{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,16]],"date-time":"2026-09-16T08:54:18Z","timestamp":1789548858080,"version":"build-2803163510"},"reference-count":139,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2026,6,17]],"date-time":"2026-06-17T00:00:00Z","timestamp":1781654400000},"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>Alzheimer\u2019s disease (AD) is usually framed as a proteinopathy and network disorder, but this view may be incomplete. We propose a mechanobiological hypothesis in which synaptic micromechanics, regional brain softening, vascular pulsatility, and glymphatic transport are parts of a coupled fluid\u2013solid system whose failure contributes to AD progression. In this framework, early synaptic and glial mechanical fragility reduces the capacity of vulnerable circuits to maintain stable structure, efficient signaling, and waste clearance, while age-related tissue softening and impaired perivascular transport amplify amyloid and tau accumulation, network dysfunction, and cognitive decline. This framework integrates converging evidence from dendritic spine to glymphatic system biology, concordant results obtained with diffusion MRI and magnetic resonance elastography, and treats altered tissue mechanics not merely as a correlate of degeneration but as a potentially active multicomponent of disease expression. It further predicts that biomechanical alterations should be detectable before gross atrophy, should covary with glymphatic impairment, and may help explain why molecular pathology and clinical symptoms are often only partly aligned. By positioning brain mechanics as an interface between protein aggregation, synaptic dysfunction, and impaired clearance, this framework identifies testable imaging biomarkers and suggests potential early-stage intervention strategies aimed at preserving tissue resilience as well as reducing pathological protein burden.<\/jats:p>","DOI":"10.3389\/fnins.2026.1858655","type":"journal-article","created":{"date-parts":[[2026,6,17]],"date-time":"2026-06-17T05:55:55Z","timestamp":1781675755000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":1,"title":["Synaptic micromechanics and brain softening as a mechanobiological hypothesis for Alzheimer\u2019s disease"],"prefix":"10.3389","volume":"20","author":[{"given":"Denis","family":"Le Bihan","sequence":"first","affiliation":[{"name":"NeuroSpin, Joliot Institute, CEA, CEA-Saclay Center, Paris-Saclay University","place":["Gif-sur-Yvette, France"]}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1965","published-online":{"date-parts":[[2026,6,17]]},"reference":[{"key":"ref1","doi-asserted-by":"publisher","first-page":"6178","DOI":"10.1038\/s41598-017-05586-5","article-title":"Modulation of water diffusion by activation-induced neural cell swelling in Aplysia californica","volume":"7","author":"Abe","year":"2017","journal-title":"Sci. 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