EARLY DEMYELINATION OF THE HIPPOCAMPAL COMMISSURE DRIVES FUNCTIONAL NETWORK DISINTEGRATION BEFORE OVERT NEURODEGENERATION IN ALZHEIMER’S DISEASE

Emerging evidence suggests that white matter pathology may play a crucial role in the earliest stages of Alzheimer’s disease (AD). In this study, we investigate whether demyelination of the hippocampal commissure constitutes an early neuropathological event contributing to interhemispheric disconnection before overt neurodegeneration.
We applied a multimodal, multiscale approach combining histological analyses in young APP/PS1 transgenic mice (4–6 months), and diffusion tensor imaging (DTI) and electroencephalography (EEG)-based network metrics in human participants across the AD continuum, from mild cognitive impairment (MCI) to AD.
In the AD mouse model, structural alterations in hippocampal commissural white matter were detected, including reduced tract integrity. Molecular analyses revealed a significant decrease in major myelin proteins in the dorsal hippocampal commissure, while axonal density remained preserved, indicating primary myelin damage. These changes were accompanied by increased cellular accumulation and diffusion restriction, together with microglial activation but not astrogliosis, suggesting an early pro-inflammatory response.
In humans, DTI-based tractography demonstrated a progressive reduction in hippocampal commissure integrity from healthy controls to MCI and AD. Functionally, EEG network analysis revealed compensatory reorganisation in MCI and a marked decrease in network integration in AD, consistent with progressive functional disconnection.
Collectively, our findings identify early demyelination of the hippocampal commissure as a key mechanism underlying the transition from myelin damage to network disintegration in AD. This process precedes overt neurodegeneration and highlights hippocampal commissure integrity as a promising early biomarker of medial temporal lobe connectivity loss, with potential implications for early diagnosis, prognosis, and therapeutic strategies.