System Maintenance Notice

Please note that maintenance work is scheduled between 4 AM and 5 AM - CET. During this time, you may experience reduced performance. Thanks for your patience.

Publications

Journal Article Ppublish

PubMed: 42761049 DOI: 10.1186/s44477-026-00048-7

CSF proteomic quantitative trait loci mapping reveals genetic insights into Alzheimer's disease.

Mol Neurodegener Adv 2(1):40

Authors: Lianne M Reus, Chenyang Jiang, Natalia Vilor-Tejedor, Toni Boltz, Arya Yigit, Johan Gobom, Stephanie J B Vos, Kaj Blennow, Henrik Zetterberg, Pablo Martinez-Lage, Mikel Tainta, Julius Popp, Magda Tsolaki, Rik Vandenberghe, Lutz Frölich, Yvonne Freund-Levi, Valerija Dobricic, Anouk den Braber, Argonde C van Harten, Roel A Ophoff, Henne Holstege, Wiesje M van der Flier, Sven J van der Lee, Charlotte E Teunissen, Lars Bertram, Pieter Jelle Visser, Betty M Tijms

Affiliations

  • Alzheimer Center Amsterdam, Neurology, Vrije Universiteit Amsterdam, Amsterdam UMC Location VUmc, Amsterdam, The Netherlands.
  • Amsterdam Neuroscience, Neurodegeneration, Amsterdam, The Netherlands.
  • Barcelonaβeta Brain Research Center (BBRC), Pasqual Maragall Foundation, Barcelona, Spain.
  • Centre for Genomic Regulation (CRG), Barcelona Institute of Science and Technology (BIST), Barcelona, Spain.
  • Department of Genetics, Radboud University, Nijmegen, The Netherlands.
  • Stanley Center for Psychiatric Research, Broad Institute of MIT and Harvard, Cambridge, MA USA.
  • Analytic and Translational Genetics Unit, Department of Medicine, Massachusetts General Hospital, Boston, MA USA.
  • Clinical Neurochemistry Laboratory, Sahlgrenska University Hospital, Mölndal, Sweden.
  • Department of Psychiatry and Neurochemistry, Institute of Neuroscience and Physiology, The Sahlgrenska Academy at the University of Gothenburg, Gothenburg, Sweden.
  • Alzheimer Center Limburg, Department of Psychiatry and Neuropsychology, School for Mental Health and Neuroscience, Maastricht University, Maastricht, The Netherlands.
  • UK Dementia Research Institute at UC, London, UK.
  • Department of Neurodegenerative Disease, UCL Queen Square Institute of Neurology, London, UK.
  • Biogipuzkoa Health Research Institute, San Sebastian, Spain.
  • Old Age Psychiatry, University Hospital Lausanne, Lausanne, Switzerland.
  • Department of Psychiatry, Psychiatry University Hospital Zürich, Zurich, Switzerland.
  • 1st Department of Neurology, AHEPA University Hospital, Medical School, Faculty of Health Sciences, Aristotle University of Thessaloniki, Thessaloniki, Makedonia Greece.
  • Neurology Service, University Hospitals Leuven, Leuven, Belgium.
  • Laboratory for Cognitive Neurology, Department of Neurosciences, KU Leuven, Leuven, Belgium.
  • Department of Geriatric Psychiatry, Central Institute of Mental Health, Medical Faculty Mannheim/Heidelberg University, Mannheim, Germany.
  • Department of Clinical Science and Education, Södersjukhuset Karolinska Institutet Stockholm, Stockholm, Sweden.
  • Department of Geriatrics at the University Hospital Örebro County, Örebro, Sweden.
  • Faculty of Medicine and Health, Örebro University, Örebro, Sweden.
  • Department of Geriatrics, Södertälje Hospital, Södertälje, Sweden.
  • Lübeck Interdisciplinary Platform for Genome Analytics, University of Lübeck, Lübeck, Germany.
  • Department of Biological Psychology, Amsterdam Public Health Research Institute, Vrije Universiteit Amsterdam, Amsterdam, The Netherlands.
  • Center for Neurobehavioral Genetics, Semel Institute for Neuroscience and Human Behavior, University of California, Los Angeles, CA USA.
  • Department of Human Genetics, David Geffen School of Medicine, University of California Los Angeles, Los Angeles, CA USA.
  • Genomics of Neurodegenerative Diseases and Aging, Department of Human Genetics, Vrije Universiteit Amsterdam, Amsterdam UMC, Amsterdam, Amsterdam, The Netherlands.
  • Alzheimer Nederland, Amersfoort, the Netherlands.
  • Epidemiology and Data Science, Vrije Universiteit Amsterdam, Amsterdam UMC Location VUmc, Amsterdam, The Netherlands.
  • Neurochemistry Lab and Biobank, Department of Clinical Chemistry, Amsterdam Neuroscience, Amsterdam UMC, Amsterdam, The Netherlands.
  • Department of Psychiatry, Maastricht University, Maastricht, The Netherlands.

Abstract

BACKGROUND

Despite the identification of numerous genetic risk variants for Alzheimer's disease (AD), mechanisms through which these variants act remain unclear. Identifying specific proteins levels affected by genetic variation can provide valuable insights into the underlying biological pathways implicated in AD.

METHODS

To gain more insight into effects of genetic variation on AD-related processes, we conducted a genome-wide protein pQTL study using untargeted TMT mass spectrometry in cerebrospinal fluid (CSF) of 2,215 proteins across 487 individuals. Replication was assessed in the independent EMIF-AD MBD cohort of 242 individuals.

RESULTS

We identified 399 independent CSF pQTL signals (P Bonferroni < 2.26 × 10⁻11) associated with 222 proteins, 69% of which were novel. Findings included gene-protein links such as RPS23P10/HSPA6 with CSF FCGR2A, BIN2 with CSF GALNT6, APOE with CSF HS3ST1, and the HLA-region with CSF HLA-DPB1 and PLXDC2. We replicated 230 of 270 gene-protein associations. A proteome-wide association study identified genetically predicted CSF protein levels to be associated with AD, including SIRPA, PLXDC2, and GALNT6. Many AD pQTLs in CSF were enriched in neuroimmune activation, suggesting a genetic basis for neuroimmune dysregulation in AD.

CONCLUSIONS

This study highlights how genetic variation shapes protein expression in the central nervous system, offering mechanistic insight into AD.

SUPPLEMENTARY INFORMATION

The online version contains supplementary material available at https://doi.org/10.1186/s44477-026-00048-7.

MeSH

Genetic Variation, Genes, Alzheimer Disease, Quantitative Trait Loci