medwireNews: Treating patients with mild cognitive impairment (MCI) or early-onset Alzheimer’s disease (AD) with the brain-permeable iron chelator deferiprone reduces brain iron but accelerates cognitive decline and concomitant brain volume loss, indicates a study published in JAMA Neurology.
“These findings suggest that lowering iron with deferiprone is detrimental in Alzheimer disease,” say the authors.
The 12-month, phase 2 trial across nine sites in Australia was conducted between 2018 and 2023 to explore brain iron as a potential drug target, since elevated levels have “been associated with accelerated cognitive decline” in AD patients, the investigators explain.
A total of 81 patients older than 54 years with either amyloid-confirmed MCI, or early AD who scored 20 or more points on the Mini-Mental State Examination (MMSE) participated. Of these patients, 53 (mean age 73.0 years; 54.7% men) were assigned to receive deferiprone 15 mg/kg twice daily, and 28 (mean age 71.6 years; 60.7% men) to receive matching placebo.
The patients were assessed at baseline, 6 months, and 12 months for the primary composite cognitive outcome, which included memory, executive function, and attention tasks on a neuropsychological test battery (NTB).
Scott Ayton (The University of Melbourne, Victoria, Australia) and colleagues report that the intention-to-treat analysis at 12 months showed a “significantly worsened cognitive performance” among the patients treated with deferiprone. Their composite NTB z score decreased by a mean 0.80 from –0.06 at baseline, compared with a 0.30 decrease from 0.12 at baseline among patients receiving placebo.
The researchers note that “the deterioration in cognitive performance was mostly for executive function.” And this was consistent with greater volume loss in the insula cortex, lateral orbitofrontal cortex, medial orbitofrontal cortex, and pars triangularis regions in deferiprone-treated patients compared with placebo-treated patients, despite there being no difference in overall hippocampal volume between the two groups.
The patients who received deferiprone also showed a greater reduction in hippocampal iron at follow-up than those who received placebo, as measured using quantitative susceptibility mapping (QSM) magnetic resonance imaging, particularly in the caudate, pallidum, precuneus, putamen, and supramarginal cortex. Overall, levels fell by a mean 0.36 ppb from a baseline level of –8.68 ppb in deferiprone-treated patients and increased by 0.32 ppb from –6.11 ppb in those treated with placebo.
Ayton and colleagues say that while worsening cognition may in part be attributed to “decreased dopamine and other catecholamines (ie, noradrenaline),” the increased volume loss in frontal brain regions in the treatment group “is consistent with accelerated disease progression, not just symptom exacerbation.”
Additionally, they highlight that “the frequency of consent withdrawal in [deferiprone]-treated participants was more than double that of the placebo group,” at rates of 24.5% versus 10.7%, which the team says is “in accordance with the other indicators of harm caused by deferiprone.”
Serious adverse events occurred in a comparable 30% of patients in the deferiprone treatment group and 25% of those in the placebo group. Neutropenia in 7.5% of patients was considered likely related to deferiprone treatment, which the authors highlight was higher than the previously reported rate of 1.6% in a similar trial in patients with Parkinson’s disease.
The investigators say the results “may recast the interpretation of decades-old correlative findings of increased brain iron accumulation in AD and associations of higher iron with worse outcomes.”
They comment that “[i]t is possible that iron elevation in AD is an adaptive or protective mechanism or that essential iron might be sequestered inappropriately (eg, in pathology), leading to iron accumulation with functional iron deficiency.”
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