Current understanding of the Alzheimer's disease-associated microbiome and therapeutic strategies

Abstract

Alzheimer's disease (AD) is a fatal progressive neurodegenerative disease. Despite tremendous research efforts to understand this complex disease, the exact pathophysiology of the disease is not completely clear. Recently, anti-Aβ antibodies have been shown to remove amyloid from the brain and slow the clinical progression of mild dementia by ~30%. However, exploring alternative strategies is crucial to understanding and developing more effective therapeutic interventions. In recent years, the microbiota-gut-brain axis has received significant attention in the AD field. Numerous studies have suggested that alterations in the gut microbiota composition are associated with the progression of AD, and several underlying mechanisms have been proposed. However, studies in this area are still in their infancy, and many aspects of this field are just beginning to be explored and understood. Gaining a deeper understanding of the intricate interactions and signaling pathways involved in the microbiota-AD interaction is crucial for optimizing therapeutic strategies targeting gut microbiota to positively impact AD. In this review, we aim to summarize the current understanding of the microbiota-gut-brain axis in AD. We will discuss the existing evidence regarding the role of gut microbiota in AD pathogenesis, suggested underlying mechanisms, biological factors influencing the microbiome-gut-brain axis in AD, and remaining questions in the field. Last, we will discuss potential therapeutic approaches to recondition the community of gut microbiota to alleviate disease progression. An ongoing exploration of the gut-brain axis and the development of microbiota-based therapies hold the potential for advancing AD management in the future.

Fig. 1. Schematic diagram of the contribution of gut microbiota to AD pathologies and microbiota-based AD interventions.

Commensal microorganisms are essential for a healthy brain (left). However, multiple factors, including aging processes, dietary changes, and drug/alcohol consumption, can result in the unbalanced composition of gut microbial communities, influencing peripheral metabolism and immunity (right; red line). These biological processes ultimately regulate brain innate immunity and the progression of AD pathologies. Additionally, genetic risk factors (e.g., the presence of an ApoE4 allele) may contribute to or influence the presence of more disease-associated microbiota, the reactivity of brain innate immunity, and blood–brain barrier (BBB) integrity (black line). The blue line in the figure represents the therapeutic potential of putative microbiota-based interventions. Reconditioning the unbalanced gut microbiota using fecal microbiota transplantation (FMT), dietary fiber prebiotics, or probiotics limits the contribution of dysbiosis to AD progression, preventing the shift toward detrimental peripheral inflammation, metabolism, and neuroinflammation.