Dysbiosis and the gut-brain axis impairment in the pathophysiology of Alzheimer's disease and related dementias: is 'pathobiome' an etiological element?

The gut microbiome plays a pivotal role in host metabolic, cardiovascular, and immune health. Increasing evidence also links it to aging-associated neurocognitive decline and neurodegenerative disorders, including Alzheimer's disease (AD) and related dementias. While the precise mechanisms of the gut-microbiome-brain axis remain incompletely understood, recent findings challenge the traditional view of AD as a disease confined to the central nervous system. Aging-associated gut dysbiosis, marked by loss of beneficial microbes, expansion of opportunistic pathogens, and reduced microbial diversity, can compromise intestinal barrier integrity, leading to 'leaky gut' and increased translocation of microbial components or pathogens into the circulation. These elements may cross a weakened blood-brain barrier, triggering neuroinflammation, amyloid-beta accumulation, tau hyperphosphorylation, and neuronal injury. Such pathobiome-driven inflammatory cascades may initiate or accelerate AD pathology, shifting the etiological perspective beyond the amyloid and tau hypotheses toward systemic and peripheral contributors. Our work and others' have identified distinct dysbiotic microbiome signatures in AD, supporting the possibility that AD pathogenesis may begin in the gut. Restoring microbial homeostasis through targeted interventions could attenuate neuroinflammatory and neurodegenerative processes, offering a novel preventive and therapeutic avenue. This emerging paradigm underscores the need for comprehensive, mechanistic, and longitudinal studies to define how aging-driven microbiome alterations influence the gut-brain axis and contribute to AD progression.