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However, non-AD-related interindividual variation in biofluids can also affect biomarker concentrations. Here, we investigated whether normalization of CSF and plasma biomarkers to reference proteins, such as amyloid-\u03b240 (A\u03b240) and non-phosphorylated mid-region tau (np-tau), improves their robustness and reliability of representing AD pathology load.<\/jats:p>\n                  <jats:p>Using the Swedish BioFINDER-2 cohort [n = 1702, 50.7% male, mean (standard deviation) age 68.4 (12.2) years], we compared the associations between tau\/A\u03b2-PET load and fluid biomarkers alone versus biomarkers in a ratio with a reference protein (A\u03b240 or np-tau) in univariate linear regression models. Fluid biomarkers included CSF and plasma measures of p-tau217, p-tau181, p-tau205, np-tau181-190, np-tau195\u2013210, np-tau212\u2013221, A\u03b242 and A\u03b240; CSF MTBR-tau243, SNAP-25, neurogranin, YKL-40 and sTREM2; and plasma eMTBR-tau243. Biomarkers were measured with mass spectrometry assays and\/or immunoassays. In addition, we performed validation and extended analyses, comparing, for example, group-level diagnostic differences and longitudinal biomarker trajectories, in three independent prospective cohorts [BioFINDER-1, Knight Alzheimer Disease Research Center (ADRC) and Translational Biomarkers in Aging and Dementia (TRIAD)] and in an Italian multiple sclerosis cohort.<\/jats:p>\n                  <jats:p>CSF A\u03b240 normalization significantly strengthened the associations of several core CSF AD biomarkers, including CSF MTBR-tau243, p-tau isoforms and synaptic biomarkers, with tau-PET (\u0394R2 = 0.064\u20130.24) and A\u03b2-PET (\u0394R2 = 0.016\u20130.28). Normalization to CSF np-tau mainly improved concordance with A\u03b2-PET (\u0394R2 = \u22120.0059 to 0.19). The strongest association with tau-PET was observed for MTBR-tau243\/A\u03b240 (R2 = 0.78, compared with 0.65 for non-normalized MTBR-tau243), and with A\u03b2-PET for p-tau217\/np-tau (R2 = 0.65, compared with 0.46 for non-normalized p-tau217). Plasma biomarker associations with tau-PET improved when using normalization to plasma A\u03b240 or np-tau (\u0394R2 = 0.004\u20130.14), with the strongest effect for eMTBR-tau243\/np-tau (R2 = 0.72 versus 0.60). Associations with A\u03b2-PET were enhanced with np-tau normalization (\u0394R2 = 0.018\u20130.16, strongest for p-tau217\/np-tau: R2 = 0.62 versus 0.53). The results were replicated in Knight ADRC and TRIAD. Furthermore, longitudinal analyses showed that A\u03b240 normalization typically reduced interindividual rather than intra-individual variability over time. Normalization did not enhance group-level differences in inflammatory CSF biomarkers in AD, nor did it improve biomarker associations in the multiple sclerosis cohort.<\/jats:p>\n                  <jats:p>In conclusion, normalization of CSF and plasma biomarkers to reference proteins, such as A\u03b240 or np-tau, enhances their association with brain tau and A\u03b2 pathology, making already high-performing AD fluid biomarkers even more accurate.<\/jats:p>","DOI":"10.1093\/brain\/awaf375","type":"journal-article","created":{"date-parts":[[2025,10,3]],"date-time":"2025-10-03T11:55:03Z","timestamp":1759492503000},"page":"1153-1167","source":"Crossref","is-referenced-by-count":3,"title":["Reference proteins to improve Core 1 and Core 2 Alzheimer\u2019s disease CSF and plasma biomarkers"],"prefix":"10.1093","volume":"149","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-0630-772X","authenticated-orcid":false,"given":"Linda","family":"Karlsson","sequence":"first","affiliation":[{"name":"Clinical Memory Research Unit, Department of Clinical Sciences in Malm\u00f6, Lund University , Lund SE-22184 ,","place":["Sweden"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Shorena","family":"Janelidze","sequence":"additional","affiliation":[{"name":"Clinical Memory Research Unit, Department of Clinical Sciences in Malm\u00f6, Lund University , Lund SE-22184 ,","place":["Sweden"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Nicolas R","family":"Barth\u00e9lemy","sequence":"additional","affiliation":[{"name":"Department of Neurology, Washington University School of Medicine , St. Louis, MO 63108 ,","place":["USA"]},{"name":"The Tracy Family SILQ Center, Washington University School of Medicine , St. Louis, MO 63108 ,","place":["USA"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7736-2614","authenticated-orcid":false,"given":"Kanta","family":"Horie","sequence":"additional","affiliation":[{"name":"Department of Neurology, Washington University School of Medicine , St. Louis, MO 63108 ,","place":["USA"]},{"name":"The Tracy Family SILQ Center, Washington University School of Medicine , St. Louis, MO 63108 ,","place":["USA"]},{"name":"Eisai Inc. , Nutley, NJ 07110 ,","place":["USA"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7826-4781","authenticated-orcid":false,"given":"Joseph","family":"Therriault","sequence":"additional","affiliation":[{"name":"Translational Neuroimaging Laboratory, McGill University Research Centre for Studies in Aging, McConnell Brain Imaging Centre (BIC), Montreal Neurological Institute, Montreal Neurological Institute-Hospital , Montreal, Quebec H4H 1R3 ,","place":["Canada"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lorenzo","family":"Gaetani","sequence":"additional","affiliation":[{"name":"Section of Neurology, Department of Medicine and Surgery, University of Perugia , Perugia 06132 ,","place":["Italy"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Giovanni","family":"Bellomo","sequence":"additional","affiliation":[{"name":"Section of Neurology, Department of Medicine and Surgery, University of Perugia , Perugia 06132 ,","place":["Italy"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Suzanne E","family":"Schindler","sequence":"additional","affiliation":[{"name":"Department of Neurology, Washington University School of Medicine , St. Louis, MO 63108 ,","place":["USA"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jacob","family":"Vogel","sequence":"additional","affiliation":[{"name":"Department of Clinical Sciences, SciLifeLab, Lund University , Lund SE-22184 ,","place":["Sweden"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ida","family":"Arvidsson","sequence":"additional","affiliation":[{"name":"Centre for Mathematical Sciences, Lund University , Lund SE-22362 ,","place":["Sweden"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kalle","family":"\u00c5str\u00f6m","sequence":"additional","affiliation":[{"name":"Centre for Mathematical Sciences, Lund University , Lund SE-22362 ,","place":["Sweden"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2109-2955","authenticated-orcid":false,"given":"Brian A","family":"Gordon","sequence":"additional","affiliation":[{"name":"Department of Radiology, Washington University School of Medicine , St. Louis, MO 63130 ,","place":["USA"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Cyrus A","family":"Raji","sequence":"additional","affiliation":[{"name":"Department of Radiology, Washington University School of Medicine , St. Louis, MO 63130 ,","place":["USA"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tammie L S","family":"Benzinger","sequence":"additional","affiliation":[{"name":"Department of Radiology, Washington University School of Medicine , St. Louis, MO 63130 ,","place":["USA"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2967-9662","authenticated-orcid":false,"given":"John C","family":"Morris","sequence":"additional","affiliation":[{"name":"Department of Neurology, Washington University School of Medicine , St. Louis, MO 63108 ,","place":["USA"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2856-6060","authenticated-orcid":false,"given":"Johanna","family":"Nilsson","sequence":"additional","affiliation":[{"name":"Department of Psychiatry and Neurochemistry, Institute of Neuroscience and Physiology, the Sahlgrenska Academy, University of Gothenburg , M\u00f6lndal SE-43180 ,","place":["Sweden"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ann","family":"Brinkmalm","sequence":"additional","affiliation":[{"name":"Department of Psychiatry and Neurochemistry, Institute of Neuroscience and Physiology, the Sahlgrenska Academy, University of Gothenburg , M\u00f6lndal SE-43180 ,","place":["Sweden"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9267-1930","authenticated-orcid":false,"given":"Sebastian","family":"Palmqvist","sequence":"additional","affiliation":[{"name":"Clinical Memory Research Unit, Department of Clinical Sciences in Malm\u00f6, Lund University , Lund SE-22184 ,","place":["Sweden"]},{"name":"Memory Clinic, Sk\u00e5ne University Hospital , Malm\u00f6 SE-20502 ,","place":["Sweden"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Erik","family":"Stomrud","sequence":"additional","affiliation":[{"name":"Clinical Memory Research Unit, Department of Clinical Sciences in Malm\u00f6, Lund University , Lund SE-22184 ,","place":["Sweden"]},{"name":"Memory Clinic, Sk\u00e5ne University Hospital , Malm\u00f6 SE-20502 ,","place":["Sweden"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5210-9230","authenticated-orcid":false,"given":"Gemma","family":"Salvad\u00f3","sequence":"additional","affiliation":[{"name":"Clinical Memory Research Unit, Department of Clinical Sciences in Malm\u00f6, Lund University , Lund SE-22184 ,","place":["Sweden"]},{"name":"Barcelona\u03b2eta Brain Research Center (BBRC), Pasqual Maragall Foundation , Barcelona 08005 ,","place":["Spain"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Alexa","family":"Pichet Binette","sequence":"additional","affiliation":[{"name":"Clinical Memory Research Unit, Department of Clinical Sciences in Malm\u00f6, Lund University , Lund SE-22184 ,","place":["Sweden"]},{"name":"Department of Physiology and Pharmacology, Universit\u00e9 de Montr\u00e9al , Montr\u00e9al, Quebec H3T 1J4 ,","place":["Canada"]},{"name":"Centre de Recherche de L\u2019Institut Universitaire de G\u00e9riatrie de Montr\u00e9al , Montr\u00e9al, Quebec H3W 1W5 ,","place":["Canada"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2645-7477","authenticated-orcid":false,"given":"Massimiliano","family":"Di Filippo","sequence":"additional","affiliation":[{"name":"Section of Neurology, Department of Medicine and Surgery, University of Perugia , Perugia 06132 ,","place":["Italy"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lucilla","family":"Parnetti","sequence":"additional","affiliation":[{"name":"Section of Neurology, Department of Medicine and Surgery, University of Perugia , Perugia 06132 ,","place":["Italy"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9116-1376","authenticated-orcid":false,"given":"Pedro","family":"Rosa-Neto","sequence":"additional","affiliation":[{"name":"Translational Neuroimaging Laboratory, McGill University Research Centre for Studies in Aging, McConnell Brain Imaging Centre (BIC), Montreal Neurological Institute, Montreal Neurological Institute-Hospital , Montreal, Quebec H4H 1R3 ,","place":["Canada"]},{"name":"Douglas Hospital Research Centre\u2014Centre Int\u00e9gr\u00e9 Universitaire de Sant\u00e9 et Services Sociaux de L\u2019Ouest-de-L\u2019\u00cele-de-Montr\u00e9al , Verdun, Quebec H4H 1R3 ,","place":["Canada"]},{"name":"The Peter O\u2019Donnell Jr. Brain Institute (OBI), University of Texas Southwestern Medical Centre (UTSW) , Dallas, 75235 TX ,","place":["USA"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kaj","family":"Blennow","sequence":"additional","affiliation":[{"name":"Department of Psychiatry and Neurochemistry, Institute of Neuroscience and Physiology, the Sahlgrenska Academy, University of Gothenburg , M\u00f6lndal SE-43180 ,","place":["Sweden"]},{"name":"Clinical Neurochemistry Laboratory, Sahlgrenska University Hospital , M\u00f6lndal SE-43180 ,","place":["Sweden"]},{"name":"Paris Brain Institute, ICM, Piti\u00e9-Salp\u00eatri\u00e8re Hospital, Sorbonne University , Paris 75013 ,","place":["France"]},{"name":"Neurodegenerative Disorder Research Center, Division of Life Sciences and Medicine, and Department of Neurology, Institute on Aging and Brain Disorders, University of Science and Technology of China and First Affiliated Hospital of USTC , Hefei 230026 ,","place":["P.R. China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7729-1702","authenticated-orcid":false,"given":"Randall J","family":"Bateman","sequence":"additional","affiliation":[{"name":"Department of Neurology, Washington University School of Medicine , St. Louis, MO 63108 ,","place":["USA"]},{"name":"The Tracy Family SILQ Center, Washington University School of Medicine , St. Louis, MO 63108 ,","place":["USA"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8885-7724","authenticated-orcid":false,"given":"Niklas","family":"Mattsson-Carlgren","sequence":"additional","affiliation":[{"name":"Clinical Memory Research Unit, Department of Clinical Sciences in Malm\u00f6, Lund University , Lund SE-22184 ,","place":["Sweden"]},{"name":"Memory Clinic, Sk\u00e5ne University Hospital , Malm\u00f6 SE-20502 ,","place":["Sweden"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8467-7286","authenticated-orcid":false,"given":"Oskar","family":"Hansson","sequence":"additional","affiliation":[{"name":"Clinical Memory Research Unit, Department of Clinical Sciences in Malm\u00f6, Lund University , Lund SE-22184 ,","place":["Sweden"]}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"286","published-online":{"date-parts":[[2025,10,6]]},"reference":[{"key":"2026040804043738700_awaf375-B1","doi-asserted-by":"crossref","first-page":"954","DOI":"10.1038\/s41591-021-01382-x","article-title":"Biomarkers for neurodegenerative diseases","volume":"27","author":"Hansson","year":"2021","journal-title":"Nat Med"},{"key":"2026040804043738700_awaf375-B2","doi-asserted-by":"crossref","first-page":"726","DOI":"10.1016\/S1474-4422(22)00168-5","article-title":"Tau biomarkers in Alzheimer\u2019s disease: Towards implementation in clinical practice and 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