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Basic Science and Pathogenesis.

Baayla D C Boon1,2, Yoav D Piura3, Christina M Moloney1

  • 1Mayo Clinic, Jacksonville, FL, USA.

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Aducanumab treatment for Alzheimer's disease reduced amyloid-beta in superficial brain layers. Amyloid-related imaging abnormalities (ARIA) were linked to iron and inflammation in these same cortical layers.

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Area of Science:

  • Neuropathology
  • Neuroimmunology
  • Alzheimer's Disease Research

Background:

  • Monoclonal antibodies like aducanumab target amyloid-beta (Aβ) for Alzheimer's disease (AD) treatment.
  • Limited data exist on neuropathology and amyloid-related imaging abnormalities (ARIA) post-treatment.
  • This study examines neuropathology in five aducanumab-treated participants, two of whom experienced ARIA.

Purpose of the Study:

  • To investigate neuropathological changes following aducanumab treatment in Alzheimer's disease patients.
  • To analyze the relationship between aducanumab treatment, Aβ burden, and the occurrence of ARIA.
  • To assess the distribution of Aβ isoforms, phosphorylated tau, and ARIA markers in the brain.

Main Methods:

  • Matched five aducanumab-treated autopsy cases with twelve AD controls based on genetic and demographic factors.
  • Assessed cognitive measures, amyloid PET centiloid values, and ARIA risk factors.
  • Utilized multiplex immunofluorescence to stain for Aβ isoforms, phosphorylated tau, and ARIA markers (iron, fibrinogen, complement, microglia).

Main Results:

  • Aβ burden decreased in all treated participants; two experienced ARIA.
  • Aβaa1-8 and Aβ42 were reduced in cortical layer I, but not total cortex, compared to controls.
  • ARIA cases showed hemosiderin accumulation in superficial layers near vessels, with significant complement and microglial activation.

Conclusions:

  • Aβ clearance and ARIA pathology are localized primarily in superficial cortical layers.
  • These findings suggest preferential biodistribution of aducanumab to superficial cortical regions.
  • The study highlights the association between ARIA, iron deposition, and neuroinflammation in superficial cortical layers.