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[Preprint]. 2025 Oct 13:2025.10.10.25337470.
doi: 10.1101/2025.10.10.25337470.

Genomic analyses reveal new insights into Alzheimer's disease

Emil Uffelmann, Douglas P Wightman, Shahram Bahrami, Alexey A Shadrin, Vera Fominykh, Takafumi Ojima, Chenyang Jiang, Christian Benner, Elisa Moreno, Adrian I Campos, Jesper Q Thomassen, Emmanuel Minois-Genin, Hei Man Wu, G Bragi Walters, Richard Sherva, Tian Lin, Julien Bryois, Kristi Krebs, Marijn Schipper, Akira Narita, Alessandro Serretti, Anja H Simonsen, Anna L van Seumeren, Anne Corbett, Anne-Brita Knapskog, Annette M Hartmann, Anouk den Braber, Argonde C van Harten, Arvid Harder, Arvid Rongve, Bengt O Madsen, Betty M Tijms, Bitten Aagaard, Bjørn Lichtwarck, Bjørn E Kirsebom, Byron Creese, Chandra A Reynolds, Sara Hägg, Ida Karlsson, Christian Erikstrup, Christina Mikkelsen, Clive Ballard, Dag Aarsland, Daichi Shigemizu, Dan Rujescu, Daniel Gudbjartsson, Eivind Aakhus, Erik Sørensen, Eystein Stordal, Flora H Duits, Frank J Wolters, Frederic Blanc, Geert Jan Biessels, Geir Selbæk, Geir Bråthen, Gen Tamiya, Gunhild Waldemar, Harro Seelaar, Helga Eyjolfsdottir, Henne Holstege, Henning Bundgaard, Henrik Zetterberg, Henrik Ullum, Ingmar Skoog, Ingrid T Medbøen, Ingvild Saltvedt, Ingvild H Feiring, Irena Rektorova, J Michael Gaziano, Jan Haavik, Jens Hjerling-Leffler, Jiao Luo, Jon Snaedal, Everard G B Vijverberg, Julia M Sealock, Kaj Blennow, Kaja Nordengen, Karin Persson, Katja Scheffler, Koichi Matsuda, Kouichi Ozaki, Lasse Pihlstrøm, Lavinia Athanasiu, Lene Pålhaugen, Marc Hulsman, Margda Waern, Maria Averina, Marianne Wettergreen, Marta R Moksnes, Martijn Huisman, Masayuki Yamamoto, Mathias Toft, Matthew S Panizzon, Mie Topholm Bruun, Mohsen Ghanbari, Monique Franc, Nancy L Pedersen, Nathaniel Y Bell, Niccoló Tesi, Ole B Pedersen, Oleksandr Frei, Olivier Bousiges, Per Svenningsson, Pieter J Visser, Qingqin S Li, Richard Hauger, Rui Zhang, Shinichi Namba, Sigrid B Sando, Silke Kern, Srdjan Djurovic, Steinunn Thordardottir, Tanya N Phung, Thomas Truelsen, Thomas Werge, Thomas F Hansen, Tomoki Kyosaka, Torgeir Engstad, Tormod Fladby, Victoria Merritt, Sverre Bergh, Wiesje M van der Flier, Rujin Wang, Eli A Stahl, Basavaraj Hooli; 23andMe Research Institute; LifeLines Cohort Study; DBDS Genomic consortium; Regeneron Genetics Center; Penn Medicine Biobank; GHS-RGC DiscovEHR collaboration; Mayo Clinic-RGC Project Generation; Colorado Center for Personalized Medicine – RGC Collaboration; UCLA-RGC ATLAS collaboration; INDIANA-CHALASANI; Mount Sinai Million Health Discoveries Program; Estonian Biobank research team; VA Million Veteran Program; Lea K Davis, Mark W Logue, Kelli Lehto, Anna Zettergren, Ben M Brumpton, Jian Zeng, Peter M Visscher, Paul F O'Reilly, Anubha Mahajan, Manuel Ferreira, Yukinori Okada, Sven J van der Lee, Sisse R Ostrowski, Ruth Frikke-Schmidt, Hreinn Stefansson, Karl Heilbron, Ole A Andreassen, Danielle Posthuma

Genomic analyses reveal new insights into Alzheimer's disease

Emil Uffelmann et al. medRxiv. .

Abstract

Alzheimer's disease (AD) is the most common cause of dementia, with global case numbers projected to reach 153 million in 2050 1 . AD is highly heritable, with twin-based heritability estimates of 60-80% 2 . While 1,200 causal loci are predicted to exist for AD 3 , approximately 80 have been associated with AD in two recent studies 4,5 , suggesting that many loci remain to be discovered 6 . Here, we analyzed data from 183,620 AD cases and 2.6 million 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 identified microglia and, for the first time, several neuronal cell types enriched for AD-associated genetic risk. Moreover, we improved polygenic prediction and estimated a single-nucleotide polymorphism (SNP) heritability of 19%. Together, our findings offer insights into the genetic architecture and potential pathobiology of AD, as well as specific targets for future drug development research.

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