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Clinical Summary | Neurology | Gerontology | Alzheimer's Disease
Phase Two Study Investigates Iron-Chelator Deferiprone's Potential to Slow Cognitive Decline in Alzheimer's
Time to read: 09:26
Time to listen: 13:03
Published on MedED: 20 January 2025
Originally Published: 4 November 2024
Source: JAMA Neurolology
Type of article: Clinical Research Summary
MedED Catalogue Reference: MNCS002
Category: Neurology
Cross-reference: Gerontology
Keywords: Alzheimer's Disease, iron-chelation, amyloid plaques, mild cognitive impairment
Key Take Aways
1. The neurodegeneration effects of brain iron accumulation (NBIA) have prompted researchers to explore brain-permeable iron-chelator treatments for Alzheimer's disease (AD)
2. In this Phase 2 study, the iron-chelator deferiprone reduced brain iron but accelerated cognitive decline in Alzheimer's patients with amyloid-confirmed mild cognitive impairment or early AD
3. These findings challenge the idea that reducing brain iron is beneficial in AD, suggesting that iron sequestration in these patients may cause functional iron deficiency, affecting mitochondrial and metabolic functions.
4. On this basis, the researchers concluded that iron-chelating drugs such as deferiprone could be harmful to AD patients
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Study Context | Objectives | Study Design | Findings | Discussion| Limitations | Conclusion | Original Research | Funding | References
Alzheimer's disease (AD) is the most common form of dementia, affecting 60-80% of all dementia cases, with around 55 million people impacted globally and 10 million new cases each year.1
Over the past two decades, research has emphasised the role of oxidative stress in AD, particularly the involvement of transition metals like iron and copper.
These metals participate in Fenton-type reactions, generating reactive oxygen species (ROS) that damage cellular structures. Iron, the most abundant transition metal in the body, is vital for several biochemical processes but is also implicated in generating toxic pathways that contribute to AD.3
Current treatments, such as cholinergic nootropics and, more recently, monoclonal antibodies such as lecanemab and donanemab, reduce amyloid plaques and modestly slow cognitive decline. However, a major concern is their association with increased brain volume loss. This has prompted the exploration of alternative treatments targeting metals, such as iron, to reduce the rate of neurodegeneration. 3
Preclinical studies in Parkinson's disease, NBIA, and AD mouse models have shown the benefits of iron chelators like deferiprone and desferrioxamine.
Based on these findings, researchers hypothesised that deferiprone could slow cognitive decline in amyloid-confirmed mild cognitive impairment (MCI) and early AD. The results of their study entitled Deferiprone in Alzheimer Disease: A Randomised Clinical Trial were published in JAMA Neurology on 4th November 2024 and are summarised below.
In this phase 2 study, the investigators aimed to determine whether deferiprone (15 mg/kg BID orally) slowed cognitive decline in Alzheimer's patients, with secondary stated outcomes being the evaluation of iron levels in the brain and its safety profile.
Trial Registration Registered as Deferiprone to Delay Dementia (The 3D Study), ClinicalTrials.gov Identifier: NCT03234686
The Deferiprone to Delay Dementia study was a phase 2, multi-centre, prospective, parallel-group, double-masked, placebo-controlled randomised clinical trial.
The study was conducted between August 2018 and April 2023 at nine metropolitan clinical research sites across Australia and was approved by the Austin Health Human Research Ethics Committee.
Patient Selection
Inclusion criteria:
Participants were eligible for the study if they were aged 54 years or older, weighed between 40 and 120 kg, and exhibited evidence of Alzheimer's disease (AD) pathology (Aβ42 <656 pg/mL or >25 Centiloids). Mild symptoms, a mini-mental state exam score of ≥20, documented memory impairment within the past 6 months, and stable symptomatic AD treatment for at least 3 months were additional criteria.
Exclusion criteria:
Exclusion criteria included significant hematologic, iron, kidney, or liver abnormalities
Non-AD cognitive conditions included recent stroke or neurologic deficits, structural brain damage; autoimmune disorders; infections; and severe anxiety or depression
Diagnostic criteria aligned with National Institute on Aging guidelines.
Study Intervention
Patients were randomised ( 2:1) to receive either oral deferiprone, 15 mg/kg twice a day, or placebo twice a day.
Outcomes
The primary outcome was a composite cognitive measure evaluated at baseline, 6 months, and 12 months using a neuropsychological test battery assessing memory, executive function, and attention.
Secondary outcomes included changes in brain iron burden (quantitative susceptibility mapping MRI), brain volume (efficacy), and adverse events (safety analysis).
Study Evaluation
Cognition was assessed at baseline, 6 months, and 12 months using a neuropsychological test battery(NTB)
Blood tests for neutropenia and agranulocytosis were conducted weekly for 6 months, then bi-weekly thereafter
Physical and neurologic exams occurred at baseline and 3, 6, 9, and 12 months
A subset of participants underwent MRI to evaluate brain volume and quantitative susceptibility mapping (QSM) at baseline and 12 months.
Eighty-one participants were enrolled in the study.
Participants were randomly assigned in a 2:1 ratio, with 53 individuals allocated to the deferiprone group (mean age, 73.0 years; 45.3% female and 54.7% male) and 28 to the placebo group (mean age, 71.6 years; 39.3% female and 60.7% male).
Of the 81 participants, 54 completed the 12-month treatment period, comprising 33 participants (62.3%) in the deferiprone group and 21 (75.0%) in the placebo group.
Cognitive decline was notably accelerated in the deferiprone group compared to the placebo group. The decline was more pronounced in tests of executive function, with the NTB composite z-score decreasing by −0.80 in the deferiprone group, compared to −0.30 in the placebo group over 12 months.
33 participants completed the MRI scan -15 in placebo group and 18 in the deferipone group. Quantitative susceptibility mapping (QSM) revealed a notable reduction in hippocampal iron levels in the deferiprone group, with levels decreasing by −0.36 ppb. The decrease was most notable in in the caudate, pallidum, precuneus, putamen, and supramarginal cortex.
In contrast, the placebo group exhibited an increase in hippocampal iron of 0.32 ppb.
While this reduction in brain iron was achieved, at the twelve-month mark, the study found no difference in change of hippocampal volume between the two groups.
However, the deferiprone group exhibited increased volume loss in the insula cortex, lateral orbitofrontal cortex, medial orbitofrontal cortex, and pars triangularis regions, when compared to the placebo group.
Safety analyses highlighted a higher incidence of adverse events in the deferiprone group. Specifically, neutropenia was observed in 7.5% of participants receiving deferiprone. This rate exceeded those reported in comparable studies, which ranged from 1.6% to 4.4%. These findings suggest that deferiprone treatment poses significant safety risks, including haematological effects.
Discussion
The findings of this study indicate that deferiprone, administered orally at 15 mg/kg twice daily for 12 months to participants with amyloid-confirmed MCI or early AD, reduced blood ferritin and hippocampal QSM but resulted in accelerated cognitive decline and regional brain atrophy.
Executive dysfunction was the primary cognitive domain affected, correlating with volume loss in frontal lobe regions.
Although prior studies with iron chelators, including deferiprone and desferrioxamine, showed some neuroprotective potential, this trial revealed worsened symptoms potentially linked to dopamine depletion. Additionally, increased brain atrophy suggests accelerated disease progression rather than transient symptom exacerbation.
The findings challenge the prevailing hypothesis that reducing brain iron is beneficial in AD, raising the possibility that iron sequestration in AD pathology may cause functional iron deficiency, affecting mitochondrial and metabolic functions. It is significant to note that the researchers indicate that the dose of deferiprone may have been excessive for AD patients, as significant reductions in plasma ferritin and brain QSM were observed. While neutropenia occurred more frequently than in other deferiprone trials, agranulocytosis was not observed.
When taken in context, these results suggest that iron chelation therapy may be detrimental in AD, warranting reevaluation of iron's role in its pathology.
Limitations
The researchers indicated a number of limitations, noting that the interpretation of the results should be framed by their hypothesis that deferiprone would benefit AD participants. Additional limitations included the higher-than-expected dropout rate in the deferiprone group reduced the sample size, which affected the power analysis assumptions. This was further complicated by the high levels of neutropenia (7.5%) evidenced, which could have influenced study masking, and outcomes may have been perceived more favourably by those aware of treatment allocation. The small sample size, raising the risk of type 1 and type 11 errors, and the fact that the study did not allow for follow-up after the12 months were also noted as limitations.
Conclusion
The clear outcome of this study was that deferiprone (15 mg/kg twice daily) worsened cognitive performance in individuals with amyloid-confirmed MCI and mild AD. This result underscores the importance of iron in cognition in AD and raises new questions.
It suggests that elevated brain iron may be either protective or sequestered in pathology, causing functional iron deficiency. Alternatively, harmful brain iron may contribute to disease progression but was not targeted effectively by the deferiprone dose used in this trial.
Importance of this study for South Africa
Alzheimer's disease (AD) is projected to become a significant challenge in low- and middle-income countries, particularly in Africa, where it is expected that by 2050, over 68% of persons with dementia will reside, driven by demographic shifts and population growth in across the region.5
As the continent faces increasing prevalence, it's essential to recognise that the pathologies of AD in Africa may differ from those in other regions, and an understanding of these unique factors is key to addressing the disease effectively. Specifically, the role of the apolipoprotein E (APOE) ε4 allele, a well-studied genetic factor in AD, shows differential effects in African populations compared to Caucasians.5.
Furthermore, the dementia burden in Africa is not only a medical issue but also a social and economic one, affecting families, caregivers, and healthcare systems. In Africa, traditional family structures, which have supported dementia care, are gradually eroding due to socio-economic transitions and globalisation. This leaves a gap that needs to be addressed with robust healthcare solutions, informed by global advancements in dementia care, including preventive, therapeutic, and rehabilitative strategies.
Given these rapid changes and limited research, it is now crucial that Africa develop its own understanding of AD and explore the impact of new treatments in the context of its unique demographic and socio-economic challenges.
Access the Study
Ayton, S., Barton, D., Brew, B., Brodtmann, A., Clarnette, R., Desmond, P., Devos, D., Ellis, K. A., Fazlollahi, A., Fradette, C., Goh, A. M. Y., Kalinowski, P., Kyndt, C., Lai, R., Lim, Y. Y., Maruff, P., O'Brien, T. J., Rowe, C., Salvado, O., Schofield, P. W., … Bush, A. I. (2025). Deferiprone in Alzheimer Disease: A Randomized Clinical Trial. JAMA neurology, 82(1), 11–18. https://doi.org/10.1001/jamaneurol.2024.3733
Conflict of Interest, Funding and Support
Funding/Support
This research was supported by various grants from the NHMRC, contributions from ApoPharma (including deferiprone, placebo, and funding), and an operational infrastructure grant to The Florey Institute of Neuroscience and Mental Health from the Victorian government. Full information available online
Role of the Funder/Sponsor
The NHMRC reported no role in the study. Employees at ApoPharma advised on elements of the design and conduct of the study and reviewed the final manuscript.
Conflict of Interest Disclosures
This research was supported by various grants from the NHMRC, contributions from ApoPharma (including deferiprone, placebo, and funding), and an operational infrastructure grant to The Florey Institute of Neuroscience and Mental Health from the Victorian government.
References
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