{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,1]],"date-time":"2026-10-01T14:01:59Z","timestamp":1790863319428,"version":"4.1.0"},"reference-count":120,"publisher":"MDPI AG","issue":"18","license":[{"start":{"date-parts":[[2026,9,17]],"date-time":"2026-09-17T00:00:00Z","timestamp":1789603200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Int. J. Mol. Sci.","IJMS"],"abstract":"<jats:p>Alzheimer\u2019s disease (AD) has been conceptualised as a proteinopathy driven by amyloid-\u03b2 plaques and hyperphosphorylated tau neurofibrillary tangles. AD should not be understood as exclusively a proteinopathy or a metabolic\/redox disorder, but as a network of interacting processes in which metabolic dysfunction, mitochondrial impairment, redox dysregulation, amyloid-\u03b2, tau, neuroinflammation, metal dyshomeostasis, and regulated cell death reinforce one another. This review examines AD through a redox-metabolic framework integrating cerebral glucose metabolism, insulin signalling, mitochondrial bioenergetics, metal homeostasis, and regulated cell death. We discuss how glucose hypometabolism, impaired oxidative phosphorylation, and weakened antioxidant defences may promote reactive oxygen species production and self-reinforcing oxidative and metabolic dysfunction. We examine interactions with amyloid-\u03b2 and tau pathology, glial immunometabolism, gut\u2013brain signalling, neuroinflammation, and metal-mediated toxicity. Advances in multi-omics, blood-based metabolomic and lipidomic biomarkers, and imaging may enable earlier biological stratification. Therapeutic strategies targeting mitochondria, NRF2 signalling, metabolic dysfunction, metal dyshomeostasis, and regulated oxidative cell death are evaluated based on current evidence and their potential complementarity with amyloid-directed therapies. Although temporal relationships remain unresolved, redox-metabolic dysfunction may represent an early determinant and amplifier of neuronal vulnerability. Evidence for lecanemab and donanemab supports an integrative rather than replacement model of AD treatment. This framework may facilitate earlier diagnosis, patient stratification, and complementary disease-modifying interventions.<\/jats:p>","DOI":"10.3390\/ijms27188294","type":"journal-article","created":{"date-parts":[[2026,10,1]],"date-time":"2026-10-01T13:18:26Z","timestamp":1790860706000},"page":"8294","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Reframing Alzheimer\u2019s Disease Through a Redox-Metabolic Framework"],"prefix":"10.3390","volume":"27","author":[{"given":"Amador","family":"Vel\u00e1zquez De Castro-Bono","sequence":"first","affiliation":[{"name":"Hospital Central de La Defensa \u201cG\u00f3mez Ulla\u201d, 28047 Madrid, Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6928-9728","authenticated-orcid":false,"given":"Gracia","family":"Castro-Luna","sequence":"additional","affiliation":[{"name":"Department of Nursing, Physiotherapy and Medicine, University of Almer\u00eda, 04120 Almer\u00eda, Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2666-1774","authenticated-orcid":false,"given":"Jos\u00e9 Luis","family":"Guil-Guerrero","sequence":"additional","affiliation":[{"name":"Food Technology Division, University of Almer\u00eda, 04120 Almer\u00eda, Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2026,9,17]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"184","DOI":"10.1126\/science.1566067","article-title":"Alzheimer\u2019s Disease: The Amyloid Cascade Hypothesis","volume":"256","author":"Hardy","year":"1992","journal-title":"Science"},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"609","DOI":"10.1038\/s41573-020-0072-x","article-title":"Brain Energy Rescue: An Emerging Therapeutic Concept for Neurodegenerative Disorders of Ageing","volume":"19","author":"Cunnane","year":"2020","journal-title":"Nat. Rev. Drug Discov."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"486","DOI":"10.1007\/s00259-005-1762-7","article-title":"Brain Glucose Metabolism in the Early and Specific Diagnosis of Alzheimer\u2019s Disease: FDG-PET Studies in MCI and AD","volume":"32","author":"Mosconi","year":"2005","journal-title":"Eur. J. Nucl. Med. Mol. Imaging"},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"S265","DOI":"10.3233\/JAD-2010-100339","article-title":"The Alzheimer\u2019s Disease Mitochondrial Cascade Hypothesis","volume":"20","author":"Swerdlow","year":"2010","journal-title":"J. Alzheimer\u2019s Dis."},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"1403","DOI":"10.3233\/JAD-170585","article-title":"Mitochondria and Mitochondrial Cascades in Alzheimer\u2019s Disease","volume":"62","author":"Swerdlow","year":"2018","journal-title":"J. Alzheimer\u2019s Dis."},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"148","DOI":"10.1038\/s41583-019-0132-6","article-title":"Oxidative Stress, Dysfunctional Glucose Metabolism and Alzheimer Disease","volume":"20","author":"Butterfield","year":"2019","journal-title":"Nat. Rev. Neurosci."},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"30","DOI":"10.1186\/s13024-020-00376-6","article-title":"Mitochondria Dysfunction in the Pathogenesis of Alzheimer\u2019s Disease: Recent Advances","volume":"15","author":"Wang","year":"2020","journal-title":"Mol. Neurodegener."},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"689","DOI":"10.1038\/s41573-021-00233-1","article-title":"Targeting Oxidative Stress in Disease: Promise and Limitations of Antioxidant Therapy","volume":"20","author":"Forman","year":"2021","journal-title":"Nat. Rev. Drug Discov."},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"298","DOI":"10.1093\/geronj\/11.3.298","article-title":"Aging: A Theory Based on Free Radical and Radiation Chemistry","volume":"11","author":"Harman","year":"1956","journal-title":"J. Gerontol."},{"key":"ref_10","doi-asserted-by":"crossref","unstructured":"Navarro, E., and Esteras, N. (2024). Multitarget Effects of Nrf2 Signalling in the Brain: Common and Specific Functions in Different Cell Types. Antioxidants, 13.","DOI":"10.20944\/preprints202411.1766.v1"},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"715","DOI":"10.1146\/annurev-biochem-061516-045037","article-title":"Oxidative Stress","volume":"86","author":"Sies","year":"2017","journal-title":"Annu. Rev. Biochem."},{"key":"ref_12","doi-asserted-by":"crossref","unstructured":"Rostagno, A., and Ghiso, J. (2025). Alzheimer\u2019s Disease Pathogenic Mechanisms: Linking Redox Homeostasis and Mitochondria-Associated Metabolic Pathways Through Nuclear Factor Erythroid 2-Related Factor 2 (Nrf2). Antioxidants, 14.","DOI":"10.3390\/antiox14070812"},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"363","DOI":"10.1038\/s41580-020-0230-3","article-title":"Reactive Oxygen Species (ROS) as Pleiotropic Physiological Signalling Agents","volume":"21","author":"Sies","year":"2020","journal-title":"Nat. Rev. Mol. Cell Biol."},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"388","DOI":"10.1016\/S1474-4422(15)70016-5","article-title":"Neuroinflammation in Alzheimer\u2019s Disease","volume":"14","author":"Heneka","year":"2015","journal-title":"Lancet Neurol."},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"674","DOI":"10.1038\/nature11729","article-title":"NLRP3 Is Activated in Alzheimer\u2019s Disease and Contributes to Pathology in APP\/PS1 Mice","volume":"493","author":"Heneka","year":"2013","journal-title":"Nature"},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"vdad160","DOI":"10.1093\/noajnl\/vdad160","article-title":"Exploring the Multifaceted Role of NRF2 in Brain Physiology and Cancer: A Comprehensive Review","volume":"6","author":"Moubarak","year":"2024","journal-title":"Neuro-Oncol. Adv."},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"35","DOI":"10.2174\/156720512799015037","article-title":"Brain Insulin Resistance and Deficiency as Therapeutic Targets in Alzheimer\u2019s Disease","volume":"9","year":"2012","journal-title":"Curr. Alzheimer Res."},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"85","DOI":"10.1002\/ana.410420114","article-title":"Metabolic Reduction in the Posterior Cingulate Cortex in Very Early Alzheimer\u2019s Disease","volume":"42","author":"Minoshima","year":"1997","journal-title":"Ann. Neurol."},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"2013","DOI":"10.1089\/ars.2010.3208","article-title":"Reactive Oxygen Species in the Regulation of Synaptic Plasticity and Memory","volume":"14","author":"Massaad","year":"2011","journal-title":"Antioxid. Redox Signal."},{"key":"ref_20","doi-asserted-by":"crossref","unstructured":"Wang, X., and Michaelis, E.K. (2010). Selective Neuronal Vulnerability to Oxidative Stress in the Brain. Front. Aging Neurosci., 2.","DOI":"10.3389\/fnagi.2010.00012"},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"233","DOI":"10.1089\/ars.2007.9.233","article-title":"Sources and Targets of Reactive Oxygen Species in Synaptic Plasticity and Memory","volume":"9","author":"Kishida","year":"2007","journal-title":"Antioxid. Redox Signal."},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"475","DOI":"10.1007\/s00204-025-04276-w","article-title":"Pathophysiology of Reactive Oxygen Species (ROS)","volume":"100","author":"Munguira","year":"2026","journal-title":"Arch. Toxicol."},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"531","DOI":"10.1089\/ars.2021.0081","article-title":"Protein Transnitrosylation Signaling Networks Contribute to Inflammaging and Neurodegenerative Disorders","volume":"35","author":"Nakamura","year":"2021","journal-title":"Antioxid. Redox Signal."},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"10625","DOI":"10.1073\/pnas.91.22.10625","article-title":"Glutamate Uptake into Astrocytes Stimulates Aerobic Glycolysis: A Mechanism Coupling Neuronal Activity to Glucose Utilization","volume":"91","author":"Pellerin","year":"1994","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"1","DOI":"10.4196\/kjpp.24.388","article-title":"Brain Energy Homeostasis: The Evolution of the Astrocyte-Neuron Lactate Shuttle Hypothesis","volume":"29","author":"Kim","year":"2025","journal-title":"Korean J. Physiol. Pharmacol."},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"17","DOI":"10.1042\/EBC20220075","article-title":"Cross-Talk between Energy and Redox Metabolism in Astrocyte-Neuron Functional Cooperation","volume":"67","author":"Almeida","year":"2023","journal-title":"Essays Biochem."},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"147","DOI":"10.1016\/j.freeradbiomed.2016.06.027","article-title":"Adaptive Regulation of the Brain\u2019s Antioxidant Defences by Neurons and Astrocytes","volume":"100","author":"Baxter","year":"2016","journal-title":"Free Radic. Biol. Med."},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"2103","DOI":"10.1002\/jnr.24015","article-title":"Lack of Appropriate Stoichiometry: Strong Evidence against an Energetically Important Astrocyte\u2013Neuron Lactate Shuttle in Brain","volume":"95","author":"Dienel","year":"2017","journal-title":"J. Neurosci. Res."},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"e17","DOI":"10.1017\/S1462399409001094","article-title":"The Nrf2-ARE Cytoprotective Pathway in Astrocytes","volume":"11","author":"Vargas","year":"2009","journal-title":"Expert Rev. Mol. Med."},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"7130","DOI":"10.1128\/MCB.24.16.7130-7139.2004","article-title":"Oxidative Stress Sensor Keap1 Functions as an Adaptor for Cul3-Based E3 Ligase To Regulate Proteasomal Degradation of Nrf2","volume":"24","author":"Kobayashi","year":"2004","journal-title":"Mol. Cell. Biol."},{"key":"ref_31","doi-asserted-by":"crossref","unstructured":"Zakrzewski, P.K., and Boczek, T. (2025). Neuron\u2013Glia Crosstalk in the Regulation of Astrocytic Antioxidative Mechanisms Following CNS Injury. Antioxidants, 14.","DOI":"10.3390\/antiox14121415"},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"19318","DOI":"10.1073\/pnas.0804871105","article-title":"Amyloid-\u03b2 Overproduction Causes Abnormal Mitochondrial Dynamics via Differential Modulation of Mitochondrial Fission\/Fusion Proteins","volume":"105","author":"Wang","year":"2008","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_33","doi-asserted-by":"crossref","unstructured":"Johri, A. (2021). Disentangling Mitochondria in Alzheimer\u2019s Disease. Int. J. Mol. Sci., 22.","DOI":"10.3390\/ijms222111520"},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"2977","DOI":"10.1007\/s11357-024-01118-y","article-title":"Mitochondrial Disorders Leading to Alzheimer\u2019s Disease\u2014Perspectives of Diagnosis and Treatment","volume":"46","author":"Walczak","year":"2024","journal-title":"GeroScience"},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"756","DOI":"10.1002\/ana.26464","article-title":"Association between Human Blood Metabolome and the Risk of Alzheimer\u2019s Disease","volume":"92","author":"Sun","year":"2022","journal-title":"Ann. Neurol."},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"39446","DOI":"10.31083\/JIN39446","article-title":"Brain Insulin Signaling Pathway Regulation of Hippocampal Neuroplasticity in Neurocognitive Disorders: Mechanisms and Therapeutic Implications","volume":"24","author":"He","year":"2025","journal-title":"J. Integr. Neurosci."},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"1240","DOI":"10.1016\/j.bbadis.2013.10.015","article-title":"Oxidative Stress and Mitochondrial Dysfunction in Alzheimer\u2019s Disease","volume":"1842","author":"Wang","year":"2014","journal-title":"Biochim. Biophys. Acta BBA\u2014Mol. Basis Dis."},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"305395","DOI":"10.4061\/2011\/305395","article-title":"Mitochondria Are Related to Synaptic Pathology in Alzheimer\u2032s Disease","volume":"2011","author":"Baloyannis","year":"2011","journal-title":"Int. J. Alzheimer\u2019s Dis."},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"160","DOI":"10.1016\/j.cell.2013.08.032","article-title":"Mitochondrial Cristae Shape Determines Respiratory Chain Supercomplexes Assembly and Respiratory Efficiency","volume":"155","author":"Cogliati","year":"2013","journal-title":"Cell"},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"55","DOI":"10.1017\/neu.2020.43","article-title":"Systematic Review and Meta-Analysis on the Role of Mitochondrial Cytochrome c Oxidase in Alzheimer\u2019s Disease","volume":"33","author":"Morais","year":"2021","journal-title":"Acta Neuropsychiatr."},{"key":"ref_41","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1042\/BJ20081386","article-title":"How Mitochondria Produce Reactive Oxygen Species","volume":"417","author":"Murphy","year":"2009","journal-title":"Biochem. J."},{"key":"ref_42","doi-asserted-by":"crossref","first-page":"466","DOI":"10.1016\/j.exger.2010.01.003","article-title":"The Sites and Topology of Mitochondrial Superoxide Production","volume":"45","author":"Brand","year":"2010","journal-title":"Exp. Gerontol."},{"key":"ref_43","doi-asserted-by":"crossref","first-page":"S4","DOI":"10.1164\/rccm.2206007","article-title":"Reactive Oxygen Species and Cell Signaling: Respiratory Burst in Macrophage Signaling","volume":"166","author":"Forman","year":"2002","journal-title":"Am. J. Respir. Crit. Care Med."},{"key":"ref_44","doi-asserted-by":"crossref","first-page":"e1388252025","DOI":"10.1523\/JNEUROSCI.1388-25.2025","article-title":"APOE-Targeted Therapeutics for Alzheimer\u2019s Disease","volume":"45","author":"Yassine","year":"2025","journal-title":"J. Neurosci."},{"key":"ref_45","doi-asserted-by":"crossref","first-page":"e202305003","DOI":"10.1083\/jcb.202305003","article-title":"APOE Traffics to Astrocyte Lipid Droplets and Modulates Triglyceride Saturation and Droplet Size","volume":"223","author":"Windham","year":"2024","journal-title":"J. Cell Biol."},{"key":"ref_46","doi-asserted-by":"crossref","first-page":"493","DOI":"10.1016\/j.cmet.2019.06.005","article-title":"A Breakdown in Metabolic Reprogramming Causes Microglia Dysfunction in Alzheimer\u2019s Disease","volume":"30","author":"Baik","year":"2019","journal-title":"Cell Metab."},{"key":"ref_47","doi-asserted-by":"crossref","unstructured":"Kao, Y.-C., Ho, P.-C., Tu, Y.-K., Jou, I.-M., and Tsai, K.-J. (2020). Lipids and Alzheimer\u2019s Disease. Int. J. Mol. Sci., 21.","DOI":"10.3390\/ijms21041505"},{"key":"ref_48","doi-asserted-by":"crossref","first-page":"5","DOI":"10.1186\/alzrt103","article-title":"Lipidomics of Alzheimer\u2019s Disease: Current Status","volume":"4","author":"Wood","year":"2012","journal-title":"Alzheimer\u2019s Res. Ther."},{"key":"ref_49","doi-asserted-by":"crossref","first-page":"7","DOI":"10.1007\/s12017-026-08905-0","article-title":"Myelin Lipid Reserves as a Conditional Metabolic Buffer: Implications for Alzheimer\u2019s Disease and Ischemic Stroke","volume":"28","author":"Zou","year":"2026","journal-title":"Neuromol. Med."},{"key":"ref_50","doi-asserted-by":"crossref","first-page":"327","DOI":"10.1016\/B978-0-12-394816-8.00010-6","article-title":"Estrogen Regulation of Mitochondrial Bioenergetics","volume":"64","author":"Yao","year":"2012","journal-title":"Adv. Pharmacol."},{"key":"ref_51","doi-asserted-by":"crossref","unstructured":"Mosconi, L., Berti, V., Guyara-Quinn, C., McHugh, P., Petrongolo, G., Osorio, R.S., Connaughty, C., Pupi, A., Vallabhajosula, S., and Isaacson, R.S. (2017). Perimenopause and Emergence of an Alzheimer\u2019s Bioenergetic Phenotype in Brain and Periphery. PLoS ONE, 12, Correction in PLoS ONE 2018, 13, e0193314. https:\/\/doi.org\/10.1371\/journal.pone.0193314.","DOI":"10.1371\/journal.pone.0193314"},{"key":"ref_52","doi-asserted-by":"crossref","first-page":"134","DOI":"10.1016\/j.jsbmb.2016.03.012","article-title":"Age, APOE and Sex: Triad of Risk of Alzheimer\u2019s Disease","volume":"160","author":"Riedel","year":"2016","journal-title":"J. Steroid Biochem. Mol. Biol."},{"key":"ref_53","first-page":"1807104","article-title":"Ferroptosis\u2013Inflammation Crosstalk: Mechanistic Insights and Emerging Drug Targets","volume":"17","author":"Gupta","year":"2026","journal-title":"Cell Biochem. Biophys."},{"key":"ref_54","doi-asserted-by":"crossref","first-page":"445","DOI":"10.1016\/S0531-5565(00)00112-1","article-title":"Oxidative Processes in Alzheimer\u2019s Disease: The Role of A\u03b2-Metal Interactions","volume":"35","author":"Lynch","year":"2000","journal-title":"Exp. Gerontol."},{"key":"ref_55","doi-asserted-by":"crossref","unstructured":"Misrani, A., Tabassum, S., and Yang, L. (2021). Mitochondrial Dysfunction and Oxidative Stress in Alzheimer\u2019s Disease. Front. Aging Neurosci., 13.","DOI":"10.3389\/fnagi.2021.617588"},{"key":"ref_56","doi-asserted-by":"crossref","first-page":"804","DOI":"10.1111\/jnc.15519","article-title":"Ferroptosis as a Mechanism of Neurodegeneration in Alzheimer\u2019s Disease","volume":"159","author":"Jakaria","year":"2021","journal-title":"J. Neurochem."},{"key":"ref_57","doi-asserted-by":"crossref","first-page":"448","DOI":"10.1126\/science.1091230","article-title":"ABAD Directly Links A\u00df to Mitochondrial Toxicity in Alzheimer\u2019s Disease","volume":"304","author":"Lustbader","year":"2004","journal-title":"Science"},{"key":"ref_58","doi-asserted-by":"crossref","first-page":"3","DOI":"10.1007\/s10571-025-01634-1","article-title":"Tau\u2013Mitochondria Interactions in Neurodegeneration: Mechanisms and Therapeutic Potential","volume":"46","author":"Arias","year":"2025","journal-title":"Cell. Mol. Neurobiol."},{"key":"ref_59","doi-asserted-by":"crossref","first-page":"885","DOI":"10.1016\/j.bbadis.2012.01.009","article-title":"Oxidative Stress Increases BACE1 Protein Levels through Activation of the PKR-eIF2\u03b1 Pathway","volume":"1822","author":"Paquet","year":"2012","journal-title":"Biochim. Biophys. Acta BBA\u2014Mol. Basis Dis."},{"key":"ref_60","doi-asserted-by":"crossref","unstructured":"Engmann, O., and Giese, K.P. (2009). Crosstalk between Cdk5 and GSK3\u03b2: Implications for Alzheimer\u2019s Disease. Front. Mol. Neurosci., 2.","DOI":"10.3389\/neuro.02.002.2009"},{"key":"ref_61","doi-asserted-by":"crossref","first-page":"1276","DOI":"10.1016\/j.cell.2017.05.018","article-title":"A Unique Microglia Type Associated with Restricting Development of Alzheimer\u2019s Disease","volume":"169","author":"Spinrad","year":"2017","journal-title":"Cell"},{"key":"ref_62","doi-asserted-by":"crossref","first-page":"13537","DOI":"10.1038\/s41598-017-13601-y","article-title":"Gut Microbiome Alterations in Alzheimer\u2019s Disease","volume":"7","author":"Vogt","year":"2017","journal-title":"Sci. Rep."},{"key":"ref_63","doi-asserted-by":"crossref","first-page":"e00470","DOI":"10.1016\/j.neurot.2024.e00470","article-title":"Gut Microbial Metabolism in Alzheimer\u2019s Disease and Related Dementias","volume":"21","author":"Kang","year":"2024","journal-title":"Neurotherapeutics"},{"key":"ref_64","doi-asserted-by":"crossref","first-page":"86","DOI":"10.1038\/s12276-023-01146-2","article-title":"Current Understanding of the Alzheimer\u2019s Disease-Associated Microbiome and Therapeutic Strategies","volume":"56","author":"Seo","year":"2024","journal-title":"Exp. Mol. Med."},{"key":"ref_65","doi-asserted-by":"crossref","first-page":"179","DOI":"10.1016\/S1474-4422(19)30356-4","article-title":"The Gut Microbiome in Neurological Disorders","volume":"19","author":"Cryan","year":"2020","journal-title":"Lancet Neurol."},{"key":"ref_66","doi-asserted-by":"crossref","first-page":"1332","DOI":"10.1016\/j.cell.2016.05.041","article-title":"From Dietary Fiber to Host Physiology: Short-Chain Fatty Acids as Key Bacterial Metabolites","volume":"165","author":"Koh","year":"2016","journal-title":"Cell"},{"key":"ref_67","doi-asserted-by":"crossref","unstructured":"Fock, E., and Parnova, R. (2023). Mechanisms of Blood\u2013Brain Barrier Protection by Microbiota-Derived Short-Chain Fatty Acids. Cells, 12.","DOI":"10.3390\/cells12040657"},{"key":"ref_68","doi-asserted-by":"crossref","first-page":"265","DOI":"10.1080\/10408398.2023.2272769","article-title":"Gut Microbiota-Derived Short Chain Fatty Acids Act as Mediators of the Gut\u2013Brain Axis Targeting Age-Related Neurodegenerative Disorders: A Narrative Review","volume":"65","author":"Guo","year":"2025","journal-title":"Crit. Rev. Food Sci. Nutr."},{"key":"ref_69","doi-asserted-by":"crossref","first-page":"455","DOI":"10.1016\/j.chom.2017.03.002","article-title":"Age-Associated Microbial Dysbiosis Promotes Intestinal Permeability, Systemic Inflammation, and Macrophage Dysfunction","volume":"21","author":"Thevaranjan","year":"2017","journal-title":"Cell Host Microbe"},{"key":"ref_70","doi-asserted-by":"crossref","unstructured":"Zhan, X., Stamova, B., and Sharp, F.R. (2018). Lipopolysaccharide Associates with Amyloid Plaques, Neurons and Oligodendrocytes in Alzheimer\u2019s Disease Brain: A Review. Front. Aging Neurosci., 10.","DOI":"10.3389\/fnagi.2018.00042"},{"key":"ref_71","doi-asserted-by":"crossref","first-page":"1060","DOI":"10.1016\/j.cell.2012.03.042","article-title":"Ferroptosis: An Iron-Dependent Form of Nonapoptotic Cell Death","volume":"149","author":"Dixon","year":"2012","journal-title":"Cell"},{"key":"ref_72","doi-asserted-by":"crossref","first-page":"813","DOI":"10.1152\/physrev.00011.2017","article-title":"Neuronal Cell Death","volume":"98","author":"Fricker","year":"2018","journal-title":"Physiol. Rev."},{"key":"ref_73","doi-asserted-by":"crossref","first-page":"1045","DOI":"10.1016\/S1474-4422(14)70117-6","article-title":"The Role of Iron in Brain Ageing and Neurodegenerative Disorders","volume":"13","author":"Ward","year":"2014","journal-title":"Lancet Neurol."},{"key":"ref_74","doi-asserted-by":"crossref","first-page":"1254","DOI":"10.1126\/science.abf0529","article-title":"Copper Induces Cell Death by Targeting Lipoylated TCA Cycle Proteins","volume":"375","author":"Tsvetkov","year":"2022","journal-title":"Science"},{"key":"ref_75","doi-asserted-by":"crossref","first-page":"172","DOI":"10.3892\/ijmm.2025.5613","article-title":"Copper Homeostasis and Cuproptosis in Alzheimer\u2019s Disease (Review)","volume":"56","author":"Cong","year":"2025","journal-title":"Int. J. Mol. Med."},{"key":"ref_76","doi-asserted-by":"crossref","unstructured":"Sgalletta, B., Agostini, F., and Bisaglia, M. (2026). The Role of Iron in Neuronal Homeostasis: A Double-Edged Sword. Cells, 15.","DOI":"10.3390\/cells15110999"},{"key":"ref_77","doi-asserted-by":"crossref","unstructured":"Ghaderi, S., Mohammadi, S., Nezhad, N.J., Karami, S., and Sayehmiri, F. (2024). Iron Quantification in Basal Ganglia: Quantitative Susceptibility Mapping as a Potential Biomarker for Alzheimer\u2019s Disease\u2014A Systematic Review and Meta-Analysis. Front. Neurosci., 18.","DOI":"10.3389\/fnins.2024.1338891"},{"key":"ref_78","doi-asserted-by":"crossref","first-page":"e70268","DOI":"10.1002\/nbm.70268","article-title":"Optimized Quantitative Susceptibility Mapping at 7T MRI for Assessing Iron Deposition in Alzheimer\u2019s Disease","volume":"39","author":"Ma","year":"2026","journal-title":"NMR BioMed."},{"key":"ref_79","doi-asserted-by":"crossref","first-page":"301","DOI":"10.1038\/s41420-026-03034-w","article-title":"The Iron-Energy Metabolism Axis in Alzheimer\u2019s Pathogenesis: From Mechanisms to Interventions","volume":"12","author":"Zou","year":"2026","journal-title":"Cell Death Discov."},{"key":"ref_80","doi-asserted-by":"crossref","first-page":"119","DOI":"10.3892\/ijmm.2026.5790","article-title":"Ferritin in Ferroptosis: Implications for Neurodegenerative Diseases (Review)","volume":"57","author":"Chen","year":"2026","journal-title":"Int. J. Mol. Med."},{"key":"ref_81","doi-asserted-by":"crossref","first-page":"91","DOI":"10.1038\/nchembio.2239","article-title":"ACSL4 Dictates Ferroptosis Sensitivity by Shaping Cellular Lipid Composition","volume":"13","author":"Doll","year":"2017","journal-title":"Nat. Chem. Biol."},{"key":"ref_82","doi-asserted-by":"crossref","unstructured":"Sun, D., Wang, L., Wu, Y., Yu, Y., Yao, Y., Yang, H., and Hao, C. (2025). Lipid Metabolism in Ferroptosis: Mechanistic Insights and Therapeutic Potential. Front. Immunol., 16.","DOI":"10.3389\/fimmu.2025.1545339"},{"key":"ref_83","doi-asserted-by":"crossref","first-page":"1699","DOI":"10.1038\/s12276-026-01736-w","article-title":"CoQ10 Oxidoreductases in Ferroptosis and Cancer: Redox Regulation and Therapeutic Opportunities","volume":"58","author":"Lee","year":"2026","journal-title":"Exp. Mol. Med."},{"key":"ref_84","doi-asserted-by":"crossref","first-page":"5435","DOI":"10.1158\/0008-5472.CAN-20-2017","article-title":"Iron and Cancer: 2020 Vision","volume":"80","author":"Torti","year":"2020","journal-title":"Cancer Res."},{"key":"ref_85","doi-asserted-by":"crossref","first-page":"1741","DOI":"10.4103\/1673-5374.389362","article-title":"Ferroptosis Mechanism and Alzheimer\u2019s Disease","volume":"19","author":"Feng","year":"2024","journal-title":"Neural Regen. Res."},{"key":"ref_86","doi-asserted-by":"crossref","unstructured":"Masaldan, S., Belaidi, A.A., Ayton, S., and Bush, A.I. (2019). Cellular Senescence and Iron Dyshomeostasis in Alzheimer\u2019s Disease. Pharmaceuticals, 12.","DOI":"10.3390\/ph12020093"},{"key":"ref_87","doi-asserted-by":"crossref","first-page":"106","DOI":"10.1186\/s13041-019-0528-2","article-title":"Zinc Transporters in Alzheimer\u2019s Disease","volume":"12","author":"Xu","year":"2019","journal-title":"Mol. Brain"},{"key":"ref_88","doi-asserted-by":"crossref","first-page":"436","DOI":"10.1007\/s12035-026-05678-2","article-title":"The Impact of Zinc on Cellular Dynamics, Brain Function, and Its Therapeutic Potential in Neuronal Regeneration","volume":"63","author":"Umesh","year":"2026","journal-title":"Mol. Neurobiol."},{"key":"ref_89","doi-asserted-by":"crossref","unstructured":"Inamdar, A., Bugadannavar, P., Palled, M., Umarani, S., Salve, P., Gurupadayya, B., Patil, P., and Sharma, H. (2025). Biological Determinants of Blood-Based Biomarker Levels in Alzheimer\u2019s Disease: Role of Nutrition, Inflammation, and Metabolic Factors. Front. Aging Neurosci., 17.","DOI":"10.3389\/fnagi.2025.1614962"},{"key":"ref_90","doi-asserted-by":"crossref","unstructured":"Upadhyay, R., Kar, S., and Sevanan, M. (2026). Zinc-Binding Proteins in Alzheimer\u2019s Disease: Mechanisms, Therapeutic Potential, and Natural Compound Interventions. Front. Chem. Biol., 5.","DOI":"10.3389\/fchbi.2026.1836070"},{"key":"ref_91","doi-asserted-by":"crossref","unstructured":"Sabouri, S., Rostamirad, M., and Dempski, R.E. (2024). Unlocking the Brain\u2019s Zinc Code: Implications for Cognitive Function and Disease. Front. Biophys., 2.","DOI":"10.3389\/frbis.2024.1406868"},{"key":"ref_92","doi-asserted-by":"crossref","first-page":"96","DOI":"10.1007\/s00401-024-02747-5","article-title":"The Necroptosis Cell Death Pathway Drives Neurodegeneration in Alzheimer\u2019s Disease","volume":"147","author":"Balusu","year":"2024","journal-title":"Acta Neuropathol."},{"key":"ref_93","doi-asserted-by":"crossref","first-page":"e70231","DOI":"10.1111\/ejn.70231","article-title":"PANoptosis: Potential Therapeutic Prospects in Alzheimer\u2019s Disease","volume":"62","author":"Guo","year":"2025","journal-title":"Eur. J. Neurosci."},{"key":"ref_94","doi-asserted-by":"crossref","first-page":"127","DOI":"10.1038\/nrm.2016.149","article-title":"Necroptosis in Development, Inflammation and Disease","volume":"18","author":"Weinlich","year":"2017","journal-title":"Nat. Rev. Mol. Cell Biol."},{"key":"ref_95","doi-asserted-by":"crossref","first-page":"e70141","DOI":"10.1002\/imt2.70141","article-title":"Metal-dependent Regulated Cell Death: Molecular Architecture and Translational Frontiers","volume":"5","author":"Hu","year":"2026","journal-title":"iMeta"},{"key":"ref_96","first-page":"e79881","article-title":"Blood-Based \u03b2-Amyloid and Phosphorylated Tau (p-Tau) Biomarkers in Alzheimer\u2019s Disease: A Systematic Review of Their Diagnostic Potential","volume":"17","author":"Dasari","year":"2025","journal-title":"Cureus"},{"key":"ref_97","doi-asserted-by":"crossref","first-page":"4968","DOI":"10.3390\/cimb46050298","article-title":"Spatial Multi-Omics in Alzheimer\u2019s Disease: A Multi-Dimensional Approach to Understanding Pathology and Progression","volume":"46","author":"Ma","year":"2024","journal-title":"Curr. Issues Mol. Biol."},{"key":"ref_98","doi-asserted-by":"crossref","unstructured":"Chiurchi\u00f9, V., Tiberi, M., Matteocci, A., Fazio, F., Siffeti, H., Saracini, S., Mercuri, N.B., and Sancesario, G. (2022). Lipidomics of Bioactive Lipids in Alzheimer\u2019s and Parkinson\u2019s Diseases: Where Are We?. Int. J. Mol. Sci., 23.","DOI":"10.3390\/ijms23116235"},{"key":"ref_99","doi-asserted-by":"crossref","unstructured":"Maszka, P., Kwasniak-Butowska, M., Cysewski, D., Slawek, J., Smolenski, R.T., and Tomczyk, M. (2023). Metabolomic Footprint of Disrupted Energetics and Amino Acid Metabolism in Neurodegenerative Diseases: Perspectives for Early Diagnosis and Monitoring of Therapy. Metabolites, 13.","DOI":"10.3390\/metabo13030369"},{"key":"ref_100","first-page":"CD002854","article-title":"Vitamin E for Alzheimer\u2019s Dementia and Mild Cognitive Impairment","volume":"4","author":"Farina","year":"2017","journal-title":"Cochrane Database Syst. Rev."},{"key":"ref_101","doi-asserted-by":"crossref","first-page":"629","DOI":"10.1146\/annurev.pharmtox.47.120505.105110","article-title":"Targeting Antioxidants to Mitochondria by Conjugation to Lipophilic Cations","volume":"47","author":"Murphy","year":"2007","journal-title":"Annu. Rev. Pharmacol. Toxicol."},{"key":"ref_102","doi-asserted-by":"crossref","unstructured":"Nhu, N.T., Xiao, S.-Y., Liu, Y., Kumar, V.B., Cui, Z.-Y., and Lee, S.-D. (2022). Neuroprotective Effects of a Small Mitochondrially-Targeted Tetrapeptide Elamipretide in Neurodegeneration. Front. Integr. Neurosci., 15.","DOI":"10.3389\/fnint.2021.747901"},{"key":"ref_103","doi-asserted-by":"crossref","unstructured":"Tung, C., Varzideh, F., Farroni, E., Mone, P., Kansakar, U., Jankauskas, S.S., and Santulli, G. (2025). Elamipretide: A Review of Its Structure, Mechanism of Action, and Therapeutic Potential. Int. J. Mol. Sci., 26.","DOI":"10.3390\/ijms26030944"},{"key":"ref_104","doi-asserted-by":"crossref","first-page":"212","DOI":"10.1002\/ana.25934","article-title":"Safety and Efficacy of Omaveloxolone in Friedreich Ataxia (MOXIe Study)","volume":"89","author":"Lynch","year":"2021","journal-title":"Ann. Neurol."},{"key":"ref_105","doi-asserted-by":"crossref","first-page":"1098","DOI":"10.1056\/NEJMoa1114287","article-title":"Placebo-Controlled Phase 3 Study of Oral BG-12 for Relapsing Multiple Sclerosis","volume":"367","author":"Gold","year":"2012","journal-title":"N. Engl. J. Med."},{"key":"ref_106","doi-asserted-by":"crossref","first-page":"211","DOI":"10.1126\/science.1227166","article-title":"Suppression of Oxidative Stress by \u03b2-Hydroxybutyrate, an Endogenous Histone Deacetylase Inhibitor","volume":"339","author":"Shimazu","year":"2013","journal-title":"Science"},{"key":"ref_107","doi-asserted-by":"crossref","first-page":"263","DOI":"10.1038\/nm.3804","article-title":"The Ketone Metabolite \u03b2-Hydroxybutyrate Blocks NLRP3 Inflammasome\u2013Mediated Inflammatory Disease","volume":"21","author":"Youm","year":"2015","journal-title":"Nat. Med."},{"key":"ref_108","doi-asserted-by":"crossref","first-page":"353","DOI":"10.1038\/s41591-025-04106-7","article-title":"Liraglutide in Mild to Moderate Alzheimer\u2019s Disease: A Phase 2b Clinical Trial","volume":"32","author":"Edison","year":"2026","journal-title":"Nat. Med."},{"key":"ref_109","doi-asserted-by":"crossref","first-page":"2167","DOI":"10.1016\/S0140-6736(26)00459-9","article-title":"Efficacy and Safety of Oral Semaglutide 14 Mg (Flexible Dose) in Early-Stage Symptomatic Alzheimer\u2019s Disease (Evoke and Evoke+): Two Phase 3, Randomised, Placebo-Controlled Trials","volume":"407","author":"Cummings","year":"2026","journal-title":"Lancet"},{"key":"ref_110","doi-asserted-by":"crossref","first-page":"9","DOI":"10.1056\/NEJMoa2212948","article-title":"Lecanemab in Early Alzheimer\u2019s Disease","volume":"388","author":"Swanson","year":"2023","journal-title":"N. Engl. J. Med."},{"key":"ref_111","doi-asserted-by":"crossref","first-page":"512","DOI":"10.1001\/jama.2023.13239","article-title":"Donanemab in Early Symptomatic Alzheimer Disease: The TRAILBLAZER-ALZ 2 Randomized Clinical Trial","volume":"330","author":"Sims","year":"2023","journal-title":"JAMA"},{"key":"ref_112","doi-asserted-by":"crossref","first-page":"1227","DOI":"10.1002\/alz.12748","article-title":"The AHEAD 3-45 Study: Design of a Prevention Trial for Alzheimer\u2019s Disease","volume":"19","author":"Rafii","year":"2023","journal-title":"Alzheimer\u2019s Dement."},{"key":"ref_113","doi-asserted-by":"crossref","first-page":"6161","DOI":"10.7150\/thno.98172","article-title":"A Novel Ferroptosis Inhibitor, Thonningianin A, Improves Alzheimer\u2019s Disease by Activating GPX4","volume":"14","author":"Yong","year":"2024","journal-title":"Theranostics"},{"key":"ref_114","doi-asserted-by":"crossref","first-page":"535","DOI":"10.1016\/j.jalz.2018.02.018","article-title":"NIA-AA Research Framework: Toward a Biological Definition of Alzheimer\u2019s Disease","volume":"14","author":"Jack","year":"2018","journal-title":"Alzheimer\u2019s Dement."},{"key":"ref_115","doi-asserted-by":"crossref","first-page":"280","DOI":"10.1016\/j.jalz.2011.03.003","article-title":"Toward Defining the Preclinical Stages of Alzheimer\u2019s Disease: Recommendations from the National Institute on Aging-Alzheimer\u2019s Association Workgroups on Diagnostic Guidelines for Alzheimer\u2019s Disease","volume":"7","author":"Sperling","year":"2011","journal-title":"Alzheimer\u2019s Dement."},{"key":"ref_116","first-page":"43","article-title":"Alzheimer\u2019s Disease Puzzle: Delving into Pathogenesis Hypotheses","volume":"15","author":"Nasb","year":"2024","journal-title":"Aging Dis."},{"key":"ref_117","doi-asserted-by":"crossref","first-page":"9971885","DOI":"10.1155\/2021\/9971885","article-title":"Redox Homeostasis and Prospects for Therapeutic Targeting in Neurodegenerative Disorders","volume":"2021","author":"Akanji","year":"2021","journal-title":"Oxid. Med. Cell. Longev."},{"key":"ref_118","doi-asserted-by":"crossref","first-page":"564","DOI":"10.1038\/nrc3278","article-title":"NRF2 and Cancer: The Good, the Bad and the Importance of Context","volume":"12","author":"Sporn","year":"2012","journal-title":"Nat. Rev. Cancer"},{"key":"ref_119","doi-asserted-by":"crossref","first-page":"e091208","DOI":"10.1002\/alz.091208","article-title":"The Effects of Blood-brain Barrier Permeability on Alzheimer\u2019s Disease Plasma Biomarkers and Their Impact on Clinical Performance","volume":"20","author":"Pornteparak","year":"2024","journal-title":"Alzheimer\u2019s Dement."},{"key":"ref_120","doi-asserted-by":"crossref","first-page":"8","DOI":"10.1007\/s13311-022-01185-z","article-title":"Heterogeneity in Alzheimer\u2019s Disease Diagnosis and Progression Rates: Implications for Therapeutic Trials","volume":"19","author":"Duara","year":"2022","journal-title":"Neurotherapeutics"}],"container-title":["International Journal of Molecular Sciences"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/1422-0067\/27\/18\/8294\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,10,1]],"date-time":"2026-10-01T13:21:00Z","timestamp":1790860860000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/1422-0067\/27\/18\/8294"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2026,9,17]]},"references-count":120,"journal-issue":{"issue":"18","published-online":{"date-parts":[[2026,9]]}},"alternative-id":["ijms27188294"],"URL":"https:\/\/doi.org\/10.3390\/ijms27188294","relation":{},"ISSN":["1422-0067"],"issn-type":[{"value":"1422-0067","type":"electronic"}],"subject":[],"published":{"date-parts":[[2026,9,17]]}}}