IMPORTANCE: Growing epidemiological and mechanistic evidence indicates that infections substantially increase the risk of Alzheimer's disease (AD) and related dementias. Systemic immune activation and pathogen persistence may act as upstream triggers accelerating neurodegenerative cascades. OBJECTIVE: To synthesize recent evidence on infection-driven mechanisms contributing to AD pathology, emphasizing how systemic and central immune activation influence amyloid-beta (Aβ) aggregation, tau pathology, blood-brain barrier (BBB) dysfunction, and neuroinflammation. DESIGN, SETTING, AND PARTICIPANTS: This expert review integrates data from large epidemiological cohorts, neuropathological analyses, and mechanistic studies in both human and animal models to address innate and adaptive immune mechanisms linking infection to AD pathogenesis. EXPOSURES: Systemic and central nervous system (CNS) infections, including sepsis, pneumonia, viral, and chronic bacterial infections, as well as hospital-treated infections, that trigger inflammatory and immune signaling cascades impacting the brain's structural and molecular integrity. RESULTS: Infections activate the innate immune system through toll-like receptors and inflammasomes (NOD-like receptor family pyrin domain-containing 3 (NLRP3), linear ubiquitin assembly complex (LUBAC)), driving chronic neuroinflammation, pyroptosis, and the release of apoptosis-associated speck-like protein containing a caspase recruitment domain (ASC) speck that cross-seeds Aβ and tau aggregation. Additionally, cytokine-induced upregulation of interferon-induced transmembrane protein 3 (IFITM3) enhances γ-secretase activity, thereby increasing Aβ production. Therefore, peripheral inflammation compromises BBB integrity, while extracellular vesicles propagate inflammatory cargoes across the neurovascular unit. Consequently, the expansion of cytotoxic CD8⁺ T cells and the alteration of Th1/Th17 profiles are linked to adaptive immunity and neurodegeneration. Moreover, epidemiologic data show reduced AD risk following herpes zoster, Tdap/Td (tetanus, diphtheria, and acellular pertussis (Tdap) and tetanus and diphtheria (Td) vaccines), and pneumococcal vaccination, supporting immune modulation as a preventive strategy. CONCLUSIONS AND RELEVANCE: Infection-driven immune activation represents a key modifiable pathway in AD pathogenesis, highlighting novel diagnostic and therapeutic targets focused on the inflammasome.
Barichello et al. (Mon,) studied this question.