{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,4,11]],"date-time":"2026-04-11T02:17:10Z","timestamp":1775873830286,"version":"3.50.1"},"reference-count":39,"publisher":"Walter de Gruyter GmbH","issue":"1","license":[{"start":{"date-parts":[[2025,1,1]],"date-time":"2025-01-01T00:00:00Z","timestamp":1735689600000},"content-version":"unspecified","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"published-print":{"date-parts":[[2025,7,7]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                  <jats:p>Alzheimer\u2019s disease (AD) is characterized by amyloid-beta plaques and tau tangles in the brain, but these markers alone do not predict disease progression. The intersection of these pathologies with other processes including metabolic changes may contribute to disease progression. Brain glucose metabolism changes are among the earliest detectable events in AD. Pyruvate kinase (PKM) has been implicated as a potential biomarker to track these metabolic changes. We have developed an enzyme-linked immunosorbent assay (ELISA) to assess PKM levels in cerebrospinal fluid (CSF). First, we verified the relationship of CSF PKM levels with cognitive decline, revealing a correlation between elevated CSF PKM levels and accelerated cognitive decline in preclinical AD patients in a tau-dependent manner. We developed the ELISA using two PKM-specific antibodies and validated it through quality control steps, indicating robust quantification of PKM. We showed that ELISA measurements of PKM correlate with mass spectrometry values in matching samples. When tested on an independent cohort, the assay confirmed elevation of PKM in AD. These findings support the use of PKM as a potential biomarker for tracking early metabolic changes in AD, offering a novel tool for investigating metabolic alterations and their intersection with other underlying pathologies in AD progression.<\/jats:p>","DOI":"10.1515\/biol-2025-1101","type":"journal-article","created":{"date-parts":[[2025,7,8]],"date-time":"2025-07-08T11:40:10Z","timestamp":1751974810000},"source":"Crossref","is-referenced-by-count":3,"title":["Immunoassay for pyruvate kinase M1\/2 as an Alzheimer\u2019s biomarker in CSF"],"prefix":"10.1515","volume":"20","author":[{"given":"Matthijs B.","family":"de Geus","sequence":"first","affiliation":[{"name":"Massachusetts General Hospital & Harvard Medical School, Department of Neurology , Boston , MA , United States of America"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Pia","family":"Kivis\u00e4kk","sequence":"additional","affiliation":[{"name":"Massachusetts General Hospital & Harvard Medical School, Department of Neurology , Boston , MA , United States of America"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Bianca A.","family":"Trombetta","sequence":"additional","affiliation":[{"name":"Massachusetts General Hospital & Harvard Medical School, Department of Neurology , Boston , MA , United States of America"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Betty M.","family":"Tijms","sequence":"additional","affiliation":[{"name":"Alzheimer Center Amsterdam, Department of Neurology, Amsterdam Neuroscience, Vrije Universiteit Amsterdam, Amsterdam UMC , Amsterdam , The Netherlands"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Pieter Jelle","family":"Visser","sequence":"additional","affiliation":[{"name":"Alzheimer Center Amsterdam, Department of Neurology, Amsterdam Neuroscience, Vrije Universiteit Amsterdam, Amsterdam UMC , Amsterdam , The Netherlands"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Steven E.","family":"Arnold","sequence":"additional","affiliation":[{"name":"Massachusetts General Hospital & Harvard Medical School, Department of Neurology , Boston , MA , United States of America"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Becky C.","family":"Carlyle","sequence":"additional","affiliation":[{"name":"Department of Physiology, Anatomy & Genetics, University of Oxford , Oxford , United Kingdom"},{"name":"Kavli Institute for Nanoscience Discovery, University of Oxford , Oxford , United Kingdom"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"374","published-online":{"date-parts":[[2025,7,7]]},"reference":[{"key":"2025122123392374560_j_biol-2025-1101_ref_001","doi-asserted-by":"crossref","unstructured":"Duara R, Barker W. Heterogeneity in Alzheimer\u2019s disease diagnosis and progression rates: Implications for therapeutic trials. Neurotherapeutics. 2022 Jan;19(1):8\u201325.","DOI":"10.1007\/s13311-022-01185-z"},{"key":"2025122123392374560_j_biol-2025-1101_ref_002","doi-asserted-by":"crossref","unstructured":"Tijms BM, Vromen EM, Mjaavatten O, Holstege H, Reus LM, van der Lee S, et al. Cerebrospinal fluid proteomics in patients with Alzheimer\u2019s disease reveals five molecular subtypes with distinct genetic risk profiles. Nat Aging. 2024 Jan;4(1):33\u201347.","DOI":"10.1038\/s43587-023-00550-7"},{"key":"2025122123392374560_j_biol-2025-1101_ref_003","doi-asserted-by":"crossref","unstructured":"Jellinger KA. Recent update on the heterogeneity of the Alzheimer\u2019s disease spectrum. J Neural Transm. 2022 Jan;129(1):1\u201324.","DOI":"10.1007\/s00702-021-02449-2"},{"key":"2025122123392374560_j_biol-2025-1101_ref_004","unstructured":"Johnson ECB, Bian S, Haque RU, Carter EK, Watson CM, Gordon BA, et al. Cerebrospinal fluid proteomics define the natural history of autosomal dominant Alzheimer\u2019s disease. Nat Med. 2023 Aug;29(8):1979\u201388."},{"key":"2025122123392374560_j_biol-2025-1101_ref_005","doi-asserted-by":"crossref","unstructured":"Cummings J. Anti-amyloid monoclonal antibodies are transformative treatments that redefine Alzheimer\u2019s disease therapeutics. Drugs. 2023 May;83(7):569\u201376.","DOI":"10.1007\/s40265-023-01858-9"},{"key":"2025122123392374560_j_biol-2025-1101_ref_006","doi-asserted-by":"crossref","unstructured":"Kumar V, Kim SH, Bishayee K. Dysfunctional glucose metabolism in Alzheimer\u2019s disease onset and potential pharmacological interventions. Int J Mol Sci. 2022;23(17):9540. 10.3390\/ijms23179540.","DOI":"10.3390\/ijms23179540"},{"key":"2025122123392374560_j_biol-2025-1101_ref_007","doi-asserted-by":"crossref","unstructured":"Protas HD, Chen K, Langbaum JBS, Fleisher AS, Alexander GE, Lee W, et al. Posterior cingulate glucose metabolism, hippocampal glucose metabolism, and hippocampal volume in cognitively normal, late-middle-aged persons at 3 levels of genetic risk for Alzheimer disease. JAMA Neurol. 2013 Mar;70(3):320.","DOI":"10.1001\/2013.jamaneurol.286"},{"key":"2025122123392374560_j_biol-2025-1101_ref_008","doi-asserted-by":"crossref","unstructured":"Ou YN, Xu W, Li JQ, Guo Y, Cui M, Chen KL, et al. FDG-PET as an independent biomarker for Alzheimer\u2019s biological diagnosis: A longitudinal study. Alzheimers Res Ther. 2019 Jun;11(1):1\u201311. [cited 2023 Mar 29] https:\/\/alzres.biomedcentral.com\/articles\/10.1186\/s13195-019-0512-1.","DOI":"10.1186\/s13195-019-0512-1"},{"key":"2025122123392374560_j_biol-2025-1101_ref_009","doi-asserted-by":"crossref","unstructured":"van Gils V, Tao Q, Ang TFA, Young CB, Mormino EC, Qiu WQ, et al. Associations between glucose metabolism measures and amyloid-\u03b2 and tau load on PET 14 years later: Findings from the Framingham Heart Study. Diabetes Care. 2024 Oct;47(10):1787\u201393.","DOI":"10.2337\/dc24-0162"},{"key":"2025122123392374560_j_biol-2025-1101_ref_010","doi-asserted-by":"crossref","unstructured":"de Geus MB, Leslie SN, Lam TK, Wang W, Roux-Dalvai F, Droit A, et al. Mass spectrometry in cerebrospinal fluid uncovers association of glycolysis biomarkers with Alzheimer\u2019s disease in a large clinical sample. Sci Rep. 2023 Dec;13(1):1\u201314. [cited 2024 Apr 9] https:\/\/www.nature.com\/articles\/s41598-023-49440-3.","DOI":"10.1038\/s41598-023-49440-3"},{"key":"2025122123392374560_j_biol-2025-1101_ref_011","doi-asserted-by":"crossref","unstructured":"Panyard DJ, McKetney J, Deming YK, Morrow AR, Ennis GE, Jonaitis EM, et al. Large\u2010scale proteome and metabolome analysis of CSF implicates altered glucose and carbon metabolism and succinylcarnitine in Alzheimer\u2019s disease. Alzheimer\u2019s Dement. 2023;19(12):5447\u201370. 10.1002\/alz.13130.","DOI":"10.1002\/alz.13130"},{"key":"2025122123392374560_j_biol-2025-1101_ref_012","unstructured":"Johnson ECB, Dammer EB, Duong DM, Ping L, Zhou M, Yin L, et al. Large-scale proteomic analysis of Alzheimer\u2019s disease brain and cerebrospinal fluid reveals early changes in energy metabolism associated with microglia and astrocyte activation. Nat Med. 2020 Apr;26(5):769\u201380. [cited 2023 Jan 29] https:\/\/www-nature-com.ezp-prod1.hul.harvard.edu\/articles\/s41591-020-0815-6."},{"key":"2025122123392374560_j_biol-2025-1101_ref_013","doi-asserted-by":"crossref","unstructured":"Sathe G, Na CH, Renuse S, Madugundu AK, Albert M, Moghekar A, et al. Quantitative proteomic profiling of cerebrospinal fluid to identify candidate biomarkers for Alzheimer\u2019s disease. Proteom Clin Appl. 2019;13(4):e1800105. 10.1002\/prca.201800105.","DOI":"10.1002\/prca.201800105"},{"key":"2025122123392374560_j_biol-2025-1101_ref_014","doi-asserted-by":"crossref","unstructured":"Pichet Binette A, Gaiteri C, Wennstr\u00f6m M, Kumar A, Hristovska I, Spotorno N, et al. Proteomic changes in Alzheimer\u2019s disease associated with progressive A\u03b2 plaque and tau tangle pathologies. Nat Neurosci. 2024 Oct;27(10):1880\u201391.","DOI":"10.1038\/s41593-024-01737-w"},{"key":"2025122123392374560_j_biol-2025-1101_ref_015","doi-asserted-by":"crossref","unstructured":"Yang W, Lu Z. Pyruvate kinase M2 at a glance. J Cell Sci. 2015 May;128(9):1655\u201360.","DOI":"10.1242\/jcs.166629"},{"key":"2025122123392374560_j_biol-2025-1101_ref_016","doi-asserted-by":"crossref","unstructured":"Higginbotham L, Ping L, Dammer EB, Duong DM, Zhou M, Gearing M, et al. Integrated proteomics reveals brain-based cerebrospinal fluid biomarkers in asymptomatic and symptomatic Alzheimer\u2019s disease. Sci Adv. 2020;6(43):eaaz9360. 10.1126\/sciadv.aaz9360.","DOI":"10.1126\/sciadv.aaz9360"},{"key":"2025122123392374560_j_biol-2025-1101_ref_017","doi-asserted-by":"crossref","unstructured":"Mathys H, Boix CA, Akay LA, Xia Z, Davila-Velderrain J, Ng AP, et al. Single-cell multiregion dissection of Alzheimer\u2019s disease. Nature. 2024 Aug;632(8026):858\u201368.","DOI":"10.1038\/s41586-024-07606-7"},{"key":"2025122123392374560_j_biol-2025-1101_ref_018","doi-asserted-by":"crossref","unstructured":"Carlyle BC, Kandigian SE, Kreuzer J, Das S, Trombetta BA, Kuo Y, et al. Synaptic proteins associated with cognitive performance and neuropathology in older humans revealed by multiplexed fractionated proteomics. Neurobiol Aging. 2021 Sep;105:99\u2013114.","DOI":"10.1016\/j.neurobiolaging.2021.04.012"},{"key":"2025122123392374560_j_biol-2025-1101_ref_019","doi-asserted-by":"crossref","unstructured":"Traxler L, Herdy JR, Stefanoni D, Eichhorner S, Pelucchi S, Sz\u00fccs A, et al. Warburg-like metabolic transformation underlies neuronal degeneration in sporadic Alzheimer\u2019s disease. Cell Metab. 2022 Sep;34(9):1248\u201363.e6.","DOI":"10.1016\/j.cmet.2022.07.014"},{"key":"2025122123392374560_j_biol-2025-1101_ref_020","doi-asserted-by":"crossref","unstructured":"Waury K, de Wit R, Verberk IMW, Teunissen CE, Abeln S. Deciphering protein secretion from the brain to cerebrospinal fluid for biomarker discovery. J Proteome Res. 2023 Sep;22(9):3068\u201380.","DOI":"10.1021\/acs.jproteome.3c00366"},{"key":"2025122123392374560_j_biol-2025-1101_ref_021","doi-asserted-by":"crossref","unstructured":"Tariciotti L, Casadei M, Honig LS, Teich AF, McKhann Ii GM, Tosto G, et al. Clinical experience with cerebrospinal fluid A\u03b242, total and phosphorylated tau in the evaluation of 1,016 individuals for suspected dementia. J Alzheimers Dis. 2018;65(4):1417\u201325.","DOI":"10.3233\/JAD-180548"},{"key":"2025122123392374560_j_biol-2025-1101_ref_022","doi-asserted-by":"crossref","unstructured":"Chapman KR, Bing-Canar H, Alosco ML, Steinberg EG, Martin B, Chaisson C, et al. Mini mental state examination and logical memory scores for entry into Alzheimer\u2019s disease trials. Alzheimers Res Ther. 2016 Dec;8(1):9.","DOI":"10.1186\/s13195-016-0176-z"},{"key":"2025122123392374560_j_biol-2025-1101_ref_023","doi-asserted-by":"crossref","unstructured":"Est\u00e9vez\u2010Gonz\u00e1lez A, Kulisevsky J, Boltes A, Oterm\u00edn P, Garc\u00eda\u2010S\u00e1nchez C. Rey verbal learning test is a useful tool for differential diagnosis in the preclinical phase of Alzheimer\u2019s disease: comparison with mild cognitive impairment and normal aging. Int J Geriatr Psychiatry. 2003 Nov;18(11):1021\u20138.","DOI":"10.1002\/gps.1010"},{"key":"2025122123392374560_j_biol-2025-1101_ref_024","doi-asserted-by":"crossref","unstructured":"Vlassenko AG, Raichle ME. Brain aerobic glycolysis functions and Alzheimer\u2019s disease. Clin Transl Imaging. 2015 Feb;3(1):27\u201337.","DOI":"10.1007\/s40336-014-0094-7"},{"key":"2025122123392374560_j_biol-2025-1101_ref_025","doi-asserted-by":"crossref","unstructured":"Adams JN, Lockhart SN, Li L, Jagust WJ. Relationships between Tau and glucose metabolism reflect Alzheimer\u2019s disease pathology in cognitively normal older adults. Cereb Cortex. 2019 May;29(5):1997\u20132009.","DOI":"10.1093\/cercor\/bhy078"},{"key":"2025122123392374560_j_biol-2025-1101_ref_026","doi-asserted-by":"crossref","unstructured":"Hardy J. The relationship between Amyloid and Tau. J Mol Neurosci. 2003;20(2):203\u20136.","DOI":"10.1385\/JMN:20:2:203"},{"key":"2025122123392374560_j_biol-2025-1101_ref_027","doi-asserted-by":"crossref","unstructured":"Visser PJ, Reus LM, Gobom J, Jansen I, Dicks E, van der Lee SJ, et al. Cerebrospinal fluid tau levels are associated with abnormal neuronal plasticity markers in Alzheimer\u2019s disease. Mol Neurodegener. 2022 Mar;17(1):27.","DOI":"10.1186\/s13024-022-00540-0"},{"key":"2025122123392374560_j_biol-2025-1101_ref_028","doi-asserted-by":"crossref","unstructured":"Mathys H, Peng Z, Boix CA, Victor MB, Leary N, Babu S, et al. Single-cell atlas reveals correlates of high cognitive function, dementia, and resilience to Alzheimer\u2019s disease pathology. Cell. 2023 Sep;186(20):4365\u201385.e27.","DOI":"10.1016\/j.cell.2023.08.039"},{"key":"2025122123392374560_j_biol-2025-1101_ref_029","doi-asserted-by":"crossref","unstructured":"Targa Dias Anastacio H, Matosin N, Ooi L. Neuronal hyperexcitability in Alzheimer\u2019s disease: What are the drivers behind this aberrant phenotype? Transl Psychiatry. 2022 Jun;12(1):257.","DOI":"10.1038\/s41398-022-02024-7"},{"key":"2025122123392374560_j_biol-2025-1101_ref_030","doi-asserted-by":"crossref","unstructured":"Brown J, Camporesi E, Lantero-Rodriguez J, Olsson M, Wang A, Medem B, et al. Tau in cerebrospinal fluid induces neuronal hyperexcitability and alters hippocampal theta oscillations. Acta Neuropathol Commun. 2023 Apr;11(1):67.","DOI":"10.1186\/s40478-023-01562-5"},{"key":"2025122123392374560_j_biol-2025-1101_ref_031","doi-asserted-by":"crossref","unstructured":"Busche MA. Tau suppresses neuronal activity in vivo, even before tangles form. Brain. 2019 Apr;142(4):843\u20136.","DOI":"10.1093\/brain\/awz060"},{"key":"2025122123392374560_j_biol-2025-1101_ref_032","doi-asserted-by":"crossref","unstructured":"van Nifterick AM, Gouw AA, van Kesteren RE, Scheltens P, Stam CJ, de Haan W. A multiscale brain network model links Alzheimer\u2019s disease-mediated neuronal hyperactivity to large-scale oscillatory slowing. Alzheimers Res Ther. 2022 Dec;14(1):101.","DOI":"10.1186\/s13195-022-01041-4"},{"key":"2025122123392374560_j_biol-2025-1101_ref_033","doi-asserted-by":"crossref","unstructured":"Rodr\u00edguez-Giraldo M, Gonz\u00e1lez-Reyes RE, Ram\u00edrez-Guerrero S, Bonilla-Trilleras CE, Guardo-Maya S, Nava-Mesa MO. Astrocytes as a therapeutic target in Alzheimer\u2019s disease\u2013Comprehensive review and recent developments. Int J Mol Sci. 2022 Nov;23(21):13630.","DOI":"10.3390\/ijms232113630"},{"key":"2025122123392374560_j_biol-2025-1101_ref_034","doi-asserted-by":"crossref","unstructured":"Lepiarz-Raba I, Gbadamosi I, Florea R, Paolicelli RC, Jawaid A. Metabolic regulation of microglial phagocytosis: Implications for Alzheimer\u2019s disease therapeutics. Transl Neurodegener. 2023 Oct;12(1):48.","DOI":"10.1186\/s40035-023-00382-w"},{"key":"2025122123392374560_j_biol-2025-1101_ref_035","doi-asserted-by":"crossref","unstructured":"Preman P, Alfonso-Triguero M, Alberdi E, Verkhratsky A, Arranz AM. Astrocytes in Alzheimer\u2019s disease: Pathological significance and molecular pathways. Cells. 2021 Mar;10(3):540.","DOI":"10.3390\/cells10030540"},{"key":"2025122123392374560_j_biol-2025-1101_ref_036","doi-asserted-by":"crossref","unstructured":"Christofk HR, Vander Heiden MG, Harris MH, Ramanathan A, Gerszten RE, Wei R, et al. The M2 splice isoform of pyruvate kinase is important for cancer metabolism and tumour growth. Nature. 2008 Mar;452(7184):230\u20133.","DOI":"10.1038\/nature06734"},{"key":"2025122123392374560_j_biol-2025-1101_ref_037","doi-asserted-by":"crossref","unstructured":"Li X, Zhou R, Peng H, Peng J, Li Q, Mei M. Microglia PKM2 mediates neuroinflammation and neuron loss in mice epilepsy through the astrocyte C3-neuron C3R signaling pathway. Brain Sci. 2023 Feb;13(2):262.","DOI":"10.3390\/brainsci13020262"},{"key":"2025122123392374560_j_biol-2025-1101_ref_038","doi-asserted-by":"crossref","unstructured":"Kang BS, Choi BY, Kho AR, Lee SH, Hong DK, Park MK, et al. Effects of pyruvate kinase M2 (PKM2) gene deletion on astrocyte-specific glycolysis and global cerebral ischemia-induced neuronal death. Antioxidants. 2023 Feb;12(2):491.","DOI":"10.3390\/antiox12020491"},{"key":"2025122123392374560_j_biol-2025-1101_ref_039","doi-asserted-by":"crossref","unstructured":"Zhan C, Yan L, Wang L, Ma J, Jiang W, Zhang Y, et al. Isoform switch of pyruvate kinase M1 indeed occurs but not to pyruvate kinase M2 in human tumorigenesis. PLoS One. 2015 Mar;10(3):e0118663.","DOI":"10.1371\/journal.pone.0118663"}],"container-title":["Open Life Sciences"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.degruyterbrill.com\/document\/doi\/10.1515\/biol-2025-1101\/xml","content-type":"application\/xml","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/www.degruyterbrill.com\/document\/doi\/10.1515\/biol-2025-1101\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,12,21]],"date-time":"2025-12-21T23:40:48Z","timestamp":1766360448000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.degruyterbrill.com\/document\/doi\/10.1515\/biol-2025-1101\/html"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2025,1,1]]},"references-count":39,"journal-issue":{"issue":"1","published-online":{"date-parts":[[2025,3,6]]},"published-print":{"date-parts":[[2025,3,6]]}},"alternative-id":["10.1515\/biol-2025-1101"],"URL":"https:\/\/doi.org\/10.1515\/biol-2025-1101","relation":{},"ISSN":["2391-5412"],"issn-type":[{"value":"2391-5412","type":"electronic"}],"subject":[],"published":{"date-parts":[[2025,1,1]]},"article-number":"20251101"}}