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individuals with abnormal tau and\/or neurodegeneration markers but normal amyloid levels. SNAP is common in individuals with normal cognition (NC), but its underlying pathophysiology is understudied, while being relevant for clinical trial design and treatment approaches. We aimed to investigate the pathophysiology of individuals with NC who are amyloid-negative and tau-positive (SNAP) through cerebrospinal fluid (CSF) proteomics. Two hundred and ninety-one individuals with NC were classified based on CSF amyloid \u03b21-42 and phosphorylated tau 181, as amyloid-negative\/tau-negative (controls), amyloid-negative\/tau-positive (SNAP), amyloid-positive\/tau-negative and amyloid-positive\/tau-positive. We measured 3102 proteins in CSF using tandem mass tag proteomic analyses. We compared protein abundance between groups using analysis of covariance and identified enriched biological pathways using Gene Ontology. We also examined differences between groups in genetic risk for Alzheimer\u2019s disease, estimated using polygenic risk scores based on genome-wide association study data. SNAP individuals with NC showed mostly increased protein levels (n = 360) compared with controls, mainly associated with neuroplasticity, angiogenesis, and protein modification and degradation. The proteomic profile of SNAP was similar to that of amyloid-positive\/tau-positive individuals, while distinct from amyloid-positive\/tau-negative individuals, who showed mainly decreased proteins associated with neuroplasticity. Higher levels of amyloid \u03b21-40 and amyloid \u03b21-42 were observed in SNAP compared with the three other groups. Polygenic risk scores analyses showed no significant differences between SNAP, amyloid-positive\/tau-negative, and amyloid-positive\/tau-positive individuals, while SNAP showed some genetic differences from controls, which were driven by APOE. Individuals with NC and SNAP or amyloid-positive\/tau-positive status showed similar CSF proteomic profiles, while amyloid-positive\/tau-negative individuals showed a distinct CSF proteomic profile. This suggests that tau, rather than amyloid, might be the main driver of the proteomic profiles in SNAP and other amyloid\/tau subgroups. This may have implications for future proteomic studies and clinical trial design, as these findings highlight the importance of considering tau status in future studies.<\/jats:p>","DOI":"10.1093\/braincomms\/fcaf253","type":"journal-article","created":{"date-parts":[[2025,6,20]],"date-time":"2025-06-20T08:00:51Z","timestamp":1750406451000},"source":"Crossref","is-referenced-by-count":4,"title":["Cerebrospinal fluid proteomic profiling of cognitively unimpaired individuals with suspected non-Alzheimer's disease pathophysiology"],"prefix":"10.1093","volume":"7","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-8724-3010","authenticated-orcid":false,"given":"Aurore","family":"Delvenne","sequence":"first","affiliation":[{"name":"Department of Psychiatry and Neuropsychology, Alzheimer Centrum Limburg, School for Mental Health and Neuroscience, Maastricht University , Maastricht 6229 ER ,","place":["The Netherlands"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6193-6193","authenticated-orcid":false,"given":"Johan","family":"Gobom","sequence":"additional","affiliation":[{"name":"Clinical Neurochemistry Laboratory, Sahlgrenska University Hospital , Mo\u0308lndal 431 80 ,","place":["Sweden"]},{"name":"Department of Psychiatry and Neurochemistry, Institute of Neuroscience and Physiology, Sahlgrenska Academy at the University of Gothenburg , M\u00f6lndal 431 41 ,","place":["Sweden"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lianne M","family":"Reus","sequence":"additional","affiliation":[{"name":"Department of Neurology, Alzheimer Center Amsterdam, Amsterdam Neuroscience, Vrije Universiteit Amsterdam, Amsterdam UMC , Amsterdam 1081 HZ ,","place":["The Netherlands"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Valerija","family":"Dobricic","sequence":"additional","affiliation":[{"name":"L\u00fcbeck Interdisciplinary Platform for Genome Analytics, University of L\u00fcbeck , L\u00fcbeck 23562 ,","place":["Germany"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mara","family":"ten Kate","sequence":"additional","affiliation":[{"name":"Department of Neurology, Alzheimer Center Amsterdam, Amsterdam Neuroscience, Vrije Universiteit Amsterdam, Amsterdam UMC , Amsterdam 1081 HZ ,","place":["The Netherlands"]},{"name":"Department of Radiology and Nuclear Medicine, Amsterdam Neuroscience, Vrije Universiteit Amsterdam, Amsterdam UMC , Amsterdam 1081 BT ,","place":["The Netherlands"]}],"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 63110 ,","place":["USA"]},{"name":"Knight Alzheimer's Disease Research Center, Washington University School of Medicine , St. Louis, MO 63108 ,","place":["USA"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Inez","family":"Ramakers","sequence":"additional","affiliation":[{"name":"Department of Psychiatry and Neuropsychology, Alzheimer Centrum Limburg, School for Mental Health and Neuroscience, Maastricht University , Maastricht 6229 ER ,","place":["The Netherlands"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2612-1797","authenticated-orcid":false,"given":"Betty M","family":"Tijms","sequence":"additional","affiliation":[{"name":"Department of Neurology, Alzheimer Center Amsterdam, Amsterdam Neuroscience, Vrije Universiteit Amsterdam, Amsterdam UMC , Amsterdam 1081 HZ ,","place":["The Netherlands"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Rik","family":"Vandenberghe","sequence":"additional","affiliation":[{"name":"Neurology Service, University Hospitals Leuven , Leuven 3000 ,","place":["Belgium"]},{"name":"Department of Neurosciences, Laboratory for Cognitive Neurology, KU Leuven , Leuven 3000 ,","place":["Belgium"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jolien","family":"Schaeverbeke","sequence":"additional","affiliation":[{"name":"Neurology Service, University Hospitals Leuven , Leuven 3000 ,","place":["Belgium"]},{"name":"Department of Neurosciences, Laboratory for Cognitive Neurology, KU Leuven , Leuven 3000 ,","place":["Belgium"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Pablo","family":"Martinez-Lage","sequence":"additional","affiliation":[{"name":"Centre for Research and Memory Clinic, Fundacio\u0301n CITA-Alzhe\u0301imer Fundazioa , Donostia\u2014San Sebasti\u00e1n Gipuzkoa 20009 ,","place":["Spain"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mikel","family":"Tainta","sequence":"additional","affiliation":[{"name":"Centre for Research and Memory Clinic, Fundacio\u0301n CITA-Alzhe\u0301imer Fundazioa , Donostia\u2014San Sebasti\u00e1n Gipuzkoa 20009 ,","place":["Spain"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4061-0837","authenticated-orcid":false,"given":"Charlotte E","family":"Teunissen","sequence":"additional","affiliation":[{"name":"Department of Clinical Chemistry, Neurochemistry Laboratory, Amsterdam University Medical Centers (AUMC), Amsterdam Neuroscience , Amsterdam 1081 HV ,","place":["Netherlands"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Julius","family":"Popp","sequence":"additional","affiliation":[{"name":"Old Age Psychiatry, University Hospital Lausanne , Lausanne 1005 ,","place":["Switzerland"]},{"name":"Department of Psychiatry, Psychotherapy and Psychosomatics, Psychiatry University Hospital Z\u00fcrich , Z\u00fcrich 8008 ,","place":["Switzerland"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Gwendoline","family":"Peyratout","sequence":"additional","affiliation":[{"name":"Old Age Psychiatry, University Hospital Lausanne , Lausanne 1005 ,","place":["Switzerland"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Magda","family":"Tsolaki","sequence":"additional","affiliation":[{"name":"1st Department of Neurology, AHEPA University Hospital, Medical School, Faculty of Health Sciences, Aristotle University of Thessaloniki , Thessaloniki 546 36 ,","place":["Greece"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yvonne","family":"Freund-Levi","sequence":"additional","affiliation":[{"name":"Department of Neurobiology, Caring Sciences and Society (NVS), Division of Clinical Geriatrics, Karolinska Institutet , Stockholm 141 57 ,","place":["Sweden"]},{"name":"Department of Psychiatry in Region \u00d6rebro County and School of Medical Sciences, Faculty of Medicine and Health, \u00d6rebro University , \u00d6rebro 703 62 ,","place":["Sweden"]},{"name":"Department of Old Age Psychiatry, Psychology and Neuroscience, King's College , London SE5 8AB ,","place":["United Kingdom"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Simon","family":"Lovestone","sequence":"additional","affiliation":[{"name":"Department of Psychiatry, University of Oxford , Oxford OX1 2JD ,","place":["United Kingdom"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Johannes","family":"Streffer","sequence":"additional","affiliation":[{"name":"Department of Biomedical Sciences, Reference Center for Biological Markers of Dementia (BIODEM), University of Antwerp , Antwerp 2610 ,","place":["Belgium"]},{"name":"H. Lundbeck A\/S , Valby 2500 ,","place":["Denmark"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Frederik","family":"Barkhof","sequence":"additional","affiliation":[{"name":"Department of Radiology and Nuclear Medicine, Amsterdam Neuroscience, Vrije Universiteit Amsterdam, Amsterdam UMC , Amsterdam 1081 BT ,","place":["The Netherlands"]},{"name":"Queen Square Institute of Neurology and Centre for Medical Image Computing, University College London , London WC1N 3BG ,","place":["United Kingdom"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0108-124X","authenticated-orcid":false,"given":"Lars","family":"Bertram","sequence":"additional","affiliation":[{"name":"L\u00fcbeck Interdisciplinary Platform for Genome Analytics, University of L\u00fcbeck , L\u00fcbeck 23562 ,","place":["Germany"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kaj","family":"Blennow","sequence":"additional","affiliation":[{"name":"Clinical Neurochemistry Laboratory, Sahlgrenska University Hospital , Mo\u0308lndal 431 80 ,","place":["Sweden"]},{"name":"Department of Psychiatry and Neurochemistry, Institute of Neuroscience and Physiology, Sahlgrenska Academy at the University of Gothenburg , M\u00f6lndal 431 41 ,","place":["Sweden"]},{"name":"Paris Brain Institute, ICM, Piti\u00e9-Salp\u00eatri\u00e8re Hospital, Sorbonne University , Paris 75013 ,","place":["France"]},{"name":"Division of Life Sciences and Medicine, and Department of Neurology, Neurodegenerative Disorder Research Center, Institute on Aging and Brain Disorders, University of Science and Technology of China and First Affiliated Hospital of USTC , Hefei, Anhui 230026 ,","place":["PR China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3930-4354","authenticated-orcid":false,"given":"Henrik","family":"Zetterberg","sequence":"additional","affiliation":[{"name":"Clinical Neurochemistry Laboratory, Sahlgrenska University Hospital , Mo\u0308lndal 431 80 ,","place":["Sweden"]},{"name":"Department of Psychiatry and Neurochemistry, Institute of Neuroscience and Physiology, Sahlgrenska Academy at the University of Gothenburg , M\u00f6lndal 431 41 ,","place":["Sweden"]},{"name":"Department of Neurodegenerative Disease, UCL Institute of Neurology , London WC1N 3BG ,","place":["United Kingdom"]},{"name":"Fluid Biomarker Laboratory, UK Dementia Research Institute at UCL , London W1T 7NF ,","place":["United Kingdom"]},{"name":"Hong Kong Center for Neurodegenerative Diseases , Clear Water Bay, Hong Kong ,","place":["China"]},{"name":"Wisconsin Alzheimer\u2019s Disease Research Center, University of Wisconsin School of Medicine and Public Health, University of Wisconsin-Madison , Madison, WI 53792 ,","place":["USA"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Pieter Jelle","family":"Visser","sequence":"additional","affiliation":[{"name":"Department of Psychiatry and Neuropsychology, Alzheimer Centrum Limburg, School for Mental Health and Neuroscience, Maastricht University , Maastricht 6229 ER ,","place":["The Netherlands"]},{"name":"Department of Neurology, Alzheimer Center Amsterdam, Amsterdam Neuroscience, Vrije Universiteit Amsterdam, Amsterdam UMC , Amsterdam 1081 HZ ,","place":["The Netherlands"]},{"name":"Division of Neurogeriatrics, Department of Neurobiology, Care Sciences and Society, Karolinska Institutet , Stockholm 141 57 ,","place":["Sweden"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Stephanie J B","family":"Vos","sequence":"additional","affiliation":[{"name":"Department of Psychiatry and Neuropsychology, Alzheimer Centrum Limburg, School for Mental Health and Neuroscience, Maastricht University , Maastricht 6229 ER ,","place":["The Netherlands"]}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"286","published-online":{"date-parts":[[2025,6,20]]},"reference":[{"issue":"6","key":"2025082607521799400_fcaf253-B1","doi-asserted-by":"crossref","first-page":"765","DOI":"10.1002\/ana.22628","article-title":"An operational approach to National Institute on Aging-Alzheimer's Association criteria for preclinical Alzheimer disease","volume":"71","author":"Jack","year":"2012","journal-title":"Ann Neurol"},{"issue":"2","key":"2025082607521799400_fcaf253-B2","doi-asserted-by":"crossref","first-page":"117","DOI":"10.1038\/nrneurol.2015.251","article-title":"Suspected non-Alzheimer disease pathophysiology\u2013concept and controversy","volume":"12","author":"Jack","year":"2016","journal-title":"Nat Rev 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dependent on \u03b2-amyloid in normal elderly","volume":"73","author":"Knopman","year":"2013","journal-title":"Ann Neurol"},{"issue":"1","key":"2025082607521799400_fcaf253-B9","doi-asserted-by":"crossref","first-page":"143","DOI":"10.1186\/s13195-020-00711-5","article-title":"Prediction of Alzheimer's disease biomarker status defined by the \u2018ATN framework\u2019 among cognitively healthy individuals: Results from the EPAD longitudinal cohort study","volume":"12","author":"Calvin","year":"2020","journal-title":"Alzheimers Res Ther"},{"issue":"9","key":"2025082607521799400_fcaf253-B10","doi-asserted-by":"crossref","first-page":"969","DOI":"10.1001\/jamaneurol.2023.2338","article-title":"Prevalence and clinical implications of a \u03b2-amyloid-negative, tau-positive cerebrospinal fluid biomarker profile in Alzheimer disease","volume":"80","author":"Erickson","year":"2023","journal-title":"JAMA 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