Synaptic micromechanics and brain softening as a mechanobiological hypothesis for Alzheimer’s disease

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, efficien