Deferiprone accelerates cognitive decline in Alzheimer’s trial

by Justin Jackson , Medical Xpress

A) Primary outcome: 53 patients treated with deferiprone and 28 with placebo. B) and C) Secondary outcomes: 18 patients treated with deferiprone and 15 with placebo. Credit: JAMA Neurology (2024). DOI: 10.1001/jamaneurol.2024.3733

A multi-institutional study made up of 26 researchers led by the University of Melbourne has discovered that iron-reducing deferiprone accelerates cognitive decline in patients with early Alzheimer’s disease. This unexpected finding shows that reducing brain iron levels with deferiprone is detrimental for individuals with Alzheimer’s.

Alzheimer’s disease is a significant global health challenge, with current treatments offering only modest benefits. Iron accumulation in the brain has been associated with Alzheimer’s pathology, prompting the exploration of iron-reducing molecules as a potential therapeutic strategy. Deferiprone, an oral iron chelator capable of crossing the blood-brain barrier, was hypothesized to slow neurodegeneration by reducing brain iron levels.

In the study, “Deferiprone in Alzheimer Disease: A Randomized Clinical Trial,” published in JAMA Neurology, researchers detail the results of the phase 2, double-masked, placebo-controlled randomized clinical trial to assess the effects of deferiprone on cognitive decline and brain iron levels in patients with amyloid-confirmed mild cognitive impairment or early Alzheimer’s disease.

Participants were randomized in a 2:1 ratio to receive either deferiprone at a dose of 15 mg/kg twice daily or a placebo for 12 months. The primary outcome measured cognitive performance using a neuropsychological test battery that included memory, executive function, and attention assessments.

Secondary outcomes evaluated changes in brain iron levels using quantitative susceptibility mapping magnetic resonance imaging (QSM MRI), brain volume changes, and adverse events.

Results indicated that participants receiving deferiprone experienced a significant acceleration in cognitive decline compared to the placebo group. The decline was primarily observed in executive function tests.

Deferiprone treatment did successfully decrease iron levels in the hippocampus, as confirmed by QSM MRI. Contrary to expectations, lowering iron levels did not affect hippocampal volume loss and was associated with increased volume loss in frontal brain regions.

The frequency of neutropenia, characterized by low neutrophil levels, was higher in the deferiprone group than in similar studies. This raises concerns about the safety profile of deferiprone in this patient population.

These findings challenge the notion that iron chelation is beneficial in Alzheimer’s disease and suggest that iron may play a more complex role in neurodegeneration than previously thought. Further research is needed to understand the implications of iron modulation in Alzheimer’s and to explore alternative therapeutic strategies.

More information: Scott Ayton et al, Deferiprone in Alzheimer Disease, JAMA Neurology (2024). DOI: 10.1001/jamaneurol.2024.3733

Journal information:Archives of Neurology

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