{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,1]],"date-time":"2026-09-01T20:01:59Z","timestamp":1788292919726,"version":"build-2803163510"},"reference-count":35,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2026,5,22]],"date-time":"2026-05-22T00:00:00Z","timestamp":1779408000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":["frontiersin.org"],"crossmark-restriction":true},"short-container-title":["Front. Neurosci."],"abstract":"<jats:p>\n                    Studies of Alzheimer\u2019s disease (AD) have long been dominated by the amyloid cascade hypothesis, although mounting evidence suggests that amyloid-\u03b2 (A\u03b2) deposition might be a late downstream event, rather than the initiating trigger of AD. Here, I propose a unifying\n                    <jats:italic>Triple-Hit Hypothesis<\/jats:italic>\n                    in which AD develops through a sequential interaction among three causative processes that have been individually implicated before in the onset of Alzheimer\u2019s disease: (1) early blood\u2013brain barrier (BBB) breakdown, (2) entry or reactivation of microbial agents within the brain, and (3) maladaptive innate immune responses that produce chronic neuroinflammation and A\u03b2 accumulation. Converging data from human imaging, neuropathology, infectious disease studies, genetics, and vascular medicine could suggest that these three processes, which were in some previous studies linked to AD, might not be independent but rather that their temporal synergy could drive disease progression. This new conceptual framework integrates long-standing but fragmented lines of evidence and, if confirmed by experimental studies, offers the possibility for the development of new diagnostic biomarkers, new therapeutic entry points, and prevention strategies for AD. I argue that understanding AD as a disorder of the blood-brain barrier, immunity, and host\u2013pathogen interactions should be taken into account in future research on the etiology and clinical progression of AD.\n                  <\/jats:p>","DOI":"10.3389\/fnins.2026.1815976","type":"journal-article","created":{"date-parts":[[2026,5,22]],"date-time":"2026-05-22T06:09:52Z","timestamp":1779430192000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":1,"title":["The triple-hit hypothesis of Alzheimer\u2019s disease: blood\u2013brain barrier breakdown, infection, and neuroimmune activation as a unified etiological framework"],"prefix":"10.3389","volume":"20","author":[{"given":"Gregor","family":"Majdic","sequence":"first","affiliation":[{"name":"Veterinary Faculty, University of Ljubljana","place":["Ljubljana, Slovenia"]}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1965","published-online":{"date-parts":[[2026,5,22]]},"reference":[{"key":"B1","doi-asserted-by":"publisher","first-page":"65","DOI":"10.1007\/s00401-024-02820-z","article-title":"Microglia contribute to the production of the amyloidogenic ABri peptide in familial British dementia.","volume":"148","author":"Arber","year":"2024","journal-title":"Acta Neuropathol."},{"key":"B2","doi-asserted-by":"publisher","first-page":"19","DOI":"10.1016\/j.neuron.2010.08.023","article-title":"Regulation of tau pathology by the microglial fractalkine receptor.","volume":"68","author":"Bhaskar","year":"2010","journal-title":"Neuron"},{"key":"B3","doi-asserted-by":"publisher","first-page":"184","DOI":"10.1016\/S1474-4422(08)70021-8","article-title":"Cognition and diabetes: A lifespan perspective.","volume":"7","author":"Biessels","year":"2008","journal-title":"Lancet Neurol."},{"key":"B4","doi-asserted-by":"publisher","first-page":"1020","DOI":"10.1016\/j.kint.2024.09.008","article-title":"New insights into mechanisms underlying cognitive impairment in chronic kidney disease.","volume":"106","author":"Bobot","year":"2024","journal-title":"Kidney Int."},{"key":"B5","doi-asserted-by":"publisher","first-page":"eaau3333","DOI":"10.1126\/sciadv.aau3333","article-title":"Porphyromonas gingivalis in Alzheimer\u2019s disease brains: Evidence for disease causation and treatment with small-molecule inhibitors.","volume":"5","author":"Dominy","year":"2019","journal-title":"Sci. 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