{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,24]],"date-time":"2026-09-24T17:46:38Z","timestamp":1790271998489,"version":"4.1.0"},"reference-count":64,"publisher":"MDPI AG","issue":"5","license":[{"start":{"date-parts":[[2026,3,1]],"date-time":"2026-03-01T00:00:00Z","timestamp":1772323200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["JCM"],"abstract":"<jats:p>Objective: Alzheimer\u2019s disease (AD) is traditionally characterized by amyloid-\u03b2 and tau pathology; however, accumulating evidence indicates that metabolic and inflammatory dysfunctions are early, central contributors to disease development. This narrative review explores how metabolic disturbances influence AD pathophysiology. Methods: A comprehensive literature search was performed on PubMed, Embase, and Scopus. Selected studies were original studies or reviews published in English within the past five years involving human subjects. Case reports, case series, editorials, and non-human studies were excluded. A total of 64 articles were reviewed and summarized. Results: Cerebral glucose hypometabolism, mitochondrial impairment, insulin resistance, oxidative stress, and neuroinflammation were observed throughout the AD spectrum. These metabolic changes often appeared before significant amyloid accumulation and were more closely linked to tau pathology and cognitive decline. Early microglial activation was linked to transient glucose hypermetabolism, progressing to glucose hypometabolism and neurodegeneration as the disease advanced. Conclusions: AD is associated with a gradual breakdown of metabolic and inflammatory homeostasis, which occurs before and promotes the development of traditional neuropathological features. Addressing early metabolic vulnerabilities may be essential for effective disease intervention and prevention.<\/jats:p>","DOI":"10.3390\/jcm15051884","type":"journal-article","created":{"date-parts":[[2026,3,2]],"date-time":"2026-03-02T10:24:34Z","timestamp":1772447074000},"page":"1884","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":17,"title":["Metabolic Dysfunction in Alzheimer\u2019s Disease: Brain Glucose Hypometabolism as an Early Precursor to Amyloid and Tau Pathology"],"prefix":"10.3390","volume":"15","author":[{"ORCID":"https:\/\/orcid.org\/0009-0001-6857-3927","authenticated-orcid":false,"given":"Rafail C.","family":"Christodoulou","sequence":"first","affiliation":[{"name":"Division of Neuroimaging and Neurointervention, Department of Radiology, Stanford University, Stanford, CA 94304, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8399-2759","authenticated-orcid":false,"given":"Daniel","family":"Eller","sequence":"additional","affiliation":[{"name":"Division of Neuroimaging and Neurointervention, Department of Radiology, Stanford University, Stanford, CA 94304, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0007-6102-3344","authenticated-orcid":false,"given":"Platon S.","family":"Papageorgiou","sequence":"additional","affiliation":[{"name":"Department of Medicine, Medical School, National and Kapodistrian University of Athens, 11527 Athens, Greece"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1426-3384","authenticated-orcid":false,"given":"Efthalia","family":"Angelopoulou","sequence":"additional","affiliation":[{"name":"1st Department of Neurology, Medical School, National and Kapodistrian University of Athens, Eginition Hospital, 15772 Athens, Greece"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Evros","family":"Vassiliou","sequence":"additional","affiliation":[{"name":"Department of Biological Sciences, Kean University, Union, NJ 07083, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8863-3635","authenticated-orcid":false,"given":"Sokratis G.","family":"Papageorgiou","sequence":"additional","affiliation":[{"name":"1st Department of Neurology, Medical School, National and Kapodistrian University of Athens, Eginition Hospital, 15772 Athens, Greece"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2026,3,1]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"497","DOI":"10.1002\/ana.410140502","article-title":"Senile Dementia of the Alzheimer Type","volume":"14","author":"Terry","year":"1983","journal-title":"Ann. Neurol."},{"key":"ref_2","doi-asserted-by":"crossref","unstructured":"Canepa, E., and Fossati, S. (2021). Impact of Tau on Neurovascular Pathology in Alzheimer\u2019s Disease. Front. Neurol., 11.","DOI":"10.3389\/fneur.2020.573324"},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"S611","DOI":"10.3233\/JAD-179935","article-title":"Role of Amyloid-\u03b2 and Tau Proteins in Alzheimer\u2019s Disease: Confuting the Amyloid Cascade","volume":"64","author":"Gulisano","year":"2018","journal-title":"JAD"},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"e2025E001","DOI":"10.1590\/1980-5764-dn-2025-e001","article-title":"What Are the Reasons for the Repeated Failures of Clinical Trials with Anti-Amyloid Drugs for AD Treatment?","volume":"19","author":"Forlenza","year":"2025","journal-title":"Dement. Neuropsychol."},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"548","DOI":"10.1016\/j.bcp.2013.12.012","article-title":"Brain Metabolic Dysfunction at the Core of Alzheimer\u2019s Disease","volume":"88","author":"Tong","year":"2014","journal-title":"Biochem. Pharmacol."},{"key":"ref_6","doi-asserted-by":"crossref","unstructured":"Yan, X., Hu, Y., Wang, B., Wang, S., and Zhang, X. (2020). Metabolic Dysregulation Contributes to the Progression of Alzheimer\u2019s Disease. Front. Neurosci., 14.","DOI":"10.3389\/fnins.2020.530219"},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"176","DOI":"10.1006\/nimg.1997.0318","article-title":"Effects of Healthy Aging on the Regional Cerebral Metabolic Rate of Glucose Assessed with Statistical Parametric Mapping","volume":"7","author":"Landeau","year":"1998","journal-title":"NeuroImage"},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"1188","DOI":"10.1089\/ars.2019.7763","article-title":"Central and Peripheral Metabolic Defects Contribute to the Pathogenesis of Alzheimer\u2019s Disease: Targeting Mitochondria for Diagnosis and Prevention","volume":"32","author":"Peng","year":"2020","journal-title":"Antioxid. Redox Signal."},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"356","DOI":"10.1186\/s13098-025-01930-2","article-title":"A Systematic Review on Type 3 Diabetes: Bridging the Gap between Metabolic Dysfunction and Alzheimer\u2019s Disease","volume":"17","author":"Atabi","year":"2025","journal-title":"Diabetol. Metab. Syndr."},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"333","DOI":"10.1016\/j.neurobiolaging.2021.05.011","article-title":"Brain Energy Metabolism and Neurodegeneration: Hints from CSF Lactate Levels in Dementias","volume":"105","author":"Bonomi","year":"2021","journal-title":"Neurobiol. Aging"},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"49","DOI":"10.2165\/11597760-000000000-00000","article-title":"Contributions of Brain Insulin Resistance and Deficiency in Amyloid-Related Neurodegeneration in Alzheimer\u2019s Disease","volume":"72","year":"2012","journal-title":"Drugs"},{"key":"ref_12","doi-asserted-by":"crossref","unstructured":"Alkhalifa, A.E., Alkhalifa, O., Durdanovic, I., Ibrahim, D.R., and Maragkou, S. (2025). Oxidative Stress and Mitochondrial Dysfunction in Alzheimer\u2019s Disease: Insights into Pathophysiology and Treatment. JDAD, 2.","DOI":"10.20944\/preprints202408.1375.v2"},{"key":"ref_13","doi-asserted-by":"crossref","unstructured":"Meng, X., Song, Q., Liu, Z., Liu, X., Wang, Y., and Liu, J. (2024). Neurotoxic \u03b2-Amyloid Oligomers Cause Mitochondrial Dysfunction\u2014The Trigger for PANoptosis in Neurons. Front. Aging Neurosci., 16.","DOI":"10.3389\/fnagi.2024.1400544"},{"key":"ref_14","doi-asserted-by":"crossref","unstructured":"Mullins, R.J., Diehl, T.C., Chia, C.W., and Kapogiannis, D. (2017). Insulin Resistance as a Link between Amyloid-Beta and Tau Pathologies in Alzheimer\u2019s Disease. Front. Aging Neurosci., 9.","DOI":"10.3389\/fnagi.2017.00118"},{"key":"ref_15","doi-asserted-by":"crossref","unstructured":"Kciuk, M., Kruczkowska, W., Ga\u0142\u0119ziewska, J., Wanke, K., Ka\u0142uzi\u0144ska-Ko\u0142at, \u017b., Aleksandrowicz, M., and Kontek, R. (2024). Alzheimer\u2019s Disease as Type 3 Diabetes: Understanding the Link and Implications. Int. J. Mol. Sci., 25.","DOI":"10.3390\/ijms252211955"},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"5","DOI":"10.1186\/s41073-019-0064-8","article-title":"SANRA\u2014A Scale for the Quality Assessment of Narrative Review Articles","volume":"4","author":"Baethge","year":"2019","journal-title":"Res. Integr. Peer Rev."},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"e107940","DOI":"10.1002\/alz70861_107940","article-title":"Developing Topics","volume":"21","author":"Kang","year":"2025","journal-title":"Alzheimer\u2019s Dement. J. Alzheimer\u2019s Assoc."},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"163","DOI":"10.1002\/ana.27226","article-title":"Regional Brain Metabolism across the Alzheimer\u2019s Disease Continuum in Down Syndrome","volume":"98","author":"Zsadanyi","year":"2025","journal-title":"Ann. Neurol."},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"182","DOI":"10.1186\/s13195-024-01535-3","article-title":"18F-FDG PET Can Effectively Rule out Conversion to Dementia and the Presence of CSF Biomarker of Neurodegeneration: A Real-World Data Analysis","volume":"16","author":"Heyer","year":"2024","journal-title":"Alzheimers Res. Ther."},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"287","DOI":"10.3233\/JAD-210036","article-title":"Synergistic Effect of Serum Homocysteine and Diabetes Mellitus on Brain Alterations","volume":"81","author":"Byeon","year":"2021","journal-title":"J. Alzheimer\u2019s Dis."},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"327","DOI":"10.1002\/hbm.26043","article-title":"Tau as a Biomarker of Cognitive Impairment and Neuropsychiatric Symptom in Alzheimer\u2019s Disease","volume":"44","author":"Dang","year":"2023","journal-title":"Hum. Brain Mapp."},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"3286","DOI":"10.1093\/brain\/awx243","article-title":"Tau Pathology and Neurodegeneration Contribute to Cognitive Impairment in Alzheimer\u2019s Disease","volume":"140","author":"Bejanin","year":"2017","journal-title":"Brain"},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"221","DOI":"10.1002\/alz.13355","article-title":"The Impact of Tau Deposition and Hypometabolism on Cognitive Impairment and Longitudinal Cognitive Decline","volume":"20","author":"Boccalini","year":"2024","journal-title":"Alzheimer\u2019s Dement."},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"228","DOI":"10.1177\/13872877241284314","article-title":"Regional Differences in Glucose Metabolic Decline and Tau Deposition in the Alzheimer\u2019s Continuum Brain","volume":"102","author":"Ishii","year":"2024","journal-title":"J. Alzheimer\u2019s Dis."},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"3147","DOI":"10.1111\/ene.15520","article-title":"Clinical and Metabolic Imaging Features of Late-Onset and Early-Onset Posterior Cortical Atrophy","volume":"29","author":"Isella","year":"2022","journal-title":"Eur. J. Neurol."},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"1577","DOI":"10.1093\/brain\/awae352","article-title":"Hypometabolic Mismatch with Atrophy and Tau Pathology in Mixed Alzheimer\u2019s and Lewy Body Disease","volume":"148","author":"Duong","year":"2025","journal-title":"Brain"},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"100459","DOI":"10.1016\/j.tjpad.2025.100459","article-title":"Soluble and Plaque Amyloid Associations with Peripheral Glucose Dysregulation Modulated by Tau Pathology in Alzheimer\u2019s Disease","volume":"16","author":"Kang","year":"2026","journal-title":"J. Prev. Alzheimer\u2019s Dis."},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"38","DOI":"10.1016\/j.neurobiolaging.2022.03.004","article-title":"Insulin Resistance, Cognition and Alzheimer\u2019s Disease Biomarkers: Evidence That CSF A\u03b242 Moderates the Association between Insulin Resistance and Increased CSF Tau Levels","volume":"114","author":"Woodfield","year":"2022","journal-title":"Neurobiol. Aging"},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"e12487","DOI":"10.1002\/trc2.12487","article-title":"Biological Effects of Sodium Phenylbutyrate and Taurursodiol in Alzheimer\u2019s Disease","volume":"10","author":"Arnold","year":"2024","journal-title":"Alzheimer\u2019s Dement. Transl. Res. Clin. Interv."},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"61","DOI":"10.1186\/s13195-022-01004-9","article-title":"Cerebrospinal Fluid Lactate Levels along the Alzheimer\u2019s Disease Continuum and Associations with Blood-Brain Barrier Integrity, Age, Cognition, and Biomarkers","volume":"14","author":"Zebhauser","year":"2022","journal-title":"Alzheimer\u2019s Res. Ther."},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"102713","DOI":"10.1016\/j.arr.2025.102713","article-title":"Mitochondrial Dysfunction in Alzheimer\u2019s Disease","volume":"107","author":"Kanaan","year":"2025","journal-title":"Ageing Res. Rev."},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"1324","DOI":"10.1111\/ene.15246","article-title":"Mitochondrial Complex I Abnormalities Underlie Neurodegeneration and Cognitive Decline in Alzheimer\u2019s Disease","volume":"29","author":"Terada","year":"2022","journal-title":"Eur. J. Neurol."},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"28","DOI":"10.1186\/s13024-021-00448-1","article-title":"Mitochondrial Complex I Abnormalities Is Associated with Tau and Clinical Symptoms in Mild Alzheimer\u2019s Disease","volume":"16","author":"Terada","year":"2021","journal-title":"Mol. Neurodegener."},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"4436","DOI":"10.1002\/alz.13388","article-title":"Skeletal Muscle Mitochondrial Function Predicts Cognitive Impairment and Is Associated with Biomarkers of Alzheimer\u2019s Disease and Neurodegeneration","volume":"19","author":"Tian","year":"2023","journal-title":"Alzheimer\u2019s Dement."},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"1999","DOI":"10.1007\/s00415-023-12154-7","article-title":"Cerebrospinal Fluid NPTX2 Changes and Relationship with Regional Brain Metabolism Metrics across Mild Cognitive Impairment Due to Alzheimer\u2019s Disease","volume":"271","author":"Massa","year":"2024","journal-title":"J. Neurol."},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"267","DOI":"10.1186\/s13195-025-01893-6","article-title":"Cerebrospinal Fluid NPTX2 and [18F]FDG PET Track Serotonergic Vulnerability to Neurodegeneration in Prodromal Alzheimer\u2019s Disease","volume":"1","author":"Massa","year":"2025","journal-title":"Alzheimer\u2019s Res. Ther."},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"1297","DOI":"10.1002\/ptr.7387","article-title":"A Novel DPP-4 Inhibitor Gramcyclin A Attenuates Cognitive Deficits in APP\/PS1\/Tau Triple Transgenic Mice via Enhancing Brain GLP-1-Dependent Glucose Uptake","volume":"36","author":"Li","year":"2022","journal-title":"Phytother. Res."},{"key":"ref_38","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":"2025","journal-title":"Nat. Med."},{"key":"ref_39","unstructured":"Novo Nordisk A\/S (2025). Evoke Phase 3 Trials Did not Demonstrate a Statistically Significant Reduction in Alzheimer\u2019s Disease Progression, Novo Nordisk. Available online: https:\/\/www.novonordisk.com\/content\/nncorp\/global\/en\/news-and-media\/news-and-ir-materials\/news-details.html?id=916462."},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"186","DOI":"10.1186\/s12974-023-02869-9","article-title":"The Mitochondrial Protein TSPO in Alzheimer\u2019s Disease: Relation to the Severity of AD Pathology and the Neuroinflammatory Environment","volume":"20","author":"Garland","year":"2023","journal-title":"J. Neuroinflamm."},{"key":"ref_41","doi-asserted-by":"crossref","first-page":"15","DOI":"10.1016\/j.apsb.2024.10.004","article-title":"Oxidative Stress and Inflammation in the Pathogenesis of Neurological Disorders: Mechanisms and Implications","volume":"15","author":"Dash","year":"2025","journal-title":"Acta Pharm. Sin. B"},{"key":"ref_42","doi-asserted-by":"crossref","unstructured":"Hu, J., and Wang, X. (2022). Alzheimer\u2019s Disease: From Pathogenesis to Mesenchymal Stem Cell Therapy\u2014Bridging the Missing Link. Front. Cell. Neurosci., 15.","DOI":"10.3389\/fncel.2021.811852"},{"key":"ref_43","doi-asserted-by":"crossref","first-page":"1340","DOI":"10.1002\/glia.24532","article-title":"Low-grade Systemic Inflammation Stimulates Microglial Turnover and Accelerates the Onset of Alzheimer\u2019s-like Pathology","volume":"72","author":"Targett","year":"2024","journal-title":"Glia"},{"key":"ref_44","doi-asserted-by":"crossref","unstructured":"Miao, J., Ma, H., Yang, Y., Liao, Y., Lin, C., Zheng, J., Yu, M., and Lan, J. (2023). Microglia in Alzheimer\u2019s Disease: Pathogenesis, Mechanisms, and Therapeutic Potentials. Front. Aging Neurosci., 15.","DOI":"10.3389\/fnagi.2023.1201982"},{"key":"ref_45","doi-asserted-by":"crossref","first-page":"3034","DOI":"10.1002\/alz.13678","article-title":"Astroglial Activation: Current Concepts and Future Directions","volume":"20","author":"Edison","year":"2024","journal-title":"Alzheimer\u2019s Dement."},{"key":"ref_46","doi-asserted-by":"crossref","first-page":"EMMM202216987","DOI":"10.15252\/emmm.202216987","article-title":"sTREM2 Is Associated with Amyloid-Related p-Tau Increases and Glucose Hypermetabolism in Alzheimer\u2019s Disease","volume":"15","author":"Biel","year":"2023","journal-title":"EMBO Mol. Med."},{"key":"ref_47","doi-asserted-by":"crossref","first-page":"43","DOI":"10.1186\/s13024-025-00834-z","article-title":"TREM2 and sTREM2 in Alzheimer\u2019s Disease: From Mechanisms to Therapies","volume":"20","author":"Zhang","year":"2025","journal-title":"Mol Neurodegener."},{"key":"ref_48","doi-asserted-by":"crossref","first-page":"29","DOI":"10.1186\/s13195-022-00968-y","article-title":"Association of Peripheral Immunity with Cognition, Neuroimaging, and Alzheimer\u2019s Pathology","volume":"14","author":"Hou","year":"2022","journal-title":"Alzheimer\u2019s Res. Ther."},{"key":"ref_49","doi-asserted-by":"crossref","unstructured":"Cao, Y., Tang, K., Ma, P., Zhang, R., Yang, Y., Li, T., Zhang, Y., and Peng, X. (2025). The Role of Peripheral Innate Immune Cells in Alzheimer\u2019s Disease Progression. Front. Immunol., 16.","DOI":"10.3389\/fimmu.2025.1616939"},{"key":"ref_50","doi-asserted-by":"crossref","first-page":"37","DOI":"10.1186\/s13024-025-00825-0","article-title":"Decoding Microglial Immunometabolism: A New Frontier in Alzheimer\u2019s Disease Research","volume":"20","author":"Jung","year":"2025","journal-title":"Mol Neurodegener."},{"key":"ref_51","doi-asserted-by":"crossref","first-page":"111750","DOI":"10.1016\/j.mehy.2025.111750","article-title":"Glycolytic Oscillations in Reactive Astrocytes Serve as a Novel Biomarker for the Ultra-Early Diagnosis of Alzheimer\u2019s Disease","volume":"203","author":"Li","year":"2025","journal-title":"Med. Hypotheses"},{"key":"ref_52","doi-asserted-by":"crossref","first-page":"771","DOI":"10.1016\/j.ibneur.2025.05.005","article-title":"Effect of Neuroinflammation on the Progression of Alzheimer\u2019s Disease and Its Significant Ramifications for Novel Anti-Inflammatory Treatments","volume":"18","author":"Kamila","year":"2025","journal-title":"IBRO Neurosci. Rep."},{"key":"ref_53","doi-asserted-by":"crossref","first-page":"102481","DOI":"10.1016\/j.arr.2024.102481","article-title":"Pathogenesis, Diagnostics, and Therapeutics for Alzheimer\u2019s Disease: Breaking the Memory Barrier","volume":"101","author":"Kamatham","year":"2024","journal-title":"Ageing Res. Rev."},{"key":"ref_54","doi-asserted-by":"crossref","unstructured":"Sehar, U., Rawat, P., Reddy, A.P., Kopel, J., and Reddy, P.H. (2022). Amyloid Beta in Aging and Alzheimer\u2019s Disease. Int. J. Mol. Sci., 23.","DOI":"10.3390\/ijms232112924"},{"key":"ref_55","doi-asserted-by":"crossref","first-page":"629","DOI":"10.3233\/JAD-180297","article-title":"Metabolic Syndrome and Amyloid Accumulation in the Aging Brain","volume":"65","author":"Gomez","year":"2018","journal-title":"J. Alzheimers Dis."},{"key":"ref_56","doi-asserted-by":"crossref","first-page":"211","DOI":"10.1038\/s41392-024-01911-3","article-title":"Recent Advances in Alzheimer\u2019s Disease: Mechanisms, Clinical Trials and New Drug Development Strategies","volume":"9","author":"Zhang","year":"2024","journal-title":"Signal Transduct. Target. Ther."},{"key":"ref_57","doi-asserted-by":"crossref","first-page":"600","DOI":"10.1007\/s13311-019-00755-y","article-title":"Consequences of Metabolic Disruption in Alzheimer\u2019s Disease Pathology","volume":"16","author":"Ryu","year":"2019","journal-title":"Neurotherapeutics"},{"key":"ref_58","doi-asserted-by":"crossref","first-page":"115","DOI":"10.1016\/j.neuron.2017.09.003","article-title":"Apolipoprotein E4 Impairs Neuronal Insulin Signaling by Trapping Insulin Receptor in the Endosomes","volume":"96","author":"Zhao","year":"2017","journal-title":"Neuron"},{"key":"ref_59","doi-asserted-by":"crossref","first-page":"2969","DOI":"10.2147\/NSS.S561326","article-title":"Circadian Rhythm Dysfunction in Neurodegenerative Diseases: A Bidirectional Perspective and Therapeutic Potential","volume":"17","author":"Namgyal","year":"2025","journal-title":"NSS"},{"key":"ref_60","doi-asserted-by":"crossref","first-page":"13","DOI":"10.1186\/s13024-015-0007-x","article-title":"A\u03b2-Induced Degradation of BMAL1 and CBP Leads to Circadian Rhythm Disruption in Alzheimer\u2019s Disease","volume":"10","author":"Song","year":"2015","journal-title":"Mol. Neurodegener."},{"key":"ref_61","doi-asserted-by":"crossref","first-page":"1349","DOI":"10.1126\/science.1195027","article-title":"Circadian Integration of Metabolism and Energetics","volume":"330","author":"Bass","year":"2010","journal-title":"Science"},{"key":"ref_62","doi-asserted-by":"crossref","unstructured":"Angelopoulou, E., Bougea, A., Hatzimanolis, A., Scarmeas, N., and Papageorgiou, S.G. (2024). Unraveling the Potential Underlying Mechanisms of Mild Behavioral Impairment: Focusing on Amyloid and Tau Pathology. Cells, 13.","DOI":"10.3390\/cells13131164"},{"key":"ref_63","doi-asserted-by":"crossref","unstructured":"Angelopoulou, E., Androni, X., Villa, C., Hatzimanolis, A., Scarmeas, N., and Papageorgiou, S. (2025). Blood-Based Biomarkers in Mild Behavioral Impairment: An Updated Overview. Front. Neurol., 16.","DOI":"10.3389\/fneur.2025.1534193"},{"key":"ref_64","doi-asserted-by":"crossref","first-page":"e70704","DOI":"10.1002\/alz.70704","article-title":"A Phase 2A\/B Randomized Trial of Metabolic Modulators Intranasal Insulin and Empagliflozin for MCI and Early AD","volume":"21","author":"Erichsen","year":"2025","journal-title":"Alzheimer\u2019s Dement."}],"container-title":["Journal of Clinical Medicine"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/2077-0383\/15\/5\/1884\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,3,2]],"date-time":"2026-03-02T10:52:43Z","timestamp":1772448763000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/2077-0383\/15\/5\/1884"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2026,3,1]]},"references-count":64,"journal-issue":{"issue":"5","published-online":{"date-parts":[[2026,3]]}},"alternative-id":["jcm15051884"],"URL":"https:\/\/doi.org\/10.3390\/jcm15051884","relation":{},"ISSN":["2077-0383"],"issn-type":[{"value":"2077-0383","type":"electronic"}],"subject":[],"published":{"date-parts":[[2026,3,1]]}}}