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

Timsina J, Jiang C, McCartney DL, Tao F, Dalmasso MC, Najar J, Anastasi F, Ohlei O, Puerta Fuentes R, Yang C, Bradley J, Western D, Ali M, Wang C, Yang C, Wu Y, Liu M, Budde J, Williams J, Mahoney R, Castillo Morales A, Hohman TJ, Dumitrescu L, Wang TC, Tesi N, Kern S, Waern M, Skoog I, van Harten A, Pijnenburg YA, van der Flier WM, Sánchez-Juan P, Rodriguez-Rodriguez E, Kleineidam L, Peters O, Schneider A, Küçükali F, Bellenguez C, Grenier-Boley B, Heikkinen S, de Rojas I, Rujescu D, Scherbaum N, Hausner L, Düzel E, Grimmer T, Wiltfang J, Vandenberghe R, Engelborghs S, Heilmann-Heimbach S, Schmid M, Tegos T, Scarmeas N, Dols-Icardo O, Moreno F, Pérez-Tur J, Bullido MJ, Sánchez-Valle R, Álvarez V, García-González P, Mir P, Real LM, Piñol-Ripoll G, García-Alberca JM, Seelaar H, Ramakers I, Papma J, Hulsman M, Laske C, Teipel S, Priller J, Perneczky R, Buerger K, Nöthen MM, Lewczuk P, Kornhuber J, Hampel H, Giegling I, Goldhardt O, Diehl-Schmid J, Andrade V, Heneka MM, Frölich L, Vogelgsang J, Graff C, Thonberg H, Ullgren A, Papenberg G, Deleuze JF, Dufouil C, Wagner M, Jessen F, Holstege H, van Duijn C, Lebouvier T, Hannon O, Leinonen V, Soininen H, Herukka SK, Giedraitis V, Löwenmark M, Kilander L, Genius P, Rodríguez B, Luckett ES, Navarro A, Cano A, Marquié M, Blennow K, Zetterberg H, Lleo A, Boada M, Ruiz A, Lee VMY, Van Deerlin VM, Deming Y, Johnson SC, Engelman CD, Pastor P, Alvarez I, Peskind ER, Heslegrave AJ, Saykin AJ, Nho K, Schindler SE, Morris JC, Holtzman DM, McDade E, Renton AE, Goate A, Ibanez L, Riemenschneider M, Albert MS, Laws SM, Porter T, O’Brien EK, Shaw LM, Tijms BM, Ingelsson M, Visser PJ, Hiltunen M, Sleegers K, Ritchie CW, Sims R, Belloy M, Lambert JC, Vilor-Tejedor N, Fernández MV, Li QS, Nagle MW, Marioni RE, Ramirez A, Bertram L, van der Lee SJ, Cruchaga C (2026)

Publication Type: Journal article

Publication year: 2026

Journal

Book Volume: 17

Article Number: 7385

Journal Issue: 1

DOI: 10.1038/s41467-026-71682-8

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.

Authors with CRIS profile

Involved external institutions

Technische Universität München (TUM) Germany (DE) Universitätsklinikum Göttingen Germany (DE) Pitié-Salpêtrière University Hospital / Hôpital universitaire Pitié-Salpêtrière France (FR) University of Wisconsin - Madison United States (USA) (US) Health Sciences Research Institute of the “Germans Trias i Pujol” Foundation (IGTP) Spain (ES) Indiana University – Purdue University Indianapolis United States (USA) (US) Washington University in St. Louis United States (USA) (US) Icahn School of Medicine at Mount Sinai United States (USA) (US) University College London (UCL) United Kingdom (GB) Vrije Universiteit Amsterdam (VU) / University Amsterdam Netherlands (NL) Centro de Investigación de Enfermedades Neurológicas (CIEN) Spain (ES) Biomedical Research Networking Center on Neurodegenerative Diseases / Centro de Investigación Biomédica en Red Enfermedades neurodegenerativas (CIBERNED) Spain (ES) Universitätsklinikum Bonn Germany (DE) Deutsches Zentrum für Neurodegenerative Erkrankungen (DZNE) Germany (DE) University of Antwerp / Universiteit Antwerpen Belgium (BE) Universitätsklinikum Mannheim / University Medical Centre Mannheim (Universitätsmedizin Mannheim) Germany (DE) University Hospital Leuven (UZ) / Universitaire ziekenhuizen Leuven Belgium (BE) Eginition Hospital Greece (GR) University of Edinburgh United Kingdom (GB) Universitätsklinikum Köln Germany (DE) Pasqual Maragall Foundation Spain (ES) Universität zu Lübeck Germany (DE) Universitat Internacional de Catalunya Spain (ES) Cardiff University United Kingdom (GB) Vanderbilt University United States (USA) (US) Sahlgrenska University Hospital / Sahlgrenska Universitetssjukhuset Sweden (SE) Université de Lille (ULille, UDL) France (FR) University of Eastern Finland Finland (FI) Universitätsklinikum Halle (Saale) Germany (DE) Universität Duisburg-Essen (UDE) Germany (DE) Universitat de Barcelona (UB) / University of Barcelona Spain (ES) Central University Hospital of Asturias Spain (ES) Hospital Universitario Virgen de Valme Spain (ES) Hospital Universitari de Santa Maria Spain (ES) Amsterdam Neuroscience Netherlands (NL) Maastricht University Netherlands (NL) Erasmus University Medical Center (MC) Netherlands (NL) Medizinische Universität Wien Austria (AT) Karolinska Institute Sweden (SE) National Center of Human Genomics Research / Centre National de Recherche en Génomique Humaine (CNRGH) France (FR) Université de Bordeaux France (FR) Lille Neuroscience & Cognition Research Centre France (FR) Université Paris-Sud France (FR) Kuopio University Hospital / Pohjois-Savon sairaanhoitopiiri Finland (FI) Amsterdam University Medical Centers (Amsterdam UMC) / Amsterdam Universitair Medische Centra Netherlands (NL) University of Pennsylvania (UPenn) United States (USA) (US) UT Health San Antonio United States (USA) (US) Universitätsklinikum des Saarlandes (UKS) Germany (DE) Johns Hopkins Hospital United States (USA) (US) Edith Cowan University Australia (AU) University Health Network (UHN) Canada (CA) Scottish Brain Sciences United Kingdom (GB) Johnson & Johnson United Kingdom (GB)

How to cite

APA:

Timsina, J., Jiang, C., McCartney, D.L., Tao, F., Dalmasso, M.C., Najar, J.,... Cruchaga, C. (2026). GWAS meta-analysis of cerebrospinal fluid Alzheimer’s biomarkers reveals loci regulating lipids, brain volume and autophagy. Nature Communications, 17(1). https://doi.org/10.1038/s41467-026-71682-8

MLA:

Timsina, Jigyasha, et al. "GWAS meta-analysis of cerebrospinal fluid Alzheimer’s biomarkers reveals loci regulating lipids, brain volume and autophagy." Nature Communications 17.1 (2026).

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