Alzheimer’s disease remains the leading cause of dementia, with cases rising rapidly due to aging populations. Inflammation, low energy, oxidative damage, iron overload, and protein aggregates in the brain are linked to Alzheimer’s. Current Alzheimer’s treatments targeting classical biomarkers, amyloid or tau, offer limited benefits and carry significant risks, including brain atrophy. To improve outcomes, therapies targeting different pathways are urgently needed.

A recent publication in Advanced Science offers a fresh perspective on the mechanisms driving neurodegeneration: it identifies a direct connection between mitochondrial energy failure and ferroptosis, a form of iron-dependent cell death, in Alzheimer’s disease, suggesting a fundamental trigger for neuronal death independent of the classical biomarkers.

Analyzing over 600 post-mortem brains using proteomics, the researchers found a widespread loss of mitochondrial proteins in patients with Alzheimer’s disease, correlated with reduced levels of the key antioxidant glutathione (GSH). The team demonstrated that ATP, the energy currency of cells, is rate-limiting for GSH synthesis, and its depletion compromises antioxidant defenses, making neurons more vulnerable to ferroptosis. Ferroptosis markers, low GSH, high iron, and increased lipid damage are present in Alzheimer’s disease, but their physiological trigger remained unknown; this study identifies ATP depletion from mitochondrial dysfunction as the key driver, limiting GSH synthesis and weakening antioxidant defenses.

To selectively deplete ATP and consequently GSH in mammalian cells, the researchers used a novel bacterial ATP nucleosidase. Combining proteomics and molecular biology approaches, they confirmed that the initiation of ferroptosis occurred due to energy stress and not because of any shortage of cysteine or glutathione peroxidase dysfunction, both of which can cause reduced GSH in the cell.

These findings reveal a druggable pathway and support ferroptosis inhibition as a promising strategy to slow neurodegeneration.

Lead author Francesca Alves explains: “Our study reveals that low cellular energy in Alzheimer’s disease may be a driver of ferroptotic cell death. By linking mitochondrial ATP loss to impaired antioxidant defenses, we identify a new therapeutic target that could finally bridge the gap between impaired energy metabolism and neurodegeneration.”

This work paves the way for novel therapeutic strategies, including ATP-loaded liposomes, mitochondrial protectants, and ferroptosis inhibitors, which could complement existing amyloid and tau targeting drugs. This research not only redefines the understanding of Alzheimer’s disease but also holds promise for other neurodegenerative diseases characterized by energy disruption.

Reference: F. Alves et al., Aberrant Mitochondrial Metabolism in Alzheimer’s Disease Links Energy Stress with Ferroptosis. Advanced Science (2025), DOI: 10.1002/advs.202504175

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