Alzheimer's disease (AD) is a neurodegenerative process characterized by loss of neurons in the hippocampus and cerebral cortex, leading to progressive cognitive decline. Pathologically, the hallmark of AD is accumulation of "senile" plaques composed of amyloid-β (Aβ) protein surrounding neurons in affected regions. Despite extensive research into AD pathogenesis and therapeutic targets, there remains no breakthroughs in its management. In recent years, there has been a spark of interest in the connection between the brain and gastrointestinal tract, referred to as the brain-gut axis, and its potential implications for both metabolic and neurologic disease. Moreover, the gastrointestinal flora, referred to as the microbiome, appears to exert significant influence over the brain-gut axis. With the need for expanded horizons in understanding and treating AD, many have turned to the brain-gut-microbiome axis for answers. Here we provide a review of the brain-gut-microbiome axis and discuss the evidence supporting alterations of the axis in the pathogenesis of AD. Specifically, we highlight the role for the microbiome in disruption of Aβ metabolism/clearance, increased permeability of the blood-brain barrier and modulation of the neuroinflammatory response, and inhibition of hippocampal neurogenesis. The majority of the above described findings are the result of excellent, albeit basic and pre-clinical studies. Therefore, we conclude with a brief description of documented clinical support for brain-gut-microbiome axis alteration in AD, including potential microbiome-based therapeutics for AD. Collectively, these findings suggest that the brain-gut-microbiome axis may be a "lost link" in understanding and treating AD and call for future work.
Keywords: Alzheimer’s disease; dementia; gut microbiome; neurodegenerative disorders.
Effects of chronic noise exposure on the microbiome-gut-brain axis in senescence-accelerated prone mice: implications for Alzheimer's disease.J Neuroinflammation. 2018 Jun 22;15(1):190. doi: 10.1186/s12974-018-1223-4. J Neuroinflammation. 2018. PMID: 29933742 Free PMC article.
The Gut Microbiota and Alzheimer's Disease.J Alzheimers Dis. 2017;58(1):1-15. doi: 10.3233/JAD-161141. J Alzheimers Dis. 2017. PMID: 28372330 Review.
Brain-Gut-Microbiota Axis in Alzheimer's Disease.J Neurogastroenterol Motil. 2019 Jan 31;25(1):48-60. doi: 10.5056/jnm18087. J Neurogastroenterol Motil. 2019. PMID: 30646475 Free PMC article. Review.
The Gut Microbiome Alterations and Inflammation-Driven Pathogenesis of Alzheimer's Disease-a Critical Review.Mol Neurobiol. 2019 Mar;56(3):1841-1851. doi: 10.1007/s12035-018-1188-4. Epub 2018 Jun 23. Mol Neurobiol. 2019. PMID: 29936690 Free PMC article. Review.
The Gut-Brain Axis, Including the Microbiome, Leaky Gut and Bacterial Translocation: Mechanisms and Pathophysiological Role in Alzheimer's Disease.Curr Pharm Des. 2016;22(40):6152-6166. doi: 10.2174/1381612822666160907093807. Curr Pharm Des. 2016. PMID: 27604604 Review.