Alzheimer’s disease genetics converges on microglial and neuronal dysregulation

. Here we analysed data from 109,479 cases, 74,141 proxy cases, 2,131,799 controls and 499,708 proxy controls from diverse ancestries, identifying 118 loci in a multi-ancestry analysis and 9 additional loci in ancestry-specific analyses, 48 of which are new. We identified new AD risk genes, prioritized potential drug targets, and found that genes upregulated in microglia and downregulated in neurons in cases compared with controls were enriched for AD-associated genetic risk. Moreover, we improved polygenic prediction and estimated a SNP heritability of 16%, nearly threefold higher than previous estimates. Together, our findings show that the common-variant contribution to AD has been substantially underestimated, and reveal new molecular and cellular mechanisms as well as specific targets for future drug development research.

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Journal
Nature
Published
2026-10-28
DOI
https://doi.org/10.1038/s41586-026-11206-y
Primary Topic
Alzheimer's disease research and treatments
Type
article
Field-Weighted Citation Impact
0.00
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article

Alzheimer’s disease genetics converges on microglial and neuronal dysregulation

Anne‐Brita Knapskog, Mie Topholm Bruun, Maria Averina, Arvid Harder et al.
1 links
Nature
Alzheimer's disease research and treatments
article

Alzheimer’s disease genetics converges on microglial and neuronal dysregulation

Anne‐Brita Knapskog, Mie Topholm Bruun, Maria Averina, Arvid Harder, Marianne Wettergreen, Lene Pålhaugen, Emil Uffelmann, Marc Hulsman, Douglas P. Wightman, Ingvild Tina Saltvedt, Christina Mikkelsen, Geir Selbæk, Gunhild Waldemar, Irena Rektorová, Nancy L. Pedersen, Akira Narita, Argonde C. van Harten, Flora Hillegonde Duits, Julia Sealock, Henrik Ullum, Erik Sørensen, G. Bragi Walters, Tian Lin, Shahram Bahrami, Vera Fominykh, Kaj Blennow, Marijn Schipper, Kaja Nordengen, Martijn A. Huisman, Geert Jan Biessels, Betty Marije Tijms, Bjørn Lichtwarck, Helga Eyjolfsdottir, Bjørn‐Eivind Kirsebom, Margda Wærn, Eivind Aakhus, Karin Persson, Chenyang Jiang, Daniel Fannar Gudbjartsson, Chandra A. Reynolds, Alexey A. Shadrin, Lavinia Athanasiu, Dan Rujescu, Takafumi Ojima, Henne H. Holstege, Harro Seelaar, Anouk den Braber, Christian Benner, Henning Bundgaard, Dag Aarsland, Daichi Shigemizu, Kouichi Ozaki, Katja Scheffler, Jan Haavik, Anja Hviid Simonsen, Ingmar Gr. Skoog, Jesper Qvist Thomassen, Lasse Pihlstrøm, Ingrid Tøndel Medbøen, Hei Man Wu, Mohsen Ghanbari, Bitten Aagaard, Kristi Krebs, Wolters Fj, Julien Bryois, Sara Hägg, Koichi Matsuda, Geir Bråthen, Eystein Stordal, Christian Erikstrup, Matthew S. Panizzon, Mathias Toft, Gen Tamiya, Jens Hjerling‐Leffler, Richard Sherva, Henrik Zetterberg, Arvid Rongve, Nathaniel Y. Bell, Everard G.B. Vijverberg, Ida Karlsson, Marta Riise Moksnes, Byron Creese, Emmanuel Minois-Genin, Adrián I. Campos, Masayuki P. Yamamoto, Ina Giegling, Niccoló Tesi, J. Michael Gaziano, Monique A. Franc, Anna L. van Seumeren, Alessandro Serretti, Frederic Blanc, Jón Snædal, Jiao Luo, Annette M. Hartmann, Xuemin Wang, Elisa Moreno, Bengt O. Madsen, Clive Ballard, Anne Corbett
article en

Abstract

. Here we analysed data from 109,479 cases, 74,141 proxy cases, 2,131,799 controls and 499,708 proxy controls from diverse ancestries, identifying 118 loci in a multi-ancestry analysis and 9 additional loci in ancestry-specific analyses, 48 of which are new. We identified new AD risk genes, prioritized potential drug targets, and found that genes upregulated in microglia and downregulated in neurons in cases compared with controls were enriched for AD-associated genetic risk. Moreover, we improved polygenic prediction and estimated a SNP heritability of 16%, nearly threefold higher than previous estimates. Together, our findings show that the common-variant contribution to AD has been substantially underestimated, and reveal new molecular and cellular mechanisms as well as specific targets for future drug development research.

Nature
Statens Serum Institut (DK), Broad Institute (US), Boston University (US), Hiroshima University (JP), F. Hoffmann-La Roche AG (CH), University of Copenhagen (DK), Oslo University Hospital (NO), Brigham and Women's Hospital (US), University Hospital of North Norway (NO), deCODE Genetics (Iceland) (IS), Harvard University (US), The University of Queensland (AU), University of Iceland (IS), Genentech (US), King's College London (GB), University of Oslo (NO), Regeneron (United States) (US), University of Colorado Boulder (US), Tohoku University (JP), Aarhus University (DK), Norwegian University of Science and Technology (NO), Masaryk University (CZ), Innlandet Hospital Trust (NO), University of Exeter (GB), Università degli Studi di Enna Kore (IT), Aalborg University Hospital (DK), Stavanger University Hospital (NO), Akershus University Hospital (NO), Haukeland University Hospital (NO), Sahlgrenska University Hospital (SE), Odense University Hospital (DK), VA Boston Healthcare System (US), Erasmus MC (NL), Sykehuset i Vestfold (NO), Aarhus University Hospital (DK), Copenhagen University Hospital (DK), Rigshospitalet (DK), Namsos Hospital (NO), Karolinska Institutet (SE), University Medical Center Utrecht (NL), University of California San Diego (US), Massachusetts General Hospital (US), Central European Institute of Technology – Masaryk University (CZ), Sørlandet Hospital Arendal (NO), St Olav's University Hospital (NO), National University Hospital of Iceland (IS), Amsterdam Neuroscience (NL), RIKEN (JP), RIKEN Center for Advanced Intelligence Project (JP), I.R.C.C.S. Oasi Maria SS (IT), Tohoku Medical Megabank Organization (JP), St. Anne's University Hospital Brno (CZ), Hôpitaux Universitaires de Strasbourg (FR), RIKEN Center for Integrative Medical Sciences (JP), Novo Nordisk Foundation Center for Basic Metabolic Research (DK), Stanley Center for Psychiatric Research (US), Fonna Hospital Trust (NO), Centre for Healthy Brain Ageing (AU), Norwegian National Centre for Ageing and Health (NO), Institute for Molecular Bioscience (AU), Medical Genome Center, National Center for Geriatrics and Gerontology (JP), Research Institute, National Center for Geriatrics and Gerontology (JP), University of Bergen (NO), University of Tartu (EE), Brunel University of London (GB), Nagoya University (JP), The University of Tokyo (JP), Medical University of Vienna (AT), UiT The Arctic University of Norway (NO), Vrije Universiteit Amsterdam (NL), University of Gothenburg (SE), Amsterdam UMC Location Vrije Universiteit Amsterdam (NL), The University of Osaka (JP), Delft University of Technology (NL), Icahn School of Medicine at Mount Sinai (US)
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Alzheimer's disease research and treatments
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