Down syndrome with Alzheimer's disease brains have increased iron and associated lipid peroxidation consistent with ferroptosis

PMCID: PMC12177674

PMID: 40536124

DOI: 10.1002/alz.70322

Journal: Alzheimer's & dementia : the journal of the Alzheimer's Association

Publication Date: 2025-6-19

Authors: Thorwald MA, Godoy‐Lugo JA, Kerstiens E, Garcia G, Kim M, et al.

Key Points

• DSAD demonstrates more pronounced iron-mediated oxidative stress compared to sporadic AD
• Iron levels were 2× higher in DSAD patients, indicating increased neurological vulnerability
• Lipid raft protein alterations may represent a critical mechanism in neurodegenerative progression

Summary

This study investigated the relationship between iron metabolism, microbleeds (MBs), and neurodegeneration in Alzheimer's disease (AD), with a specific focus on Down syndrome-associated AD (DSAD). Researchers examined protein changes in lipid rafts within the prefrontal cortex and cerebellum of patients, revealing significant differences in iron load and oxidative stress mechanisms between sporadic AD and DSAD.

The research demonstrated that DSAD patients exhibited twofold higher iron levels compared to control and sporadic AD groups, accompanied by increased lipid peroxidation and decreased antioxidant defenses. Notably, the glutathione synthesis protein GCLM was reduced by 50% in both AD variants, while the protective enzyme GPx4 activity decreased by at least 30%, suggesting compromised cellular protection against oxidative damage.