{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,7,7]],"date-time":"2026-07-07T11:18:13Z","timestamp":1783423093926,"version":"3.54.6"},"reference-count":21,"publisher":"IMR Press","issue":"6","license":[{"start":{"date-parts":[[2026,6,16]],"date-time":"2026-06-16T00:00:00Z","timestamp":1781568000000},"content-version":"unspecified","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Front. Biosci. (Landmark Ed)"],"abstract":"<jats:p>Alzheimer\u2019s disease (AD) is increasingly recognized as a multifactorial and systems-level disorder that extends beyond the classical amyloid cascade hypothesis. Rather than dismissing established concepts such as tau pathology, synaptic dysfunction, vascular compromise, mitochondrial abnormalities, and impaired proteostasis, emerging evidence suggests that these processes may interact dynamically with chronic immune activation, microbial signaling, and systemic metabolic stress. Recent studies examining the microbiome-gut-brain axis, chronic infection, innate immunity, and systemic immune-metabolic dysfunction have broadened the conceptual framework of AD pathogenesis. Importantly, amyloid-\u03b2 (A\u03b2) is now understood to possess evolutionarily conserved antimicrobial and immunomodulatory properties, suggesting that amyloid deposition may initially represent a protective host-defense response rather than solely a toxic pathological event. This perspective does not overturn the amyloid cascade model but instead reframes amyloid biology within a broader adaptive evolutionary context in which chronic or dysregulated activation becomes maladaptive during aging. The present opinion article integrates these converging concepts into a unified framework in which AD emerges from the prolonged interaction among immune responses, microbial exposures, metabolic disturbances, mitochondrial dysfunction, vascular injury, and age-associated failures in proteostatic resilience. This integrative interpretation seeks to humanize the disease process by viewing neurodegeneration not simply as isolated protein accumulation, but as the gradual exhaustion of ancient host-defense and energy-regulatory systems that were originally evolutionarily advantageous for survival.<\/jats:p>","DOI":"10.31083\/fbl53859","type":"journal-article","created":{"date-parts":[[2026,7,7]],"date-time":"2026-07-07T10:50:51Z","timestamp":1783421451000},"source":"Crossref","is-referenced-by-count":0,"title":["Beyond Amyloid: Evolutionary and Immune-Metabolic Perspectives on Alzheimer\u2019s Disease"],"prefix":"10.31083","volume":"31","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-8146-0740","authenticated-orcid":true,"given":"George B.","family":"Stefano","sequence":"first","affiliation":[{"name":"Department of Psychiatry, First Faculty of Medicine, Charles University and General University Hospital, 116 36 Prague, Czech Republic"},{"name":"Mind-Cell LLC, Baltimore, MD 21230, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"16242","published-online":{"date-parts":[[2026,6,16]]},"reference":[{"key":"ref1","doi-asserted-by":"publisher","unstructured":"Stefano GB, Pilonis N, Ptacek R, Raboch J, Vnukova M, Kream RM. 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