Microbes and Microbial Chemical Matter in the Seeding of Alzheimer's Disease: Prospects for Orthogonal Therapies.

Alzheimer's disease (AD) remains the leading cause of dementia, with mortality rates having doubled over the past two to three decades and projected to rise with continued population aging. Despite its profound health and economic impact, effective therapeutic and preventive interventions remain limited, largely owing to an incomplete understanding of its etiopathogenesis. Emerging evidence indicates that microbes, including viruses, bacteria, and fungi, as well as their associated metabolites, toxins, and structural components, are involved in the development of AD. Microbial invasion, through dysbiosis or infection, can trigger neuroinflammation that drives overproduction of amyloid β peptide (AβP). AβP functions as a broad-spectrum antimicrobial agent, and its accumulation, a key pathological hallmark of AD, is promoted by microbial presence as part of the immune response. Maintaining microbial eubiosis, preventing infections that impact the nervous system (e.g., herpes zoster), supporting gut microbiome homeostasis through prebiotics, and the judicious use of antimicrobial interventions may mitigate AD onset and progression. This Review delineates the involvement of microbes and their components in the initiation of AD and presents the prospects of orthogonal therapies to control AD.