References

  1. Salloway et al., wo Phase 3 Trials of Bapineuzumab in Mild-to-Moderate Alzheimer's Disease, NEJM, 2014

  2. Schneider et al., Lack of evidence for the efficacy of memantine in mild Alzheimer disease., JAMA, 2011

  3. Bolos, Alzheimer's disease as an inflammatory disease., Biomol Concepts, 2017

  4. Schluesener et al., Antimicrobial peptides in the brain: neuropeptides and amyloid Hermann, Frontiers in Bioscience, 2012

  5. Gosztyla et al., Alzheimer’s Amyloid-beta is an Antimicrobial. Peptide: A Review of the Evidence, J. Alzheimer’s Disease, 2018

  6. Welling et al., Potential role of antimicrobial peptides in the early onset of Alzheimer's disease, Alzheimers Dement, 2015

  7. Zakaria et al., Lipopolysaccharide-Induced Memory Impairment in Rats: a Model of Alzheimer’s Disease, Physiol Res, 2017

  8. O'Connor et al., Lipopolysaccharide-induced depressive-like behavior is mediated by indoleamine 2,3-dioxygenase activation in mice, Mol Psychiatry, 2009

  9. Escribano et al., Lipopolysaccharide Binding Protein and Oxidative Stress in a Multiple Sclerosis Model, Neurotherapeutics, 2017

  10. Zhang et al., Circulating endotoxin and systemic immune activation in sporadic Amyotrophic Lateral Sclerosis (sALS), J Neuroinflammation, 2009

  11. Leblhuber et al., Elevated fecal calprotectin in patients with Alzheimer's dementia indicates leaky gut, J Neural Transm, 2015

  12. Lee et al., Neuro-inflammation induced by lipopolysaccharide causes cognitive impairment through enhancement of beta-amyloid generation., J Neuroinflammation, 2008

  13. Guan et al., Peripheral immune activation by lipopolysaccharide decreases neurotrophins in the cortex and hippocampus in rats. Brain Behav Immun, 2006

  14. Shimada et al., A Large, Cross-Sectional Observational Study of Serum BDNF, Cognitive Function, and Mild Cognitive Impairment in the Elderly, 2015, Frontier in Aging Neuroscience

  15. Vogt et al., Gut microbiome alterations in Alzheimer’s disease, Scientific Reports, 2017

  16. Frieland and Chapman, The role of microbial amyloid in neurodegeneration, PLOS Pathogens, 2017

  17. Akbari et al., Effect of Probiotic Supplementation on Cognitive Function and Metabolic Status in Alzheimer's Disease: A Randomized, Double-Blind and Controlled Trial, Front. Aging Neurosci, 2016