Fight Aging!

The balance of microbial populations making up the gut microbiome changes with age in ways that provoke chronic inflammation, as well as reduce production of beneficial metabolites. In recent years, researchers have shown that Alzheimer's patients exhibit a distinctly dysregulated gut microbiome in comparison to other older individuals. This raises the question of whether there is a significant contribution to risk of Alzheimer's resulting from specific changes in microbial populations of the intestinal tract. Alternatively, since the immune system is responsible for gardening the gut microbiome, eliminating undesirable microbes, does the Alzheimer's gut microbiome reflect a specific or greater incapacity of the immune system that independently drives both changes in the gut microbiome and the development of neurodegeneration?

In today's open access paper, researchers discuss the path towards a better understanding of the role of the gut microbiome in Alzheimer's disease. At present a correlation is established, but how to move beyond that to identify specific mechanisms and microbial populations? One possible approach to the question of causation is to attempt to reverse age-related or disease-related changes in the gut microbiome via fecal microbiota transplant from a young, healthy individual. Finding out whether this improves Alzheimer's patient outcomes, and to what degree, would be an important step forward. If the problem is that microbes make their way from a leaky gut to the brain and there causing issues, changing the gut microbiome may not help in later stages of the condition, however. If the problem is altered inflammatory signaling and metabolite production in the intestines, then changing the microbiome may be more helpful.

New approaches for understanding the potential role of microbes in Alzheimer's disease

This article summarizes research presented at the virtual symposium and workshop, "New Approaches for Understanding the Potential Role of Microbes in Alzheimer's Disease." The objective of these events was to review the evidence base and catalyze research to address knowledge gaps in the hypothesis that infections or microbes play some causative role in the development or progression of Alzheimer's disease. Alzheimer's disease is a complex disease; this symposium was rooted in an understanding that its pathogenesis could be triggered by both microbe-dependent and microbe-independent pathways and the two are not mutually exclusive.

The symposium was introduced with a keynote lecture describing the origins and accumulating evidence for the theory around amyloid-β (Aβ) as an antimicrobial protein that protects the brain against infection. The next session highlighted epidemiological and mechanistic data for a potential link between COVID-19 and Alzheimer's disease. The program then featured brief lectures that explored these topics: single-cell genomic studies in Alzheimer's disease that may suggest immune response to microbes, a potential role for antiviral vaccines in Alzheimer's disease, investigations into which microbes could cause Alzheimer's, activation of endogenous retroviruses in tauopathy, and gut-microbe brain communications.

Speakers presented emerging evidence that COVID-19 infection confers increased risk of dementia and discussed how COVID-19 may promote AD pathology. Although no definitive evidence exists to prove or disprove the direct involvement of any specific microbe in human AD, speakers agreed that there are multiple plausible ways that microbes could be implicated. One model that has been extensively investigated that has direct relevance to central nervous system (CNS)/microbiome interactions are the effects of lipopolysaccharide (LPS) on blood-brain barrier (BBB) functions. LPS is derived from gram negative bacteria and is a powerful activator of the innate immune system. LPS's actions either directly on BBB functions or indirectly through the induction of the release of cytokines and other immune-related substances affect the CNS.

Data also shows that some microbes appear to be overabundant in Alzheimer's brains, sometimes by large margins. These microbes are species typically encountered in human infections - for example, Streptococcus and Staphylococcus, as well as several Aspergillus-like, Candida-like, and Cryptococcus-like fungi, of interest because Cryptococcus in particular is a known cause of dementia 'masquerading' as Alzheimer's disease. Infections appeared to be locally restricted - some samples with a heavy microbial burden were adjacent to tissues largely lacking microbes. Conversely, some atypical microbes were seen in more than one brain region, indicative of in vivo spreading. However, whether microbes cause Alzheimer's remains an open question. One way to evaluate this would be to determine which brain microbes are present in each individual (perhaps through analysis of cerebrospinal fluid), and then to explore whether appropriate therapy might mitigate or slow Alzheimer's disease.