荷兰阿姆斯特丹自由大学Emil Uffelmann等合作在研究中取得进展。他们发现阿尔茨海默病遗传风险汇聚于小胶质细胞和神经元失调，并识别出48个新风险位点。2026年10月28日出版的《自然》杂志发表了这项成果。

阿尔茨海默病（AD）是痴呆最常见的原因，预计到2050年全球病例数将达到1.53亿。AD具有高度遗传性，基于双胞胎的遗传力估计为60–80%。尽管预测AD存在1,200个因果位点，但近期两项研究仅将约80个位点与AD关联。基于单核苷酸多态性（SNP）的遗传力估计较低，促使人们提出常见变异风险几乎已无可发现之处。在此，研究人员分析了来自不同祖先的109,479例病例、74,141例替代病例、2,131,799名对照和499,708名替代对照的数据，在多祖先分析中鉴定出118个位点，在祖先特异性分析中额外鉴定出9个位点，其中48个为新位点。研究人员识别出新的AD风险基因，优先筛选了潜在药物靶点，并发现与对照相比，病例中在小胶质细胞中上调、在神经元中下调的基因富集了AD相关遗传风险。此外，研究人员改善了多基因预测，并估计SNP遗传力为16%，比此前估计高出近三倍。总之，研究结果表明，常见变异对AD的贡献被大幅低估，并揭示了新的分子和细胞机制以及未来药物开发研究的特定靶点。

附：英文原文

Title: Alzheimer’s disease genetics converges on microglial and neuronal dysregulation

Author: Uffelmann, Emil, Wightman, Douglas P., Bahrami, Shahram, Shadrin, Alexey A., Fominykh, Vera, Ojima, Takafumi, Jiang, Chenyang, Benner, Christian, Moreno, Elisa, Campos, Adrian I., Thomassen, Jesper Q., Minois-Genin, Emmanuel, Wu, Hei Man, Walters, G. Bragi, Sherva, Richard, Lin, Tian, Wang, Xuemin, Bryois, Julien, Krebs, Kristi, Schipper, Marijn, Narita, Akira, Serretti, Alessandro, Simonsen, Anja H., van Seumeren, Anna L., Corbett, Anne, Knapskog, Anne-Brita, Hartmann, Annette M., den Braber, Anouk, van Harten, Argonde C., Harder, Arvid, Rongve, Arvid, Madsen, Bengt O., Tijms, Betty M., Aagaard, Bitten, Lichtwarck, Bjrn, Kirsebom, Bjrn-Eivind, Creese, Byron, Reynolds, Chandra A., Hgg, Sara, Karlsson, Ida K., Erikstrup, Christian, Mikkelsen, Christina, Ballard, Clive, Aarsland, Dag, Shigemizu, Daichi, Rujescu, Dan, Gudbjartsson, Daniel, Aakhus, Eivind, Srensen, Erik, Stordal, Eystein, Duits, Flora H., Wolters, Frank J., Blanc, Frederic, Biessels, Geert Jan, Selbk, Geir, Brthen, Geir, Tamiya, Gen, Waldemar, Gunhild, Seelaar, Harro, Eyjolfsdottir, Helga, Holstege, Henne

Issue&Volume: 2026-10-28

Abstract: Alzheimer’s disease (AD) is the most common cause of dementia, with global case numbers projected to reach 153 million in 20501. AD is highly heritable, with twin-based heritability estimates of 60–80%2. Although 1,200 causal loci are predicted to exist for AD3, approximately 80 loci have been associated with AD in two recent studies4,5. Low single-nucleotide polymorphism (SNP)-based heritability estimates have prompted the suggestion that little further common-variant risk remains to be found6. 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.

DOI: 10.1038/s41586-026-11206-y

Source:https://www.nature.com/articles/s41586-026-11206-y