Staging of Neuropil Morphological Alterations in Alzheimer's Disease.

Authors

Zhi-Yi Zhang, Xin-Meng Wang, Xin Ma, Yi Wang, Shuai-Deng Wang, Yi-Lin Peng, Kun Cheng, Yue-Ru Shen, Guo-Zhang Tang, Chen-Wei Wang, Jiang-Ning Zhou

Published in

Aging and disease. Jun 24, 2026. Epub Jun 24, 2026.

Abstract

Alzheimer's disease (AD) involves the progressive fragmentation of neural connectivity. This study aims to investigate the morphological degeneration of neuropil fibers in AD and evaluate their utility as a marker for pathological severity. Post-mortem brain tissues from 92 cases across eight distinct regions were analyzed. We used Bielschowsky silver staining with automated quantitative morphometry to measure neuritic fiber length and curvature in the neuropil, and immunofluorescence to detect neurite cytoskeletal markers. Finally, a novel histological staging system for neuropil disruption was established to assess disease progression. Morphometric analysis revealed progressive reductions in neuritic fiber length and increased curvature tracking with disease severity, a significant negative correlation confirmed these are coupled degenerative manifestations. Immunofluorescence demonstrated extensive cytoskeletal fragmentation that corresponded to the pattern observed with silver staining. Based on morphometric analysis, a novel four-tier staging system was established, defined neuropil by homogeneous compactness (-), initial (+), extensive (++) disruption, and complete fragmentation (+++), which correlated preferentially with Phospho-Tau load. Crucially, subtle neuropil alterations were detectable in the entorhinal cortex, amygdala, and anterior hippocampus even in Braak 0 stage, suggesting a potential association between these early changes and the initial stages of tau pathogenesis. This study establishes a staging system for assessing neuropil degeneration, demonstrating that neuropil fragmentation and geometric distortion are candidate AD pathological markers. By systematically analyzing neuritic fiber morphology and proposing a neuropil disruption stage, this work provides critical insights into early AD pathogenesis, offering a foundation for future diagnostic strategies pending validation in independent cohorts with clinical correlations.

PMID:
42372231
Bibliographic data and abstract were imported from PubMed on 30 Jun 2026.

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