{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,7]],"date-time":"2026-09-07T20:32:45Z","timestamp":1788813165990,"version":"build-2803163510"},"reference-count":179,"publisher":"MDPI AG","issue":"11","license":[{"start":{"date-parts":[[2026,6,2]],"date-time":"2026-06-02T00:00:00Z","timestamp":1780358400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["IJMS"],"abstract":"<jats:p>Alzheimer\u2019s disease (AD) is undergoing a profound paradigm shift, transitioning from a localized, monolithic proteinopathy into a complex, multisystem disorder. This critical review synthesizes recent mechanistic, translational, and clinical insights to dismantle the traditional linear amyloid cascade hypothesis. We explore the synergistic interplay between amyloid-\u03b2 (A\u03b2) and tau propagation, positioning chronic neuroinflammation, endolysosomal failure, and metabolic starvation\u2014often framed as \u201cType 3 Diabetes\u201d\u2014as fundamental disease drivers. Crucially, we highlight the emerging biological bridge of CNS-PNS crosstalk, where central neurodegeneration and peripheral neuropathies are linked by systemic immune activation and microbiota\u2013gut\u2013brain axis dysbiosis. The recent validation of disease-modifying therapies (DMTs) confirms A\u03b2 clearance as a viable pharmacological target; however, the marginal clinical gains and severe radiological risks, such as Amyloid-Related Imaging Abnormalities (ARIA), expose the profound limitations of monotherapy. Ultimately, we argue that isolated amyloid clearance is merely an induction phase. The future of AD therapeutics mandates a sequential combination approach\u2014pairing early plaque debulking with lifelong metabolic and neuroimmune maintenance. Supported by scalable fluid biomarkers (e.g., plasma p-tau217) and the expanded ATN(I) framework, the field must embrace proactive precision medicine and inclusive clinical trial designs to successfully transform AD into a manageable chronic condition.<\/jats:p>","DOI":"10.3390\/ijms27115042","type":"journal-article","created":{"date-parts":[[2026,6,3]],"date-time":"2026-06-03T00:50:28Z","timestamp":1780447828000},"page":"5042","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":1,"title":["Beyond the Amyloid Hypothesis: Systemic Drivers, CNS-PNS Crosstalk, and the Future of Alzheimer\u2019s Disease Therapeutics"],"prefix":"10.3390","volume":"27","author":[{"given":"Amador","family":"Vel\u00e1zquez de Castro-Bono","sequence":"first","affiliation":[{"name":"Hospital Central de la Defensa \u201cG\u00f3mez Ulla\u201d, 28047 Madrid, Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6928-9728","authenticated-orcid":false,"given":"Gracia","family":"Castro-Luna","sequence":"additional","affiliation":[{"name":"Department of Nursing, Physiotherapy and Medicine, University of Almer\u00eda, 04120 Almer\u00eda, Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2666-1774","authenticated-orcid":false,"given":"Jos\u00e9 Luis","family":"Guil-Guerrero","sequence":"additional","affiliation":[{"name":"Food Technology Division, University of Almer\u00eda, 04120 Almer\u00eda, Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2026,6,2]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"173","DOI":"10.1007\/s13311-021-01146-y","article-title":"Neuropathology of Alzheimer\u2019s Disease","volume":"19","author":"Yachnis","year":"2022","journal-title":"Neurotherapeutics"},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"3969","DOI":"10.1093\/brain\/awad159","article-title":"The Amyloid Cascade Hypothesis: An Updated Critical Review","volume":"146","author":"Kepp","year":"2023","journal-title":"Brain"},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"580","DOI":"10.1038\/s41582-021-00520-w","article-title":"Developing the ATX(N) Classification for Use across the Alzheimer Disease Continuum","volume":"17","author":"Hampel","year":"2021","journal-title":"Nat. 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