The gut microbiome in Alzheimer's disease: what we know and what remains to be explored

Abstract

Alzheimer's disease (AD), the most common cause of dementia, results in a sustained decline in cognition. There are currently few effective disease modifying therapies for AD, but insights into the mechanisms that mediate the onset and progression of disease may lead to new, effective therapeutic strategies. Amyloid beta oligomers and plaques, tau aggregates, and neuroinflammation play a critical role in neurodegeneration and impact clinical AD progression. The upstream modulators of these pathological features have not been fully clarified, but recent evidence indicates that the gut microbiome (GMB) may have an influence on these features and therefore may influence AD progression in human patients. In this review, we summarize studies that have identified alterations in the GMB that correlate with pathophysiology in AD patients and AD mouse models. Additionally, we discuss findings with GMB manipulations in AD models and potential GMB-targeted therapeutics for AD. Lastly, we discuss diet, sleep, and exercise as potential modifiers of the relationship between the GMB and AD and conclude with future directions and recommendations for further studies of this topic.

Keywords: Amyloid; Diet; Exercise; Gut microbiome; Human; Mouse; Neuroinflammation; Peripheral immunity; Sleep; Tau; Therapeutics.

Fig. 1

Theory of GMB involvement in AD. Environmental factors, such as diet, sleep, and exercise and the development of AD due to genetics contribute to an inflammatory environment in the gut microbiota, which leads to changes in composition and diversity over time. Changes in the gut microbiota influence gut microbiome-derived metabolites and peripheral immunity by altering peripheral immune cell gene expression and cytokine release. Changes in peripheral immunity, possibly gut-derived metabolites directly, and vagus nerve trafficked gut-derived hormones can then alter phenotype of the blood brain barrier and central nervous system cell types (microglia, astrocytes, neurons), which can then modulate amyloidosis, tauopathy, and neurodegeneration and contribute to disease pathogenesis

Fig. 2

Microbiome-related therapeutic strategies for AD. Preliminary evidence from mouse and human studies suggests that probiotics/prebiotics, fecal matter transplant from healthy donors into AD patients, microbiome modifying drugs, and direct targeting of gut microbiome controlled neuroinflammatory pathways may potentially be disease modifying therapeutic strategies and may reduce amyloid, tau, and neurodegeneration