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Cerebrospinal fluid (CSF) proteins are promising candidates for reflecting brain pathology; however, their diagnostic utility may be compromised by natural variability between individuals, weakening their association with disease. Here, we measured the levels of 69 pre-selected proteins in cerebrospinal fluid using antibody-based suspension bead array technology in a multi-disease cohort of 499 individuals with neurodegenerative disorders including Alzheimer\u2019s disease (AD), behavioral variant frontotemporal dementia, primary progressive aphasias, amyotrophic lateral sclerosis (ALS), corticobasal syndrome, primary supranuclear palsy, along with healthy controls. We identify significant inter-individual variability in overall CSF levels of brain-derived proteins, which could not be attributed to specific disease associations. Using linear modelling, we show that adjusting for median CSF levels of brain-derived proteins increases the diagnostic accuracy of proteins previously identified as altered in CSF in the context of neurodegenerative disorders. We further demonstrate a simplified approach for the adjustment using pairs of correlated proteins with opposite alteration in the diseases. With this approach, the proteins adjust for each other and further increase the biomarker performance through additive effect. When comparing the diseases, two proteins\u2014neurofilament medium and myelin basic protein\u2014showed increased levels in ALS compared to other diseases, and neurogranin showed a specific increase in AD. Several other proteins showed similar trends across the studied diseases, indicating that these proteins likely reflect shared processes related to neurodegeneration. Overall, our findings suggest that accounting for inter-individual variability is crucial in future studies to improve the identification and performance of relevant biomarkers. Importantly, we highlight the need for multi-disease studies to identify disease-specific biomarkers.<\/jats:p>","DOI":"10.1038\/s41598-024-83281-y","type":"journal-article","created":{"date-parts":[[2025,1,3]],"date-time":"2025-01-03T06:40:55Z","timestamp":1735886455000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":16,"title":["Addressing inter individual variability in CSF levels of brain derived proteins across neurodegenerative diseases"],"prefix":"10.1038","volume":"15","author":[{"given":"S\u00e1ra","family":"Mravinacov\u00e1","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sofia","family":"Bergstr\u00f6m","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jennie","family":"Olofsson","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Nerea G\u00f3mez","family":"de San Jos\u00e9","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sarah","family":"Anderl-Straub","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Janine","family":"Diehl-Schmid","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Klaus","family":"Fassbender","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Klaus","family":"Fliessbach","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Holger","family":"Jahn","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Johannes","family":"Kornhuber","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"G. 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Kohlhammer GmbH medical publishers and is inventor in a patent \u201cOral Phenylbutyrate for Treatment of Human 4-Repeat Tauopathies\u201d (EP 23 156 122.6) filed by LMU Munich. In addition, he reports compensation for serving as chief medical officer for MODAG GmbH,is beneficiary of the phantom share program of MODAG GmbH and is inventor in a patent \u201cPharmaceutical Composition and Methods of Use\u201d (EP 22 159 408.8) filed by MODAG GmbH, all activities outside the submitted work. Jens Wiltfang has been an honorary speaker for Actelion, Amgen, Beeijing Yibai Science and Technology Ltd., Gloryren, Janssen Cilag, Med Update GmbH, Pfizer, Roche Pharma, and has been a member of the advisory boards of Abbott, Biogen, Boehringer Ingelheim, Lilly, MSD Sharp & Dohme, and Roche Pharma and receives fees as a consultant for Immungenetics, Noselab and Roboscreen and holds the following patents: PCT\/EP 2011 001724 and PCT\/EP 2015 052945.","order":2,"name":"Ethics","group":{"name":"EthicsHeading","label":"Competing interests"}}],"article-number":"668"}}