Reduced Hippocampal Iron Accelerates Cognitive Decline in Alzheimer’s Disease - EMJ

Reduced Hippocampal Iron Accelerates Cognitive Decline in Alzheimer’s Disease

1 Mins
Neurology

A RANDOMISED clinical trial found that lowering levels of iron in the brain using the iron chelator deferiprone may accelerate cognitive decline in patients with early-stage Alzheimer’s disease (AD).  

Researchers aimed to assess whether deferiprone could slow cognitive deterioration by reducing brain iron, a factor associated with neurodegeneration in AD. Conducted across nine sites in Australia from 2018 to 2023, this phase 2, double-masked, placebo-controlled trial involved 81 participants aged 54 or older, all with amyloid-confirmed mild cognitive impairment or early Alzheimer’s disease. Participants were randomly assigned in a 2:1 ratio to receive either deferiprone (15 mg/kg twice daily) or placebo for 12 months. The primary outcome was cognitive performance measured by a neuropsychological test battery (NTB) evaluating memory, executive function, and attention, assessed at baseline, six months, and 12 months. Secondary outcomes included brain iron levels, quantified via quantitative susceptibility mapping (QSM) MRI, changes in brain volume, and safety measures. Out of the initial 81 patients, 54 completed the study, with a higher dropout rate in the deferiprone group (37.7%) than the placebo group (25.0%). 

The results showed that deferiprone significantly reduced brain iron in the hippocampus, as indicated by QSM changes (deferiprone group, −0.36 ppb; placebo group, 0.32 ppb), confirming target engagement. However, the cognitive decline accelerated in the deferiprone group compared to placebo, with a more pronounced deterioration in executive function (change in NTB composite z score for deferiprone, −0.80; placebo, −0.30). Brain imaging also revealed increased volume loss in the frontal regions in patients receiving deferiprone. Additionally, deferiprone was associated with an increased incidence of neutropenia (7.5%), exceeding rates seen in similar studies. 

In conclusion, these findings indicate that deferiprone, while effective in reducing hippocampal iron levels, may have adverse effects on cognitive function and brain volume in AD patients. The observed acceleration in cognitive decline and frontal brain atrophy highlights the need for caution when targeting iron reduction in AD. Future research should further explore the mechanisms by which iron chelation may impact neurodegeneration and cognitive outcomes in Alzheimer’s and identify alternative therapeutic approaches that may address the progression of AD without exacerbating cognitive decline. Clinicians should carefully consider these risks before incorporating iron chelation as an intervention in Alzheimer’s treatment plans. 

Reference 

Ayton S et al. Deferiprone in alzheimer disease: a randomized clinical trial. JAMA Neurol. 2024;DOI:10.1001/jamaneurol.2024.3733.  

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