Interconnections between the Gut Microbiome and Alzheimer's Disease: Mechanisms and Therapeutic Potential

Abstract

Alzheimer's disease (AD) is a neurodegenerative disease that is known to accumulate amyloid-β (Aβ) and tau protein. Clinical studies have not identified pathogenesis mechanisms or produced an effective cure for AD. The Aβ monoclonal antibody lecanemab reduces Aβ plaque formation for the treatment of AD, but more studies are required to increase the effectiveness of drugs to reduce cognitive decline. The lack of AD therapy targets and evidence of an association with an acute neuroinflammatory response caused by several bacteria and viruses in some individuals has led to the establishment of the infection hypothesis during the last 10 years. How pathogens cross the blood-brain barrier is highly topical and is seen to be pivotal in proving the hypothesis. This review summarizes the possible role of the gut microbiome in the pathogenesis of AD and feasible therapeutic approaches and current research limitations.

Keywords: Alzheimer’s disease (AD); gut microbiome; lipopolysaccharide (LPS); short-chain fatty acids (SCFAs).

Figure 1

A possible pathway of how the gut microbiome contributes to AD in the elderly.

Figure 2

SCFAs in mice enhanced the tight junction and reduced the accumulation of Aβ.

Figure 3

Gut microbiome’s role in neurotransmitter production and cognitive decline.

Figure 4

The role of LPSs in the gut microbiome and cognitive decline.

Figure 5

Role of inflammation and gut microbiome in pathogenesis of AD. (1) An imbalance in the gut microbiome, known as dysbiosis, leads to increased intestinal permeability. (2) There is an obvious rise in serum diamine oxidase levels, a biomarker indicating this increased permeability of the intestine. (3) A significant reduction is observed in the Lachnospiraceae bacterial strain, which is crucial for butyrate production. (4) Additionally, there is an elevation in endotoxin levels originating from the gut microbiome. (5) These changes collectively may contribute to systemic inflammation, a key risk factor in the development of AD.