Distinct regional vulnerability to Aβ and iron accumulation in post mortem AD brains

Abstract INTRODUCTION The paramagnetic iron, diamagnetic amyloid beta (Aβ) plaques and their interaction are crucial in Alzheimer's disease (AD) pathogenesis, complicating non‐invasive magnetic resonance imaging for prodromal AD detection. METHODS We used a state‐of‐the‐art sub‐voxel quantitative susceptibility mapping method to simultaneously measure Aβ and iron levels in post mortem human brains, validated by histology. Further transcriptomic analysis using Allen Human Brain Atlas elucidated the underlying biological processes. RESULTS Regional increased paramagnetic and diamagnetic susceptibility were observed in medial prefrontal, medial parietal, and para‐hippocampal cortices associated with iron deposition ( R = 0.836, p = 0.003) and Aβ accumulation ( R = 0.853, p = 0.002) in AD brains. Higher levels of gene expression relating to cell cycle, post‐translational protein modifications, and cellular response to stress were observed. DISCUSSION These findings provide quantitative insights into the variable vulnerability of cortical regions to higher levels of Aβ aggregation, iron overload, and subsequent neurodegeneration, indicating changes preceding clinical symptoms. Highlights The vulnerability of distinct brain regions to amyloid beta (Aβ) and iron accumulation varies. Histological validation was performed on stained sections of ex‐vivo human brains. Regional variations in susceptibility were linked to gene expression profiles. Iron and Aβ levels in ex‐vivo brains were simultaneously quantified.