Iron Buildup Linked to Increased Brain Damage In Down Syndrome-Associated Alzheimer’s Disease

A study from the USC Leonard Davis School of Gerontology reveals a significant relationship between elevated iron levels in the brain and greater cellular damage in individuals with both Down syndrome and Alzheimer’s disease (DSAD). The research indicates that the accumulation of iron in the brain may contribute to the accelerated and more severe symptoms of Alzheimer's seen in individuals with Down syndrome.

Down syndrome and Alzheimer’s disease: an ongoing challenge

Down syndrome, which results from the presence of an extra copy of chromosome 21, includes the gene for amyloid precursor protein (APP). This gene is involved in the production of amyloid-beta (Aβ), a protein that forms plaques in the brains of Alzheimer’s patients. Due to the third copy of the APP gene, individuals with Down syndrome produce more amyloid-beta, increasing their risk of developing Alzheimer’s. By age 60, about half of individuals with Down syndrome show signs of Alzheimer’s disease, occurring approximately 20 years earlier than in the general population.

Max Thorwald, the lead author of the study, emphasized that understanding the role of increased iron in the brains of people with Down syndrome could shed light on why Alzheimer’s manifests more aggressively in this group.

Iron buildup and cellular damage in DSAD

The research team examined brain tissue from individuals with Alzheimer’s, DSAD, and healthy controls, focusing on the prefrontal cortex, an area of the brain responsible for thinking, planning, and memory. Their findings included:

• Higher iron levels in DSAD brains: Compared to Alzheimer’s-only and healthy brains, DSAD brains had double the amount of iron. This buildup is likely linked to microbleeds—tiny leaks in blood vessels in the brain—that occur more frequently in DSAD and are associated with elevated APP levels.
• Damage to lipid-rich cell membranes: The team observed increased markers of lipid peroxidation, a process in which fatty compounds in cell membranes are damaged by oxidative stress. This was more pronounced in DSAD brains than in those with Alzheimer’s alone or healthy controls.
• Weakened antioxidant defense: The researchers found reduced activity of protective enzymes in DSAD brains, particularly in lipid rafts, which are critical regions in the cell membrane involved in protein processing and signaling.

Ferroptosis: A new cell death pathway

These findings suggest that the damage in DSAD brains is driven by ferroptosis, a type of cell death linked to iron-induced lipid peroxidation. Thorwald explained that iron buildup leads to oxidative stress, which damages cell membranes and overwhelms the brain’s ability to protect itself, contributing to accelerated cell death.

Role of lipid rafts in disease progression

Lipid rafts, essential for cell signaling and the regulation of APP processing, were also significantly damaged in DSAD brains. This damage, combined with increased β-secretase activity—which promotes amyloid-beta production—may contribute to the growth of amyloid plaques, accelerating Alzheimer's progression in people with Down syndrome.

Insights from rare Down syndrome variants

The researchers also explored rare cases of individuals with partial Down syndrome, where only some cells carry the third chromosome 21 copy. These individuals had lower levels of APP and iron in their brains, and often lived longer than those with complete trisomy 21 and DSAD. This suggests that the amount of APP—and by extension, iron—may play a crucial role in how Alzheimer's develops.

Potential for new treatments

The study’s findings could inform potential treatments for those with Down syndrome at high risk of Alzheimer's. Preliminary research in mice indicates that iron-chelating treatments—drugs that bind to iron and help remove it from the body—may reduce signs of Alzheimer’s pathology. Thorwald suggested that therapies aimed at removing excess iron or boosting antioxidant defenses could offer hope for preventing or slowing Alzheimer's in individuals with Down syndrome.

The study, Down syndrome with Alzheimer’s disease brains have increased iron and associated lipid peroxidation consistent with ferroptosis, was published in Alzheimer’s & Dementia: The Journal of the Alzheimer’s Association on June 19, 2025.

Reference: Thorwald MA, Godoy-Lugo JA, Kerstiens E, et al. Down syndrome with Alzheimer’s disease brains have increased iron and associated lipid peroxidation consistent with ferroptosis. Alzheimer’s Dement. 2025. doi: 10.1002/alz.70322

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