Genomic analyses reveal new insights into Alzheimer's disease

作者：Emil Uffelmann, Douglas P. Wightman, Shahram Bahrami, Alexey Shadrin, Vera Fominykh, Takafumi Ojima, Chenyang Jiang, Christian Benner, Elisa Moreno, Adrián I. Campos, Jesper Qvist Thomassen, Emmanuel Minois-Genin, Hei Man Wu, G. Bragi Walters, Richard Sherva, Tian Lin, Xuemin Wang, Julien Bryois, Kristi Krebs, Marijn Schipper, Akira Narita, Alessandro Serretti, Anja Hviid Simonsen, Anna L. van Seumeren, Anne Corbett, Anne‐Brita Knapskog, Annette M. Hartmann, Anouk den Braber, Arvid Harder, Arvid Harder, Arvid Rongve, Bengt O Madsen, Betty M. Tijms, Bitten Aagaard, Bjørn Lichtwarck, Bjorn E Kirsebom, Byron Creese, Chandra A. Reynolds, Sara Hägg, Ida Karlsson, Christian Erikstrup, Christina Mikkelsen, Clive Ballard, Dag Aarsland, Daichi Shigemizu, Dan Rujescu, Daníel F. Guðbjartsson, 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 Tøndel Medbøen, Ingvild Saltvedt, Ingvild Hjorth Feiring, Irena Rektorová, J. Michael Gaziano, Jan Haavik, Jens Hjerling‐Leffler, Jiao Luo, Jón Snædal, Everard G.B. Vijverberg, Julia Sealock, Kaj Blennow, Kaja Nordengen, Karin Persson, Katja Scheffler, Koichi Matsuda, Kouichi Ozaki, Lasse Pihlstrøm, Lavinia Athanasiu, Lene Pålhaugen, Marc Hulsman, Margda Wærn, 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 Birger Pedersen, Oleksandr Frei, Olivier Bousiges, Per Svenningsson, Pieter Jelle Visser, Qingqin S. Li, Richard L. Hauger, Rui Zhang, Shinichi Namba, Sigrid B. Sando, Silke Kern, Srdjan Djurovic, Steinunn Þórðardóttir, Tanya N. Phung, Thomas Truelsen, Thomas Werge, Thomas Folkmann Hansen, Tomoki Kyosaka, Torgeir Engstad, Tormod Fladby, Victoria C. Merritt, Sverre Bergh, Wiesje M. van der Flier, Rujin Wang, Eli A Stahl, Basavaraj Hooli, LifeLines Cohort Study, Penn Medicine Biobank, INDIANA-CHALASANI, Mount Sinai Million Health Discoveries Program, VA Million Veteran Program, Lea K. Davis, Mark W. Logue, Kelli Lehto, Anna Zettergren, Ben Brumpton, Jian Zeng, Peter M. Visscher, Paul F. O’Reilly, Anubha Mahajan, Manuel Ferreira, Yukinori Okada, Sven J. van der Lee, Sisse Rye Ostrowski, Ruth Frikke‐Schmidt, Hreinn Stefánsson, Karl Heilbron, Ole A. Andreassen, Daniëlle Posthuma · 发表于：medRxiv · 年份：2025 · DOI：10.1101/2025.10.10.25337470 · 被引用次数：4 · 研究领域：Genetic Associations and Epidemiology、Bioinformatics and Genomic Networks、Metabolomics and Mass Spectrometry Studies

Alzheimer's disease (AD) is the most common cause of dementia, with global case numbers projected to reach 153 million in 2050. AD is highly heritable, with twin-based heritability estimates of 60-80%. While 1,200 causal loci are predicted to exist for AD, approximately 80 have been associated with AD in two recent studies, suggesting that many loci remain to be discovered. Here, we analyzed 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 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 16%. Together, our findings offer insights into the genetic architecture and potential pathobiology of AD, as well as specific targets for future drug development research.