PHILADELPHIA — Among the many mysteries of Alzheimer’s disease is the role that iron plays. The metal is vital for transporting oxygen in the blood and producing energy from mitochondria, but some scientists think too much iron in the brain can be a bad thing.
Excess iron can cause a unique form of cell death called ferroptosis that is believed to contribute to Alzheimer’s. In one study, people with more iron in their brains at death had a faster rate of cognitive decline. In another, higher levels of the iron-storing protein ferritin in spinal fluid were linked to worse scores on cognitive tests.
Naturally, some scientists have wondered whether mopping up the metal with a drug such as deferiprone — an iron chelator approved for removing extraneous iron in blood diseases — might help patients. But a new test of that hypothesis has backfired.
In a clinical trial of 81 people with mild cognitive impairment or early Alzheimer’s disease, patients given deferiprone markedly worsened over a year and declined nearly three times faster than those who got a placebo.
Scott Ayton“We were assuming that the iron was bad. But now we have to revisit this,” Scott Ayton, a director at The Florey Institute of Neuroscience and Mental Health at the University of Melbourne who led the study, told Endpoints News in an interview.
The study measured cognitive decline on an exam called the Neuropsychological Test Battery. Patients who got a placebo pill declined by an average of 0.295 points, while those who got deferiprone declined 0.863 points. The biggest changes were on tests that measure executive functions like planning and organizing.
The results of the Phase 2 study were presented in a poster for the first time at the Alzheimer’s Association International Conference in Philadelphia on Wednesday. Ayton said the study is currently under review for publication in a medical journal.
Deferiprone is marketed as Ferriprox by Italy’s Chiesi, and Ayton said that the company wasn’t involved in the study. The academic-led trial was partly inspired by old findings suggesting that iron chelation could help patients with Parkinson’s disease, another neurodegenerative disorder linked to excess iron in the brain.
In 2016, a large group of researchers that included Ayton began putting the deferiprone hypothesis to a more rigorous test. In late 2022, the group published the results of the 372-person study showing the drug worsened Parkinson’s disease. By then, the similarly-fated Alzheimer’s study was already well underway.
“I feel sad for the patients. This didn’t benefit them. But scientifically, this is fascinating,” Ayton said. “We see such a large effect, and that tells us that iron is important for the disease. And maybe, maybe if we can target iron-related pathways, we could get a benefit.”
But the solution likely isn’t as simple as giving patients more iron, he added.
“Maybe iron is an adaptive response, and the brain is summoning more iron to fight against the disease. Or maybe the iron is being trapped and unavailable for use,” Ayton said. “These types of thinking might lead us to get that benefit.”