{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,13]],"date-time":"2026-10-13T19:29:18Z","timestamp":1791919758745,"version":"4.3.4"},"reference-count":213,"publisher":"MDPI AG","issue":"1","license":[{"start":{"date-parts":[[2025,1,5]],"date-time":"2025-01-05T00:00:00Z","timestamp":1736035200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"Research &amp; Innovation Foundation of Cyprus\u2014Excellence Hubs 2021","award":["EXCELLENCE\/0421\/0543"],"award-info":[{"award-number":["EXCELLENCE\/0421\/0543"]}]},{"name":"Research &amp; Innovation Foundation of Cyprus\u2014Excellence Hubs 2021","award":["#101031962"],"award-info":[{"award-number":["#101031962"]}]},{"name":"European Commission Marie Sk\u0142odowska-Curie fellowship","award":["EXCELLENCE\/0421\/0543"],"award-info":[{"award-number":["EXCELLENCE\/0421\/0543"]}]},{"name":"European Commission Marie Sk\u0142odowska-Curie fellowship","award":["#101031962"],"award-info":[{"award-number":["#101031962"]}]},{"name":"IDSA Foundation","award":["EXCELLENCE\/0421\/0543"],"award-info":[{"award-number":["EXCELLENCE\/0421\/0543"]}]},{"name":"IDSA Foundation","award":["#101031962"],"award-info":[{"award-number":["#101031962"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Microorganisms"],"abstract":"<jats:p>For decades, Alzheimer\u2019s Disease (AD) research has focused on the amyloid cascade hypothesis, which identifies amyloid-beta (A\u03b2) as the primary driver of the disease. However, the consistent failure of A\u03b2-targeted therapies to demonstrate efficacy, coupled with significant safety concerns, underscores the need to rethink our approach to AD treatment. Emerging evidence points to microbial infections as environmental factors in AD pathoetiology. Although a definitive causal link remains unestablished, the collective evidence is compelling. This review explores unconventional perspectives and emerging paradigms regarding microbial involvement in AD pathogenesis, emphasizing the gut\u2013brain axis, brain biofilms, the oral microbiome, and viral infections. Transgenic mouse models show that gut microbiota dysregulation precedes brain A\u03b2 accumulation, emphasizing gut\u2013brain signaling pathways. Viral infections like Herpes Simplex Virus Type 1 (HSV-1) and Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) may lead to AD by modulating host processes like the immune system. A\u03b2 peptide\u2019s antimicrobial function as a response to microbial infection might inadvertently promote AD. We discuss potential microbiome-based therapies as promising strategies for managing and potentially preventing AD progression. Fecal microbiota transplantation (FMT) restores gut microbial balance, reduces A\u03b2 accumulation, and improves cognition in preclinical models. Probiotics and prebiotics reduce neuroinflammation and A\u03b2 plaques, while antiviral therapies targeting HSV-1 and vaccines like the shingles vaccine show potential to mitigate AD pathology. Developing effective treatments requires standardized methods to identify and measure microbial infections in AD patients, enabling personalized therapies that address individual microbial contributions to AD pathogenesis. Further research is needed to clarify the interactions between microbes and A\u03b2, explore bacterial and viral interplay, and understand their broader effects on host processes to translate these insights into clinical interventions.<\/jats:p>","DOI":"10.3390\/microorganisms13010090","type":"journal-article","created":{"date-parts":[[2025,1,6]],"date-time":"2025-01-06T10:40:52Z","timestamp":1736160052000},"page":"90","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":32,"title":["Shattering the Amyloid Illusion: The Microbial Enigma of Alzheimer\u2019s Disease Pathogenesis\u2014From Gut Microbiota and Viruses to Brain Biofilms"],"prefix":"10.3390","volume":"13","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-3380-7356","authenticated-orcid":false,"given":"Anna","family":"Onisiforou","sequence":"first","affiliation":[{"name":"Translational Neuropharmacology Laboratory, Department of Psychology, University of Cyprus, 75 Kallipoleos Avenue, 1678 Nicosia, Cyprus"},{"name":"Center of Applied Neuroscience, 75 Kallipoleos Avenue, 1678 Nicosia, Cyprus"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5755-0375","authenticated-orcid":false,"given":"Eleftheria G.","family":"Charalambous","sequence":"additional","affiliation":[{"name":"Translational Neuropharmacology Laboratory, Department of Psychology, University of Cyprus, 75 Kallipoleos Avenue, 1678 Nicosia, Cyprus"},{"name":"Department of Psychiatry and Psychotherapy, University Medicine Greifswald, 1\u20132, Ellernholzstr., 17489 Greifswald, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1968-8648","authenticated-orcid":false,"given":"Panos","family":"Zanos","sequence":"additional","affiliation":[{"name":"Translational Neuropharmacology Laboratory, Department of Psychology, University of Cyprus, 75 Kallipoleos Avenue, 1678 Nicosia, Cyprus"},{"name":"Center of Applied Neuroscience, 75 Kallipoleos Avenue, 1678 Nicosia, Cyprus"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2025,1,5]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"32","DOI":"10.1186\/s13024-019-0333-5","article-title":"The Neuropathological Diagnosis of Alzheimer\u2019s Disease","volume":"14","author":"Deture","year":"2019","journal-title":"Mol. 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