Synaptic micromechanics and brain softening as a mechanobiological hypothesis for Alzheimer’s disease
Open accessAbstract
Alzheimer’s 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–solid 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.
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Diffusion MRI raised the possibility of sensing rapid changes in the intrinsic physical state of neural tissue itself.
“Diffusion MRI, therefore, raised the possibility of sensing rapid changes in the intrinsic physical state of neural tissue itself (Fig. 6) (Le Bihan, 2026).”
From 40 Years of diffusion MRI in the brain: From history to emerging frontiers (2026) · cites this paper as Le Bihan, 2026
Diffusion-based virtual MRE appears as an attractive, scalable noninvasive biomarker to investigate brain stiffness in the aging brain and for longitudinal or interventional studies of neurodegenerative diseases, such as Alzheimer's disease including intervention stratification.
“Diffusion-based virtual MRE also appears as an attractive, scalable noninvasive biomarker to investigate brain stiffness in the aging brain and for longitudinal or interventional studies of neurodegenerative diseases, such as Alzheimer’s disease including intervention stratification (Le Bihan, 2026).”
From 40 Years of diffusion MRI in the brain: From history to emerging frontiers (2026) · cites this paper as Le Bihan, 2026
Regional stiffness maps may provide a mesoscale index of cumulative microstructural failure and of how strongly pathology has destabilized the local tissue environment.
“Regional stiffness maps may thus provide a mesoscale index of cumulative microstructural failure and of how strongly pathology has destabilized the local tissue environment (Coelho & Sousa, 2022; Y. Feng et al., 2024; Le Bihan, 2026).”
From 40 Years of diffusion MRI in the brain: From history to emerging frontiers (2026) · cites this paper as Le Bihan, 2026
Diffusion-vMRE could provide a surrogate marker of parenchymal mechanics relevant to glymphatic function, allowing from individual brain elasticity values to assess vulnerability to Alzheimer's disease and potentially identify patients who might benefit from early interventions.
“Diffusion-vMRE could provide a surrogate marker of parenchymal mechanics relevant to glymphatic function, allowing from individual brain elasticity values to assess vulnerability to Alzheimer’s disease and potentially identify patients who might benefit from early interventions (Le Bihan, 2026).”
From 40 Years of diffusion MRI in the brain: From history to emerging frontiers (2026) · cites this paper as Le Bihan, 2026
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40 Years of diffusion MRI in the brain: From history to emerging frontiers
Le Bihan, D. (2026) · Imaging Neuroscience · doi:10.1162/imag.a.1365
“6) ( Le Bihan, 2026).”
Influential
- Authors
- Le Bihan, D.
- Affiliations
- NeuroSpin, Joliot Institute, CEA, CEA-Saclay Center, Paris-Saclay University
- Venue
- Frontiers in Neuroscience
- Publisher
- Frontiers Media SA
- Published
- 2026-06-17
- Volume
- 20
- Pages
- 1858655-1858655
- ISSN
- 1662-453X (ISSN-L)
- PMC
- PMC13318895
- OpenAlex
- W7165033284
- Cited by
- 1
- References
- 136
- Citations by year
- 2026: 1
- FWCI
- 4.57
- Type
- journal article
- Language
- en
- Open access
- gold
- doi.org
- Licence
- Locations
- Frontiers in Neuroscience (publishedVersion, cc-by)
- PubMed (publishedVersion)
- DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion)
- Topics
- Health Sciences › Medicine › Physiology › Alzheimer's disease research and treatments
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Cell Biology › Cellular Mechanics and Interactions
- Health Sciences › Medicine › Psychiatry and Mental health › Dementia and Cognitive Impairment Research
- Keywords
- Alzheimer's disease, mechanobiology, brain tissue mechanics, cerebral softening, glymphatic system, amyloid accumulation, tau accumulation, waste clearance, magnetic resonance elastography, diffusion MRI, imaging biomarkers, dendritic spines
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