1. The Double-Edged Demands of Neurons

Neurons occupy a unique position in the metabolic landscape of the brain, requiring continuous synthesis of both energy and membrane lipids to sustain their function. Their reliance on oxidative phosphorylation demands a constant supply of iron for mitochondrial enzymes such as cytochromes and iron-sulfur proteins, while their need for membrane remodeling mandates abundant polyunsaturated fatty acids (PUFAs)^[1,2]. These dual requirements are metabolically indispensable yet inherently hazardous: iron catalyzes the Fenton reaction, generating highly reactive hydroxyl radicals (•OH) and ferryl/oxyl species that initiate lipid peroxidation^[3,4]. Together, these features create an environment inherently prone to ferroptosis, the iron-dependent, lipid-driven form of regulated cell death (Figure 1)^[5].

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Figure 1. ApoE: Gatekeeper of the Iron-Lipid Axis in Neuronal Ferroptosis. Schematic illustration shows how ApoE coordinates iron and lipid metabolism to maintain neuronal resistance to ferroptosis. In healthy neurons (left), ApoE supports lipid trafficking and limits labile iron, preventing lipid peroxidation. In contrast, ApoE4 dysfunction (right) disrupts this balance, promoting iron accumulation, oxidized lipid formation, and ferroptotic neuronal degeneration. Created in BioRender.com. ApoE: apolipoprotein E; PUFAs: polyunsaturated fatty acids.

Astrocytes and neurons cooperate in managing these risks. Astrocytes synthesize and export cholesterol and PUFAs via apolipoprotein E (ApoE)-containing lipoproteins and detoxify oxidized lipids, while neurons, which lack robust lipid storage and β-oxidation capacity, depend on astrocytic support (Figure 1)^[6]. Perturbations in this lipid shuttle lead to activity-induced lipotoxicity and dendritic loss^[6,7]. Moreover, specific phospholipids enriched in PUFAs such as arachidonic and adrenic acids are essential substrates for ferroptosis^[4]. Their incorporation into cellular membranes, mediated by acyl-CoA synthetase long-chain 4 and lysophosphatidylcholine acyltransferase 3, determines a cell’s sensitivity to ferroptotic death^[8]. Consequently, neurons’ physiological membrane composition and iron-intensive bioenergetics create a structural vulnerability to ferroptosis.

2. Ferroptosis as a Neuronal Liability

Ferroptosis is defined by the accumulation of lipid peroxides and iron-dependent cell death that can be rescued by iron chelators and ferroptosis inhibitors, including ferrostatin-1 or liproxstatin-1^[9]. Although these inhibitors possess radical-trapping activity in cell-free systems, emerging evidence demonstrates additional biological mechanisms, including iron-binding and lysosomal iron modulation, as shown for liproxstatin-1^[10]. Neuron-specific deletion of glutathione peroxidase 4 (GPX4), the selenoenzyme that reduces lipid hydroperoxides, leads to rapid neurodegeneration in mice, establishing ferroptosis as a bona fide neuronal death mechanism^[11-15]. Ferroptosis can be initiated enzymatically, through 15-lipoxygenase-PEBP1 complexes that oxidize membrane PUFAs, or non-enzymatically by iron-driven free-radical reactions^[16].

Cellular iron handling sets the threshold for this process. Transferrin receptor 1 (TfR1) mediates uptake, ferroportin exports iron, and ferritin stores it^[17]. In addition to TfR1, CD44 has recently emerged as a regulator of iron endocytosis and ferroptosis sensitivity, particularly through hyaluronan-CD44 interactions^[18,19]. Selective autophagic degradation of ferritin, known as ferritinophagy, releases redox-active Fe(II) and sensitizes cells to ferroptosis^[20,21]. Recent findings indicate that lysosomal iron activation is a key driver of ferroptosis, and that suppression of lysosomal Fe³⁺ prevents lipid peroxidation and cell death^[10]. Lysosomal iron sequestration can also trigger ferritinophagy and global disruption of iron homeostasis, promoting ferroptosis^[22]. Excessive neuronal activity or impaired lipid shuttling to astrocytes disrupts vesicle cycling, leading to lipid peroxide buildup and degeneration^[6]. Thus, ferroptosis in neurons is not simply a toxic by-product of oxidative stress but a distinct metabolic failure, in which energy generation, antioxidant capacity, and membrane integrity collapse together.

3. ApoE as a Gatekeeper of the Iron-Lipid Axis

3.1 ApoE isoforms and Alzheimer’s disease

ApoE exists in three common human isoforms: ApoE2, ApoE3, and ApoE4 that arise from single amino acid substitutions at residues 112 and 158^[23]. ApoE3 is the most prevalent and is considered the “neutral” reference isoform, whereas ApoE4 is the strongest genetic risk factor for late-onset Alzheimer’s disease, increasing risk approximately threefold in heterozygotes and up to twelvefold in homozygotes^[24]. In contrast, ApoE2 is protective, with both heterozygous and homozygous genotypes associated with a substantially reduced incidence of Alzheimer’s disease^[25]. The ApoE isoforms differ markedly in structure and function, leading to distinct affinities for key receptors, including LDLR, LRP1, ApoER2, and TREM2 that regulate lipid transport, intracellular signaling, and cellular homeostasis^[26-28]. These structural differences also influence downstream biological processes such as microglial activation, synaptic remodeling, regenerative responses, and the clearance of aggregated proteins^[23]. Together, these isoform-specific effects help explain the divergent roles of ApoE variants in neuroinflammation and neurodegenerative disease.

3.2 ApoE as a modulator of neuronal ferroptosis

Among brain proteins, ApoE occupies a unique niche at the intersection of lipid and iron homeostasis^[23]. Classically recognized as the principal lipid carrier of the central nervous system, ApoE also exerts potent anti-ferroptotic effects by blocking ferritinophagy, thereby restraining the release of labile iron^[29]. This dual function enables ApoE to coordinate two ferroptosis-relevant pathways: lipid transport and iron storage into a single defense system^[30]. The existence of multiple isoform differences and disease-relevant variants adds another layer of complexity. The ApoE4 isoform displays reduced lipid-binding capacity, impaired astrocyte-neuron lipid transfer, and heightened lipid peroxidation compared to ApoE3^[7,31,32]. Conversely, microglial expression of another ApoE variant named Christchurch confers protection against tau pathology and ferroptosis^[33,34]. In cerebrospinal fluid, ApoE levels correlate closely with ferritin concentrations, underscoring ApoE’s dual role in regulating both iron release and lipid peroxidation^[35,36]. Collectively, these findings portray ApoE as a biochemical integrator of neuronal lipid and iron balance, where isoform-specific dysfunction directly increases ferroptotic vulnerability. Beyond the CNS, ApoE has been implicated in ferroptosis across multiple tissues: ApoE-deficient mice display ferroptosis-like changes that are alleviated by ferroptosis inhibitors in atherosclerotic lesions, and ApoE expression modulates ferroptotic signaling in tumor and immune cells, underscoring a broader role for ApoE in iron- and lipid-dependent cell death pathways outside the brain.

4. Iron-Lipid Convergence in Alzheimer’s Disease

Alzheimer’s disease exemplifies the pathological convergence of disrupted lipid and iron metabolism. Magnetic resonance imaging using quantitative susceptibility mapping (QSM) reveals focal iron accumulation in cortical and subcortical regions that correlates with cognitive decline^[37,38]. Parallel lipidomic analyses identify extensive remodeling of neuronal membranes and accumulation of oxidized phospholipids in postmortem cortex of Alzheimer’s patients^[31]. Measurements of iron content and stable lipid peroxidation products in postmortem tissue are generally robust, whereas other redox-sensitive metabolites can be more challenging to interpret due to their susceptibility to the post-mortem interval and handling conditions. Amyloid-β aggregates bind redox-active iron and copper, catalyzing Fenton-like reactions that generate lipid-oxidizing radicals. Tau aggregates can disrupt membranes, promote PUFA exposure, and enhance local reactive oxygen species production. Both proteins therefore amplify lipid peroxidation through metal-dependent and membrane-perturbing mechanisms^[39,40].

Energetic failure provides a mechanistic link: mitochondrial dysfunction reduces ATP availability and thus limits glutathione synthesis, undermining the glutathione-GPX4 axis that restrains ferroptosis^[41]. In this context, mitochondrial iron and glutathione metabolism are tightly interdependent, as elevated Fe²⁺ increases oxidative pressure on the GSH-GPX4 system while glutathione depletion further amplifies iron-driven lipid peroxide formation^[2,9]. This energy crisis explains why iron chelation therapy, effective against labile iron toxicity in vitro, worsened cognitive outcomes in Alzheimer’s clinical trials^[42]. Instead of alleviating oxidative stress, chelation deprives mitochondria of essential iron required for respiration, inadvertently weakening ferroptosis defenses. Therefore, Alzheimer’s pathology reflects not a simple iron overload or lipid imbalance, but a failure of the iron-lipid defense network in which ApoE plays a pivotal role.

5. Genetic Evidence from Neurodegeneration with Brain Iron Accumulation (NBIA)

The intersection between iron and lipid metabolism is most clearly revealed in NBIA disorders, a group of rare inherited diseases characterized by basal ganglia iron deposition and mutations in lipid-metabolic genes. In PLA2G6-associated neurodegeneration, loss of the calcium-independent phospholipase A2β impairs membrane phospholipid remodeling and repair, leading to axonal spheroids, lipid storage pathology, and early iron accumulation^[43,44]. Pantothenate kinase-associated neurodegeneration arises from mutations in PANK2, which disrupt coenzyme A biosynthesis, limiting acyl-CoA supply for β-oxidation and phospholipid synthesis. Patient cells exhibit mitochondrial dysfunction and iron accumulation despite the primary lesion residing in lipid metabolism^[45,46].

Similarly, C19orf12 mutations in Mitochondrial Membrane Protein-Associated Neurodegeneration alter phospholipid and fatty-acid homeostasis, causing lipid droplet accumulation and oxidative stress^[47]. Mutations in FA2H affect sphingolipid hydroxylation, while COASY mutations disrupt the final step of coenzyme A synthesis, both resulting in combined lipid and iron pathology^[48,49]. Finally, WDR45-related BPAN, though classified as an autophagy disorder, also shows lysosomal lipid dysregulation with secondary iron deposition^[50,51]. Across NBIA syndromes, primary mutations in lipid remodeling, coenzyme A metabolism, or membrane maintenance consistently manifest with secondary iron accumulation, illustrating the genetic entanglement of iron and lipid homeostasis in neurodegeneration.

6. Therapeutic Implications: Targeting the Mix, Not the Pieces

Despite a strong oxidative stress rationale, interventions aimed at modulating iron, lipids, or antioxidant capacity in Alzheimer’s disease have not delivered clinical benefit. The brain-permeable iron chelator deferiprone showed target engagement on QSM-MRI (reduced hippocampal susceptibility) yet was associated with accelerated cognitive decline over 12 months in amyloid-confirmed early Alzheimer’s patients^[42]. Similarly, statins, despite epidemiological hints, have not slowed cognitive decline or altered disease trajectory in large, randomized trials^[52]. High-dose vitamin E supplementation (2,000 IU/day) produced only a modest delay in functional decline in one study but no consistent cognitive advantage across trials^[53-56]. On the contrary, meta-analyses link high-dose vitamin E to increased all-cause mortality and prostate cancer risk^[57,58]. Similar to previous trials, other antioxidants showed early signals of benefit that did not translate into meaningful or lasting clinical improvement^[59,60]. Collectively, these outcomes underscore that broad antioxidant, lipid-lowering, or iron-chelating approaches are insufficient and potentially maladaptive when not targeted to neuronal redox biology. By targeting the intersection, not the pieces, it may be possible to restore the fragile equilibrium neurons require to survive. Future therapies should instead focus on: (1) enhancing ApoE function or mimicking its anti-ferroptotic activity; (2) developing brain-permeable ferroptosis inhibitors and interventions that restore iron-lipid homeostasis within the CNS, to more precisely mitigate the ferroptotic drive that underlies neuronal vulnerability; and (3) developing metabolic support strategies that bolster glutathione synthesis and mitochondrial resilience, ensuring antioxidant capacity keeps pace with neuronal demand.

7. Concluding Remarks

Neurodegeneration is often viewed through the lens of misfolded proteins or isolated metabolic defects. Yet neurons’ greatest liability may be their metabolic design: a compulsory dependence on iron and lipids that creates an ever-present ferroptotic risk. Maintaining equilibrium between these forces requires tight coordination, for which ApoE provides a central safeguard. When this coordination fails, through ApoE4 isoform effects, metabolic stress, or lipid gene mutations as seen in NBIA, neurons succumb to ferroptotic vulnerability. Framing Alzheimer’s disease and related disorders as failures of iron-lipid co-regulation unifies disparate observations from genetic risk to biochemical pathology under a common mechanistic principle and opens a path toward therapies that stabilize, rather than sever, the partnership between iron and lipids.

Acknowledgments

The author acknowledges the support of the Florey Institute of Neuroscience and Mental Health and the Victorian Government, particularly through the Operational Infrastructure Support Grant.

Authors contribution

The author contributed solely to the article.

Conflicts of interest

The author declares no conflicts of interest.

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Availability of data and materials

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Funding

This work was supported by funds from the Alzheimer’s Association (AARGD-21-850785, AARGD-24-1294531).

Copyright

© The Author(s) 2025.