Iron & Alzheimer's: Is There a Link?

Clinical Evidence

The review “Insights into targeted ferroptosis in mechanisms, biology, and role of Alzheimer’s disease: an update” (2025) synthesizes pre‑clinical and limited clinical data linking iron‑mediated ferroptosis to Alzheimer’s disease (AD) pathology. The authors cite observational studies showing increased brain iron concentrations in AD patients (e.g., 1.5‑fold higher cortical iron measured by MRI in AD versus controls, p < 0.01) and correlations between iron load and cognitive decline scores (r = 0.42, p = 0.003). However, no randomized controlled trials (RCTs) of iron supplementation or chelation specifically targeting ferroptosis in AD were identified. The review therefore concludes that while iron accumulation is consistently associated with AD pathology, direct clinical evidence that modifying iron intake alters disease progression remains lacking.

Mechanisms of Action

Ferroptosis is defined as iron‑dependent, non‑apoptotic cell death driven by lipid peroxidation when antioxidant defenses (e.g., glutathione peroxidase 4, GP‑X4) are insufficient. The review outlines several molecular pathways linking iron to AD:

• Iron overload promotes the Fenton reaction, generating hydroxyl radicals that oxidize polyunsaturated fatty acids in neuronal membranes.
• GP‑X4 inhibition (by depletion of glutathione or direct inhibition) impairs detoxification of lipid hydroperoxides, precipitating ferroptosis.
• Amyloid‑β (Aβ) aggregation can sequester iron, creating localized oxidative hotspots that amplify lipid peroxidation.
• Tau pathology may disrupt iron export (via ferroportin) and increase intracellular labile iron, further sensitizing neurons to ferroptosis.

Collectively, these mechanisms suggest that dysregulated iron homeostasis can amplify oxidative stress, contributing to neurofibrillary tangle formation and synaptic loss.

Safety Profile

The review does not present primary safety data for iron supplementation in AD. It does note that systemic iron overload can cause gastrointestinal irritation, hepatic injury, and oxidative stress, especially in individuals with hereditary hemochromatosis or concurrent use of pro‑oxidant drugs (e.g., certain antibiotics, chemotherapy agents). Potential drug‑iron interactions include reduced absorption of oral iron when co‑administered with proton‑pump inhibitors or tetracyclines. The authors caution that systemic iron chelators (e.g., deferoxamine) have been associated with neutropenia and renal toxicity at high doses, underscoring the need for careful monitoring.

Dosage Information

Because the article is a narrative review, it does not report specific dosing regimens for iron supplementation or chelation in AD. It references pre‑clinical studies using iron chelators (e.g., deferiprone 30 mg/kg/day in mouse models) that reduced ferroptosis markers, but these doses are not directly translatable to human supplementation. No human dosing data for ferroptosis‑targeted interventions were presented.

Evidence Quality Assessment

The evidence presented is low‑to‑moderate quality: it consists primarily of observational imaging studies and mechanistic pre‑clinical experiments. No RCTs or longitudinal intervention trials evaluating iron supplementation or chelation for AD were identified. Consequently, while the mechanistic rationale for iron‑mediated ferroptosis in AD is biologically plausible, the clinical evidence supporting therapeutic modulation of iron in AD remains limited and largely indirect.