New research from the USC Leonard Davis School of Gerontology reveals a strong link between elevated brain iron and increased cell damage in individuals with both Down syndrome and Alzheimer’s disease (DSAD). The findings may help explain why people with Down syndrome often develop Alzheimer’s earlier and with more severe symptoms.

In the study, researchers analyzed brain tissue and found that those with DSAD had twice as much iron and significantly more oxidative damage in their brain cell membranes compared to individuals with Alzheimer’s alone or those without either condition. This suggests that iron-driven cell death, a process known as ferroptosis, may be accelerating the disease in this population.

“This gives us a vital clue about the unique and early brain changes in people with Down syndrome who develop Alzheimer’s,” said lead author Max Thorwald, a postdoctoral fellow in the lab of University Professor Emeritus Caleb Finch.

Why Down Syndrome Increases Alzheimer’s Risk
Down syndrome occurs due to a third copy of chromosome 21, which includes the APP gene, responsible for producing amyloid-beta (Aβ) a protein that forms Alzheimer’s plaques. With an extra APP gene, people with Down syndrome make more of this protein, putting them at significantly higher risk. By age 60, over half show signs of Alzheimer’s roughly 20 years earlier than the general population.

“Understanding the biology of Down syndrome is critical to Alzheimer’s research,” added Finch, the study’s senior author.

Key Findings: The Role of Ferroptosis
The team focused on the prefrontal cortex, the brain area involved in memory and decision-making. Their discoveries include:

Elevated iron levels: DSAD brains had twice as much iron, likely due to frequent microbleeds tiny blood vessel leaks more common in DSAD than Alzheimer’s alone.

Increased membrane damage: More lipid peroxidation byproducts a sign of oxidative stress were found in DSAD brains.

Weakened antioxidant defenses: Enzymes that protect and repair brain cell membranes were significantly reduced, especially in lipid rafts key membrane regions involved in cell signaling and Aβ processing.

Together, these factors point to ferroptosis, where iron accumulation leads to oxidative damage and overwhelms the brain's ability to protect itself.

“Iron builds up, causes damage, and pushes the cell toward death,” Thorwald explained.

Lipid Rafts: Ground Zero for Damage
Lipid rafts critical for signaling and amyloid processing showed more oxidative damage and fewer protective enzymes in DSAD brains. They also had higher activity of β-secretase, an enzyme that processes APP into harmful Aβ. This likely accelerates the formation of plaques and the disease’s progression in people with Down syndrome.

Rare Genetic Cases Offer Insight
The team also studied individuals with mosaic or partial Down syndrome, where only some cells carry the extra chromosome. These individuals had lower APP and iron levels, lived longer, and had less brain damage, reinforcing the idea that APP overexpression and iron accumulation drive disease severity.

“These rare cases really highlight how the amount of APP and the iron it brings impacts Alzheimer’s progression,” Finch said.

Toward Future Treatments
The researchers believe their findings could guide new treatments for people with Down syndrome at high risk of Alzheimer’s. Iron-chelating drugs, which bind and remove excess iron, have shown promise in early animal studies. Boosting the brain’s antioxidant defenses may also help.

“We need to address not just amyloid plaques but also the underlying factors like iron and oxidative stress,” Thorwald emphasized.

Source: https://gero.usc.edu/2025/06/19/study-iron-plays-a-major-role-in-down-syndrome-associated-alzheimers-disease