Cerebrospinal fluid proteomic profiling of cognitively unimpaired individuals with suspected non-Alzheimer's disease pathophysiology

Suspected non-Alzheimer's disease pathophysiology (SNAP) is a biomarker-based concept describing 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 β1-42 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's disease, estimated using polygenic risk scores based on genome-wide association study data. SNAP individuals with NC showed mostly increased protein levels (<i>n</i> = 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 β1-40 and amyloid β1-42 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 <i>APOE</i>. 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.

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Publication Details

Journal
Brain Communications
Published
2025-01-01
DOI
https://doi.org/10.1093/braincomms/fcaf253
Citations
2
Primary Topic
Alzheimer's disease research and treatments
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article
Field-Weighted Citation Impact
2.33

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article

Cerebrospinal fluid proteomic profiling of cognitively unimpaired individuals with suspected non-Alzheimer's disease pathophysiology

Simon Lovestone, Lars Bertram, Johan Gobom, Johannes Streffer et al.
2 citations
Brain Communications
Alzheimer's disease research and treatments
2.33
article

Cerebrospinal fluid proteomic profiling of cognitively unimpaired individuals with suspected non-Alzheimer's disease pathophysiology

Simon Lovestone, Lars Bertram, Johan Gobom, Johannes Streffer, Julius Popp, Pieter Jelle Visser, Betty Marije Tijms, Lianne M. Reus, Pablo Martínez‐Lage, Magda Tsolaki, Frederik Barkhof, Stephanie J. B. Vos, Rik R. Vandenberghe, Valerija Dobričić, Charlotte Elisabeth Teunissen, Aurore Delvenne, Henrik Zetterberg, Mara ten Kate, Jolien Schaeverbeke, Mikel Tainta, Yvonne Freund‐Levi, Gwendoline Peyratout, Suzanne E. Schindler, Kaj Blennow, Inez Ramakers
article en
2 citations

Abstract

Suspected non-Alzheimer's disease pathophysiology (SNAP) is a biomarker-based concept describing 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 β1-42 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's disease, estimated using polygenic risk scores based on genome-wide association study data. SNAP individuals with NC showed mostly increased protein levels (<i>n</i> = 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 β1-40 and amyloid β1-42 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 <i>APOE</i>. 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.

Brain CommunicationsVol. 7(4)
University of Science and Technology of China (CN), Lundbeck (Denmark) (DK), University of Wisconsin–Madison (US), University of Antwerp (BE), King's College London (GB), University of Zurich (CH), Washington University in St. Louis (US), Aristotle University of Thessaloniki (GR), Örebro University (SE), AHEPA University Hospital (GR), Sahlgrenska University Hospital (SE), Karolinska Institutet (SE), Maastricht University (NL), Sorbonne Université (FR), University of Oxford (GB), Örebro County Council (SE), University Hospital of Zurich (CH), Amsterdam Neuroscience (NL), Pitié-Salpêtrière Hospital (FR), UK Dementia Research Institute (GB), Science Oxford (GB), National Hospital for Neurology and Neurosurgery (GB), Amsterdam University Medical Centers (NL), Fundacion CITA Alzheimer (ES), Institut du Cerveau (FR), Institute of Neurobiology (BG), University College London (GB), Vrije Universiteit Amsterdam (NL), University of Gothenburg (SE), University of Lübeck (DE), University of Lausanne (CH), KU Leuven (BE)
Alzheimer's Association, Alzheimer's Drug Discovery Foundation, Eli Lilly and Company, Biogen, Foundation for Barnes-Jewish Hospital, Familjen Erling-Perssons Stiftelse, Cure Alzheimer's Fund, Stiftelsen för Gamla Tjänarinnor, EU Joint Programme – Neurodegenerative Disease Research, European Federation of Pharmaceutical Industries and Associations, Prothena, Union Chimique Belge, Celltrion, Apellis Pharmaceuticals, National Institute for Health and Care Research, University College London, European Commission, National Research Foundation, Schweizerischer Nationalfonds zur Förderung der Wissenschaftlichen Forschung, ZonMw, Eusko Jaurlaritza, Fonds Wetenschappelijk Onderzoek, Eisai, Hjärnfonden, Novo Nordisk, Vetenskapsrådet, Fujirebio Europe, Siemens Healthineers, Vlaamse regering, Julius Clinical, UK Dementia Research Institute, Bentham-Moxon Trust, Olav Thon Stiftelsen, National Institutes of Health, Avid Radiopharmaceuticals, HORIZON EUROPE Framework Programme, Charles F. and Joanne Knight Alzheimer Disease Research Center, Washington University in St. Louis, Instituto de Salud Carlos III, National Institute on Aging, Janssen Pharmaceuticals, H2020 Marie Skłodowska-Curie Actions
Good health and well-being
Openalex Percentile: Top 12%
Alzheimer's disease research and treatments
2.33
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