Structural and Ultrastructural Neuropathological Changes in Alzheimer's Disease: Biomarkers, Current Insights and Emerging Perspectives.

Alzheimer's Disease (AD) involves progressive brain changes at both the structural and ultrastructural levels, which begin long before patients present with clinical symptoms. These changes relate to the complex processes of amyloid-β deposition, tau accumulation, synaptic damage, glial activation, impaired vascular function, and disruption of large-scale brain networks. Understanding these neurobiological changes is essential for improving diagnosis, biomarker development, and targeted therapy. We conducted a search across PubMed, Scopus, and Web of Science using the terms "Alzheimer's disease," "brain structure," "ultrastructure," "cryo-electron microscopy," and "neuroimaging." We limited our review to peer-reviewed papers published in English. Recent developments in cryo-electron microscopy, super-resolution imaging, in situ cryo-electron tomography, and correlative microscopy have revealed the molecular and subcellular features of amyloid plaques and tau filaments, as well as the associated cellular pathology of AD. These investigations refine current pathophysiological models and improve understanding of molecular-level changes in the brain. Improvements in structural and molecular imaging provide potential new biomarkers and therapeutic targets in AD. Advances in imaging and structural neuroscience could support earlier disease detection and improve clinical outcomes. These advances are helping to connect molecular pathology with structural brain remodelling and may support more precise biomarker interpretation and therapeutic development.