Negative Effect of Deferiprone Points to Impact of Iron Lowering in Alzheimer Disease

Scott Ayton, PhD

In a recently published randomized controlled trial, treatment with deferiprone, 15 mg/kg twice a day, worsened cognitive performance in patients with amyloid-confirmed mild cognitive impairment (MCI) and mild Alzheimer disease (AD). These findings underscore the critical role of iron in cognition in AD and raises intriguing questions.¹

Published in JAMA Neurology, the double-masked, placebo-controlled study randomly assigned 81 patients 2:1 to either deferiprone 15 mg/kg twice a day or placebo for 12 months. Deferiprone, a medication that chelates iron and is used to treat iron overload in thalassemia major, was found to decrease brain iron accumulation; however, treated patients still showed accelerated cognitive deterioration.

In the intent-to-treat analysis, those on deferiprone demonstrated greater accelerated deterioration on the Neuropsychological Test Battery (NTB) primary outcome (ß for interaction = –0.50; 95% CI, –0.80 to –0.20) compared with placebo (change in NTB composite z score for deferiprone: –0.80 [95% CI, –0.98 to –0.62]; for placebo: –0.30 [95% CI, –0.54 to –0.06]). The deterioration in cognitive performance was mostly for executive dysfunction, a result that was consistent with accelerated volume loss to frontal lobe areas.

In the conclusion of the research, lead author Scott Ayton, PhD, director for the Center of Research Excellence in Enhanced Dementia Diagnosis at The Florey, offered some potential reasons for these findings. Ayton and colleagues concluded that elevated iron levels in AD could represent an adaptive or protective response, or essential iron might be sequestered in pathological processes, leading to accumulation alongside functional deficiency. Alternatively, a harmful pool of iron in the brain may drive disease progression, but remined unaffected by the deferiprone doses used in the trial.

In the study, randomization variables for participants included APOE ε4 status and AD medication (present or absent) at baseline. A total of 54 participants completed the 12-month treatment period, comprising 21 participants (75.0%) in the placebo group and 33 (62.3%) in the deferiprone group. Consent withdrawal, the most common reason for discontinuation, was more apparent in the deferiprone group (24.5%) than those on placebo (10.7%).

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When looking at the individual tests of the NTB, deferiprone worsened performance on tests of executive function (ß for interaction range: –0.64 [95% CI, –1.00 to –0.27; P <.001] for the Delis-Kaplan Executive Function System) to –0.35 [95% CI, –0.64 to –0.06; P = .02 for the WAIS-IV Coding Subtest) more so than tests of memory β for interaction range: −0.19 [95% CI, −0.58 to 0.20] P = .34 for the Cogstate International Shopping List Test] to −0.12 [95% CI, −0.71 to 0.47] P = .69 for the Cogstate Groton Maze Learning Test]) and attention (β for interaction range: −0.54 [95% CI, −0.97 to −0.12] P = .01 for the Cogstate Identification test] to −0.10 [95% CI, −0.63 to 0.44] P = .72 for the Cogstate Detection test]).

At 52 weeks, investigators found no between-group differences in Mini-Mental State Examination scores (ß for interaction = –1.43; 95% CI, –3.63 to 0.76; P = .20), an exploratory outcome. In addition, at this time, there was no difference in change in hippocampal volume between the deferiprone and placebo groups (deferiprone: –0.03 mL [95% CI, –0.04 to –0.02 mL; placebo: –0.02 mL [95% CI, –0.03 to 0.01; P = .61). Notably, a greater loss of brain volume was more evident in the deferiprone group compared with the placebo group in the insula cortex, lateral orbitofrontal cortex, medial orbitofrontal cortex, and pars triangularis (ß for interaction range: 0.40 [95% CI, –0.75 to –0.05] P = .03 in the medial orbitofrontal cortex] to –0.24 [95% CI, –0.44 to –0.04; P = .02 in the insula cortex).

A total of 33 participants completed MRI scans: 15 (53.6%) in the placebo group and 18 (34.0%) in the deferiprone group. After 12 months, deferiprone reduced iron levels in the hippocampus compared to placebo (change in deferiprone group: −0.36 ppb; placebo: 0.32 ppb; P = .03). Exploratory analyses also showed that deferiprone reduced iron levels in several brain regions, including the caudate, pallidum, precuneus, putamen, and supramarginal cortex, with the most significant reduction observed in the pallidum (P < .001).

After 12 months of treatment, the deferiprone (–3.6 g/L) and placebo (–0.7 g/L) groups showed no difference in hemoglobin levels (ß for interaction = –2.9 [95% CI, –6.9 to 1.2]; P = .17). In addition, deferiprone caused a significant decrease in ferritin compared with placebo by 12 months (deferiprone: –102.9 ug/L; placebo: –27.9 ug/L; ß for interaction = –75 [95% CI, –112.8 to –37.1; P <.001).

REFERENCE
1. Ayton S, Barton D, Brew B, et al. Deferiprone in Alzheimer disease: a randomized clinical trial. JAMA Neurol. Published online November 4, 2024. doi:10.1001/jamaneurol.2024.3733