Sex differences in brain iron deposition and microglial ferritin in Alzheimer's disease

Abstract

Objective: Iron is the most abundant metal in the human brain, and plays a crucial role in many biological processes. However, disruptions in brain iron metabolism can lead to iron buildup, which occurs with aging and is linked to several brain disorders, including Alzheimer's disease. Microglia, the brain's resident immune cells, have the highest capacity to store iron, which is stored intracellularly within ferritin complexes. Importantly, women are at a higher risk of developing Alzheimer's disease and experience faster disease progression compared to men. Methods: We used postmortem brain samples from patients with Alzheimer's disease and small vessel disease patients of both sexes for immunohistochemical studies. Samples were stained with the Prussian blue method to visualize iron deposits and with antibodies against the microglia marker Iba1 and ferritin light chain. Results: Our study reveals that the number of iron deposits and the levels of ferritin light chain in microglia are positively correlated in men with Alzheimer's disease, but negatively correlated in women. There is no correlation between brain iron deposition and ferritin in samples from patients with small vessel disease of both sexes. Conclusions: These results could inform more tailored approaches to the treatment and management of Alzheimer's disease based on sex-specific differences in brain iron metabolism and microglial iron storage capacity.