Iron overload may explain why Alzheimer’s hits harder in people with Down syndrome

A recent study by researchers at the University of Southern California (USC) has uncovered a crucial link that may explain why individuals with Down syndrome develop Alzheimer’s disease earlier and more severely than the general population. The culprit? Excess iron in the brain, which leads to a destructive form of cell death called ferroptosis.

Published by scientists at the USC Leonard Davis School of Gerontology, the research found that people with both Down syndrome and Alzheimer’s disease (DSAD) had twice as much iron in the brain’s prefrontal cortex compared to those with only Alzheimer’s or neither condition. This iron buildup, the study suggests, leads to oxidative stress and damage to cell membranes, accelerating the progression of the disease.

“This is a major clue that helps explain the unique and early changes we see in the brains of people with Down syndrome who develop Alzheimer’s,” said Max Thorwald, the study’s lead author and a postdoctoral fellow at USC. “We’ve long known that people with Down syndrome are at higher risk, but now we’re starting to understand how iron may be making things worse.”

Down syndrome is caused by an extra copy of chromosome 21, which includes the APP gene—responsible for producing amyloid precursor protein. This protein gives rise to amyloid-beta, the sticky substance that forms plaques in the brains of people with Alzheimer’s. With three copies of the APP gene instead of two, individuals with Down syndrome produce more amyloid-beta. As a result, around 50% of them show signs of Alzheimer’s by the age of 60, about two decades earlier than the general population.

“This makes understanding the biology of Down syndrome incredibly important for Alzheimer’s research,” said Caleb Finch, the study’s senior author and University Professor Emeritus at USC.

The USC team studied brain tissue donated by individuals with Alzheimer’s, DSAD. The scientists focused on the prefrontal cortex—a brain region responsible for memory, planning, and decision-making and they found iron overload. DSAD brains had double the iron content compared to the other groups. Researchers suspect this may be due to microbleeds—tiny leaks in brain blood vessels—which are more common in DSAD patients. They also found increased membrane damage. Cell membranes, made of fatty compounds called lipids, are highly vulnerable to oxidative damage. The activity of enzymes that normally protect the brain from oxidative damage and repair cell membranes was significantly lower in DSAD brains, especially in critical membrane regions known as lipid rafts.

Together, these patterns point to ferroptosis, a recently identified form of programmed cell death driven by iron-dependent lipid oxidation. “Essentially, iron builds up, triggers chemical reactions that destroy cell membranes, and overwhelms the brain’s ability to defend itself,” explained Thorwald.

These findings offer a new lens through which to view Alzheimer’s in people with Down syndrome. The researchers believe that therapies targeting iron accumulation and oxidative stress could help slow the disease’s progression.

“Medications that remove excess iron from the brain or enhance antioxidant systems might offer new hope,” Thorwald said. In early animal studies, iron-chelating drugs—which bind to iron and help eliminate it from the body—have shown promise in reducing Alzheimer’s-related damage.

“This study gives us a clearer picture of what’s going wrong in the brain, and that’s the first step to finding better treatments,” said Finch.

Health