Deferiprone Accelerates Cognitive Decline in Patients With Early AD
Deferiprone administered twice a day at 15 mg/kg may accelerate cognitive decline in patients with amyloid-confirmed early Alzheimer disease (AD), according to recent results from a randomized controlled trial published in JAMA Neurology.
“This outcome highlights the importance of iron for cognition in AD and provokes new questions,” noted lead author Scott Ayton, PhD, The Florey Institute of Neuroscience and Mental Health, The University of Melbourne, Parkville, Australia, and co-authors. “Contrary to this trial’s hypothesis, these results indicate that the decrease of brain iron appears to be detrimental in patients with AD. This result may recast the interpretation of decades-old correlative findings of increased brain iron accumulation in AD and associations of higher iron with worse outcomes.”
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The 12-month, phase 2, double-masked, placebo-controlled randomized clinical trial was conducted at 9 sites in Australia between August 2, 2018, and April 1, 2023. Patients older than 54 years with amyloid-confirmed mild cognitive impairment or early AD (a Mini-Mental State Examination score of 20 or higher) were screened. Randomization was 2:1 and masked to participants and all study staff. Participants received deferiprone at 15 mg/kg twice a day or an oral placebo. Participants’ cognitive states were measured at baseline, 6 months, and 12 months with a neuropsychological test battery (NTB) of memory, executive function, and attention tasks. Researchers also measured the participants’ change in brain iron burden using quantitative susceptibility mapping (QSM) magnetic resonance imaging (target engagement), brain volume changes (secondary efficacy measure), and adverse events (safety analysis).
A total of 81 participants were included, with 53 being randomly assigned to the deferiprone group (mean age, 73.0 years; 29 male [54.7%]) and 28 to the placebo group (mean age, 71.6 years; 17 male [60.7%]). Out of the 81 total participants, 54 completed the study (7 [25.0%] withdrew from the placebo group and 20 [37.7%] from the deferiprone group). Participants in the deferiprone group showed accelerated cognitive decline in the NTB measures (β 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 QSM confirmed that the active drug decreased iron in the hippocampus as opposed to placebo (change in hippocampal QSM for deferiprone, −0.36 ppb [95% CI, −0.76 to 0.04 ppb]; for placebo, 0.32 ppb [95% CI, −0.12 to 0.75 ppb]; β for interaction = −0.68 [95% CI, −1.27 to −0.09]). Longitudinal hippocampal volume loss was not affected by deferiprone, but exploratory analysis of other brain regions revealed increased volume loss with deferiprone in frontal areas. The frequency of the adverse effect of neutropenia (4 participants [7.5%] in the deferiprone group) was also higher than in similar studies.
This study has several limitations, as noted by the authors. First, the authors’ hypothesis that deferiprone would benefit participants with AD frames the results and their interpretation. A higher-than-expected dropout rate in the deferiprone group reduced the sample size, potentially affecting study power. Masking integrity may have been compromised by the high neutropenia rate (7.5%) and differential cognitive outcomes, leading to potential unmasking and biased self-reports. Recruitment was impacted by the COVID-19 pandemic, and small sample sizes risk both type I and type II errors, especially with MRI data, which may include false-positive and false-negative findings. Additionally, the lack of demographic data limits understanding of the drug's effects across diverse populations, and the absence of follow-up beyond 12 months leaves long-term effects uncertain.
“It 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,” Dr Ayton and co-authors concluded. “It is also possible that there is a damaging pool of iron within the brain of patients with AD that may contribute to disease progression but was not targeted by deferiprone at the doses used in this trial.”
