{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,15]],"date-time":"2026-09-15T20:23:44Z","timestamp":1789503824845,"version":"build-2803163510"},"reference-count":52,"publisher":"Wiley","issue":"7","license":[{"start":{"date-parts":[[2024,5,23]],"date-time":"2024-05-23T00:00:00Z","timestamp":1716422400000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by-nc-nd\/4.0\/"}],"content-domain":{"domain":["alz-journals.onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["Alzheimer's &amp;amp; Dementia"],"published-print":{"date-parts":[[2024,7]]},"abstract":"<jats:title>Abstract<\/jats:title><jats:sec><jats:label\/><jats:p>This perspective offers an alternative to the amyloid hypothesis in the etiology of Alzheimer's disease (AD). We review evidence for a novel signaling mechanism based on a little\u2010known peptide, T14. T14 could drive neurodegeneration as an aberrantly activated process of plasticity selective to interconnecting subcortical nuclei, the isodendritic core, where cell loss starts at the pre\u2010symptomatic stages of the disease. Each of these cell groups has the capacity to form T14, which can stimulate production of p\u2010Tau and \u03b2\u2010amyloid, suggestive of an upstream driver of neurodegeneration. Moreover, results in an animal AD model show that antagonism of T14 with a cyclated variant, NBP14, prevents formation of \u03b2\u2010amyloid, and restores cognitive function to that of wild\u2010type counterparts. Any diagnostic and\/or therapeutic strategy based on T14\u2010NBP14 awaits validation in clinical trials. However, an understanding of this novel signaling system could bring much\u2010needed fresh insights into the progression of cell loss underlying AD.<\/jats:p><\/jats:sec><jats:sec><jats:title>Highlights<\/jats:title><jats:p><jats:list list-type=\"bullet\">\n<jats:list-item><jats:p>The possible primary mechanism of neurodegeneration upstream of amyloid.<\/jats:p><\/jats:list-item>\n<jats:list-item><jats:p>Primary involvement of selectively vulnerable subcortical nuclei, isodendritic core.<\/jats:p><\/jats:list-item>\n<jats:list-item><jats:p>Bioactive peptide T14 trophic in development but toxic in context of mature brain.<\/jats:p><\/jats:list-item>\n<jats:list-item><jats:p>Potential for early\u2010stage biomarker to detect Alzheimer's disease.<\/jats:p><\/jats:list-item>\n<jats:list-item><jats:p>Effective therapeutic halting neurodegeneration, validated already in 5XFAD mice.<\/jats:p><\/jats:list-item>\n<\/jats:list><\/jats:p><\/jats:sec>","DOI":"10.1002\/alz.13869","type":"journal-article","created":{"date-parts":[[2024,5,23]],"date-time":"2024-05-23T07:00:06Z","timestamp":1716447606000},"page":"5027-5034","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":13,"title":["Evidence for a novel neuronal mechanism driving Alzheimer's disease, upstream of amyloid"],"prefix":"10.1002","volume":"20","author":[{"given":"Sara","family":"Garcia Rat\u00e9s","sequence":"first","affiliation":[{"name":"Neuro\u2010Bio Ltd Building F5, Culham Campus  Abingdon UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mar\u00eda\u2010Salud","family":"Garc\u00eda\u2010Ayll\u00f3n","sequence":"additional","affiliation":[{"name":"Unidad de Investigaci\u00f3n Hospital General Universitario de Elche, FISABIO Elche Spain"},{"name":"Instituto de Neurociencias de Alicante Universidad Miguel Hern\u00e1ndez\u2010CSIC  Sant Joan d'Alacant Spain"},{"name":"Centro de Investigaci\u00f3n Biom\u00e9dica en Red sobre Enfermedades Neurodegenerativas (CIBERNED)  Madrid Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Neus","family":"Falg\u00e0s","sequence":"additional","affiliation":[{"name":"Alzheimer's disease and other cognitive disorders Unit Hospital Cl\u00ednic de Barcelona. 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