GWAS meta-analysis of cerebrospinal fluid Alzheimer’s biomarkers reveals loci regulating lipids, brain volume and autophagy

Cerebrospinal fluid amyloid beta 42, total tau, and phosphorylated tau 181 are well accepted markers of Alzheimer's disease. These biomarkers better reflect disease pathogenesis compared to clinical diagnosis. Here, we perform a genome wide association study meta-analysis including 18,948 individuals of European ancestry and identify 12 genome-wide significant loci across all three biomarkers, eight of them novel. We replicate the association of biomarkers with APOE, CR1, GMNC/CCDC50 and C16orf95/MAP1LC3B. Novel loci include BIN1 for amyloid beta and GNA12, MS4A6A, SLCO1A2 with both total tau and phosphorylated tau 181, as well as additional loci on chr. 8, near ANGPT1 and chr. 9 near SMARCA2. We also demonstrate that these variants have significant association with Alzheimer's disease risk, disease progression and/or brain amyloidosis. The associated genes are implicated in lipid metabolism independent of APOE, coupled with autophagy and brain volume regulation driven by total tau and phosphorylated tau 181 dysregulation.

Authors

Institutions

Publication Details

Journal
Nature Communications
Published
2026-04-21
DOI
https://doi.org/10.1038/s41467-026-71682-8
Primary Topic
Alzheimer's disease research and treatments
Type
article
Field-Weighted Citation Impact
0.00

Funders

Controls
|||
ALL TIME
JAN
FEB
MAR
APR
MAY
JUN
JUL
AUG
SEP
OCT
article

GWAS meta-analysis of cerebrospinal fluid Alzheimer’s biomarkers reveals loci regulating lipids, brain volume and autophagy

L Frölich, Jonathan S. Vogelgsang, Olena Ohlei, Marc Hulsman et al.
Nature Communications
Alzheimer's disease research and treatments
article

GWAS meta-analysis of cerebrospinal fluid Alzheimer’s biomarkers reveals loci regulating lipids, brain volume and autophagy

L Frölich, Jonathan S. Vogelgsang, Olena Ohlei, Marc Hulsman, Olivier Hannon, Timothy J. Hohman, Pablo Mir, Vilmantas Giedraitis, Ying Wu, Oliver Goldhardt, Daniel Western, Eloy Rodríguez‐Rodríguez, Norbert Scherbaum, Itziar de Rojas, Logan C. Dumitrescu, Wiesje M. van der Flier, Margda Wærn, Chengran Yang, Daniel L. McCartney, Victoria Álvarez, Sebastiaan Engelborghs, Luca Kleineidam, Ville Leinonen, Ina Giegling, Dan Rujescu, Lucrezia Hausner, Muhammad Ali, Henne Holstege, Harro Seelaar, Jean‐François Deleuze, José María García‐Alberca, Julie Williams, Ciyang Wang, Stefanie Heilmann‐Heimbach, Fahri Küçükali, John Budde, María J. Bullido, Federica Anastasi, Joseph Bradley, Céline Bellenguez, Jenna Najar, Sami Heikkinen, Rebecca Mahoney, Carolina Dalmasso, Janine Diehl‐Schmid, Hilkka Soininen, Oriol Dols‐Icardo, Thibaud Lebouvier, Pablo García‐González, Fermín Moreno, Thomas Tegos, Markus M. Nöthen, C van Duijn, Niccoló Tesi, Jigyasha Timsina, Inez Ramakers, Benjamin Grenier‐Boley, Jordi Perez-Tur, Raquel Puerta Fuentes, Luis M. Real, R Perneczky, E Düzel, O Peters, Josef Priller, T Grimmer, M Wagner, C Laske, F Jessen, M R Steffner Yongjian Liu, Janne Papma, Michael MT. Heneka, Gerard Piñol-Ripoll, Yolande A. L. Pijnenburg, Rik Vandenberghe, Silke Kern, Jens Wiltfang, Ingmar Skoog, Feifei Tao, Caroline Graff, Pascual Sánchez-Juan, Johannes Kornhuber, Anja Schneider, Chenyang Jiang, Hakan Thonberg, Matthias Schmid, Harald Hampel, Victor Andrade, Goran Papenberg, Atahualpa Castillo Morales, Nikolaos Scarmeas, Chenyu Yang, Stefan Teipel, Piotr Lewczuk, Sanna-Kaisa Herukka, Abbe Ullgren, Carole Dufouil, Argonde van Harten, Katharina Buerger, Ting-Chen Wang, Raquel Sánchez-Valle
article en

Abstract

Cerebrospinal fluid amyloid beta 42, total tau, and phosphorylated tau 181 are well accepted markers of Alzheimer's disease. These biomarkers better reflect disease pathogenesis compared to clinical diagnosis. Here, we perform a genome wide association study meta-analysis including 18,948 individuals of European ancestry and identify 12 genome-wide significant loci across all three biomarkers, eight of them novel. We replicate the association of biomarkers with APOE, CR1, GMNC/CCDC50 and C16orf95/MAP1LC3B. Novel loci include BIN1 for amyloid beta and GNA12, MS4A6A, SLCO1A2 with both total tau and phosphorylated tau 181, as well as additional loci on chr. 8, near ANGPT1 and chr. 9 near SMARCA2. We also demonstrate that these variants have significant association with Alzheimer's disease risk, disease progression and/or brain amyloidosis. The associated genes are implicated in lipid metabolism independent of APOE, coupled with autophagy and brain volume regulation driven by total tau and phosphorylated tau 181 dysregulation.

Nature Communications
Uppsala University (SE), Karolinska University Hospital (SE), University of Bonn (DE), Harvard University (US), Medical University of Białystok (PL), University of Antwerp (BE), Université de Bordeaux (FR), Consejo Nacional de Investigaciones Científicas y Técnicas (AR), Inserm (FR), Stockholm University (SE), University of Eastern Finland (FI), University of Cologne (DE), Friedrich-Alexander-Universität Erlangen-Nürnberg (DE), National and Kapodistrian University of Athens (GR), Washington University in St. Louis (US), Université Paris Cité (FR), Aristotle University of Thessaloniki (GR), Heidelberg University (DE), Université de Lille (FR), Commissariat à l'Énergie Atomique et aux Énergies Alternatives (FR), Université Paris-Saclay (FR), University Hospital Bonn (DE), Universitair Ziekenhuis Leuven (BE), Institut Pasteur de Lille (FR), Sahlgrenska University Hospital (SE), McLean Hospital (US), Instituto de Salud Carlos III (ES), German Center for Neurodegenerative Diseases (DE), Hospital de Sant Pau (ES), Erasmus MC (NL), Edinburgh Cancer Research (GB), TUM Klinikum (DE), Karolinska Institutet (SE), Centre Hospitalier Universitaire de Bordeaux (FR), Centre Hospitalier Universitaire de Lille (FR), LMU Klinikum (DE), Universitat Internacional de Catalunya (ES), Maastricht University (NL), Humboldt-Universität zu Berlin (DE), Sorbonne Université (FR), University of Oxford (GB), Centre National de Recherche en Génomique Humaine (FR), Biomedical Research Networking Center on Neurodegenerative Diseases (ES), Universitätsklinikum Erlangen (DE), Hospital Universitari de Santa Maria (ES), Kuopio University Hospital (FI), Region Västra Götaland (SE), Assistance Publique – Hôpitaux de Paris (FR), Zimmer Biomet (Germany) (DE), Marqués de Valdecilla University Hospital (ES), Biogipuzkoa Health Research Institute (ES), Hospital La Paz Institute for Health Research (ES), Central Institute of Mental Health (DE), Bordeaux Population Health (FR), Hôpital Broca (FR), Pasqual Maragall Foundation (ES), Amsterdam Neuroscience (NL), Munich Cluster for Systems Neurology (DE), Centro de Investigación Biomédica en Red (ES), Pitié-Salpêtrière Hospital (FR), UK Dementia Research Institute (GB), Universitair Ziekenhuis Brussel (BE), Barcelonaβeta Brain Research Center (ES), CEA Paris-Saclay (FR), Hospital Del Mar (ES), VIB-UAntwerp Center for Molecular Neurology (BE), Instituto de Biomedicina de Sevilla (ES), Instituto de Investigación Biomédica de Lleida (ES), Hospital Universitario Central de Asturias (ES), Centre for Genomic Regulation (ES), Cologne Excellence Cluster on Cellular Stress Responses in Aging Associated Diseases (DE), Berlin Institute of Health at Charité - Universitätsmedizin Berlin (DE), Eginition Hospital (GR), Hertie Institute for Clinical Brain Research (DE), Centro de Biología Molecular Severo Ochoa (ES), Hospital Universitario de Valme (ES), Instituto de Biomedicina de Valencia (ES), Eisai (United States) (US), Amsterdam University Medical Centers (NL), Hospital Universitario Virgen del Rocío (ES), University Hospital Cologne (DE), Fundacion Centro De Investigacion De Enfermedades Neurologicas (ES), VIB-KU Leuven Center for Brain & Disease Research (BE), Artificial Intelligence in Medicine (Canada) (CA), Instituto de Investigación Sanitaria del Principado de Asturias (ES), Centre d'Investigation Clinique Plurithématique de Bordeaux, Alzheimer Precision Medicine (FR), University of Rostock (DE), Imperial College London (GB), University of Duisburg-Essen (DE), Technical University of Munich (DE), Universidad Autónoma de Madrid (ES), Martin Luther University Halle-Wittenberg (DE), Universitat de Barcelona (ES), Medical University of Vienna (AT), Columbia University (US), Charité - Universitätsmedizin Berlin (DE), Universidad de Sevilla (ES), University of Tübingen (DE), Ludwig-Maximilians-Universität München (DE), Universidad de Málaga (ES), Vrije Universiteit Amsterdam (NL), University of Gothenburg (SE), Vanderbilt University Medical Center (US), Amsterdam UMC Location Vrije Universiteit Amsterdam (NL), Erasmus University Rotterdam (NL), University of Lübeck (DE), Otto-von-Guericke-Universität Magdeburg (DE), Delft University of Technology (NL)
U.S. Department of Defense, Alzheimer's Association, Japan Agency for Medical Research and Development, Hope Center for Neurological Disorders, Korea Health Industry Development Institute, Deutsches Zentrum für Neurodegenerative Erkrankungen, Ministry of Science and ICT, South Korea, Fleni, National Institutes of Health, Instituto de Salud Carlos III, National Institute on Aging
Good health and well-being
Openalex Percentile: Top 22%
Alzheimer's disease research and treatments
DOIOpen Access PDFOpenAlex
AI Navigator

Ask Laika to Summarize, Analyze, and Connect papers live on the map.

Summarize Papers & Methodologies

Extract key findings, datasets, and comparative methods across publications.

Benchmark Rankings & Visual Analytics

Rank top research institutions, authors, funders, topics, and journals by Field-Weighted Citation Impact (FWCI) and paper volume with instant charts.

Connect Distant Disciplines

Bridge topological clusters on the map to find hidden collaborative intersections.