Iron Overload May Cause Early Alzheimer’s in Down Syndrome
Researchers at the University of Southern California have found that a hidden component that contributes to the early and severe onset of Alzheimer’s in people with Down syndrome is iron excess in the brain. According to their research, those with both disorders showed significantly higher levels of oxidative damage and twice as much iron.
The most prevalent type of dementia in both the general population and those with Down syndrome is Alzheimer’s disease. Compared to the general population, individuals with Down syndrome experience it more frequently and at a younger age.
Alzheimer’s is a progressive neurodegenerative disorder of older adults that affects memory, learning, and cognitive function to the point that it interferes with the daily activities of the person. It typically affects people over the age of 65. The condition involves the build-up of beta-amyloid plaques and the creation of tau protein tangles in the brain, leading to cell damage and death. Besides aging and genetics, several lifestyle factors also contribute to its onset.
Down Syndrome (also known as trisomy 21) is a genetic disorder that occurs when a person is born with a complete or partial extra copy of chromosome 21, one of the 23 chromosomes in humans. Typically, a person inherits one copy of each human chromosome from their father and one from their mother. The majority of individuals with Down syndrome have three copies of chromosome 21 rather than the normal two because they have a complete extra copy. The additional copy, according to scientists, is the consequence of a random error in the specialized cell division that creates sperm and eggs.
What is the Link between Down Syndrome and Alzheimer’s?
Down syndrome and Alzheimer’s disease are closely related because chromosome 21 has the APP gene that makes one of the key proteins linked to the brain alterations brought on by Alzheimer’s. The APP gene produces the amyloid precursor protein; beta-amyloid plaques accumulate in the brain when this protein is present in excess. Furthermore, researchers have identified a number of genes on chromosome 21 that are associated with aging and an elevated risk of Alzheimer’s disease.
People with Down syndrome do not always get Alzheimer’s. Although all people with the syndrome are susceptible, many adults with the condition will not experience the cognitive impairments associated with the disease during their lifetime.
Individuals with Down syndrome typically produce higher amounts of beta amyloid protein because they have three copies of the APP gene instead of the usual two. By the time they are 40 years old, almost all of them develop physical symptoms of Alzheimer’s, such as brain tangles and amyloid plaques. However, most people won’t exhibit dementia symptoms for another ten years or longer. After the age of 40, the chance of getting Alzheimer’s disease rises with each decade of life, and the lifetime risk is over 90% [1].
About half of all individuals with Down syndrome exhibit symptoms of Alzheimer’s disease by the time they are 60 years old, which is about 20 years earlier than the average person. According to estimates, at least 50% of those with Down syndrome will have Alzheimer’s disease, with symptoms typically manifesting in their 50s and 60s [2].
Scientists are working hard to figure out why some people with Down syndrome get dementia while others do not. They also expect that research on Down syndrome and Alzheimer’s will benefit those who have both disorders and could result in successful treatments for all Alzheimer’s patients.
Now, a recent study by researchers at the University of Southern California has demonstrated why Alzheimer’s symptoms often manifest earlier and more severely in individuals with Down syndrome. According to the findings, iron overload is the reason behind early Alzheimer’s in Down Syndrome [3].
The Role of Iron Overload in Early Alzheimer’s in Down Syndrome
Researchers at the USC Leonard Davis School of Gerontology have shown a significant link between elevated brain iron levels and higher cell damage in individuals with both Alzheimer’s disease and Down syndrome.
Researchers discovered that compared to the brains of those with Alzheimer’s disease alone or those with neither diagnosis, the brains of people with Down syndrome and Alzheimer’s disease (DSAD) had twice as much iron and greater indications of oxidative damage in cell membranes.
The findings may contribute to the understanding of why Alzheimer’s symptoms frequently manifest earlier and more severely in people with Down syndrome. The study indicated a particular cellular death pathway mediated by iron.
Key Findings of the Study
The study team examined donated brain tissue from people who had DSAD, Alzheimer’s, and others who didn’t have either condition. They made the following significant findings while concentrating on the prefrontal cortex, a region of the brain involved in memory, planning, and thought processes.
- Much Higher Iron Levels in DSAD Brains
The amount of iron in the prefrontal cortex of DSAD brains was double that of the brains in the other groups. Researchers think that this accumulation results from microscopic blood vessel leaks in the brain, known as microbleeds, which are linked to greater levels of APP and are more common in DSAD than Alzheimer’s.
- Increased Damage to Lipid-Rich Cell Membranes
Fatty molecules known as lipids make up cell membranes. Chemical stress can easily damage these compounds. The researchers discovered higher levels of lipid peroxidation, a result of this kind of damage, in DSAD brains than in control or Alzheimer’s-only brains.
- Weakened Defence against Antioxidants
The researchers observed that the activity of numerous essential enzymes that repair cell membranes and protect the brain from oxidative damage was less in DSAD brains, especially in areas of the cell membrane known as lipid rafts.
Ferroptosis: A New Cellular Death Pathway
The findings suggest that ferroptosis, a type of cell death associated with iron-induced lipid peroxidation, is the primary cause of damage in DSAD brains. The study’s lead author, Max Thorwald, described how iron accumulation causes oxidative stress, which weakens cell membranes and overpowers the brain’s defenses, accelerating cell death.
Lipid Rafts and Disease Progression
Lipid rafts, the focus of the team’s attention, are microscopic components of the brain cell membrane that are essential for cell signaling and help control the processing of proteins like APP. They found that lipid rafts in DSAD brains showed significantly more oxidative damage and fewer defense enzymes than those in Alzheimer’s or healthy brains.
Interestingly, the β-secretase enzyme, which combines with APP to generate Aβ proteins, was also more active in these lipid rafts. Researchers clarified that individuals with Down syndrome may experience accelerated Alzheimer’s disease progression due to the combination of accelerated damage and enhanced Aβ synthesis, which could encourage the formation of amyloid plaques [4].
Variants of Rare Down Syndrome Provide Insight
The third copy of chromosome 21 is only present in some cells in people with partial Down syndrome, an uncommon condition that the researchers also investigated. Their brains showed lower levels of iron and APP, and they often lived longer than those with DSAD and complete trisomy 21. It implies that the amount of APP, and consequently iron, may be a significant factor in the course of Alzheimer’s disease.
Future Prospects: What’s Next?
According to the scientists, this research may help steer future therapies, particularly for individuals with Down syndrome who are at a heightened risk of developing Alzheimer’s. Thorwald explained that preliminary studies in mice have demonstrated that iron-chelating treatments, in which the drug attaches to metal ions and permits them to exit the body, may reduce markers of Alzheimer’s pathology.
He said there may be new hope in drugs that can boost antioxidant systems or eliminate iron from the brain. Researchers are now seeing the importance of addressing both the amyloid plaques and the factors that may be accelerating their formation.
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References
- Fortea, J., Zaman, S.H., Hartley, S., Rafii, M.S., Head, E. and Carmona-Iragui, M., 2021. Alzheimer’s disease associated with Down syndrome: a genetic form of dementia. The Lancet Neurology, 20(11), pp.930-942.
- Alzheimer’s Disease Fact Sheet. National Institute on Aging (NIH). https://www.nia.nih.gov/health/alzheimers-and-dementia/alzheimers-disease-fact-sheet. Accessed: 15th July, 2025.
- Thorwald, M.A., Godoy‐Lugo, J.A., Kerstiens, E., Garcia, G., Kim, M., Shemtov, S.J., Silva, J., Durra, S., O’Day, P.A., Mack, W.J. and Hiniker, A., 2025. Down syndrome with Alzheimer’s disease brains have increased iron and associated lipid peroxidation consistent with ferroptosis. Alzheimer’s & Dementia, 21(6), p.e70322.
- Iron overload: The hidden culprit behind early Alzheimer’s in Down syndrome. Science Daily. https://www.sciencedaily.com/releases/2025/06/250620231852.htm. Published Online: 21st June, 2025. Accessed: 15th July, 2025.
- Iron Buildup Linked to Increased Brain Damage In Down Syndrome-Associated Alzheimer’s Disease. Technology Networks: Neuroscience News & Research. https://www.technologynetworks.com/neuroscience/news/iron-buildup-linked-to-increased-brain-damage-in-down-syndrome-associated-alzheimers-disease-401259. Published Online: 19th June, 2025. Accessed: 15th July, 2025.
- Down Syndrome and Alzheimer’s Disease. Alzheimer’s Association. https://www.alz.org/alzheimers-dementia/what-is-dementia/types-of-dementia/down-syndrome. Accessed: 15th July, 2025.
- Alzheimer’s Disease & Down Syndrome. National Down Syndrome Society. https://ndss.org/resources/alzheimers. Accessed: 15th July, 2025.
- Down syndrome and Alzheimer’s. Better Health Channel. https://www.betterhealth.vic.gov.au/health/conditionsandtreatments/down-syndrome-and-alzheimers. Accessed: 15th July, 2025.
- Alzheimer’s Disease in People With Down Syndrome. National Institute on Aging. https://www.nia.nih.gov/health/alzheimers-causes-and-risk-factors/alzheimers-disease-people-down-syndrome. Accessed: 15th July, 2025.
