Bonham Luke W, Sirkis Daniel W, Pang Alina P S, Sugrue Leo P, Santamaría-García Hernando, Ibáñez Agustín M, Miller Bruce L, Yokoyama Jennifer S, Corley Michael J
Department of Radiology and Biomedical Imaging, University of California, San Francisco, San Francisco, CA USA.
Memory and Aging Center, Department of Neurology, Weill Institute for Neurosciences, University of California, San Francisco, San Francisco, CA USA.
NPJ Dement. 2025;1(1):7. doi: 10.1038/s44400-025-00007-1. Epub 2025 May 27.
Cross-sectional studies suggest a limited relationship between accelerated epigenetic aging derived from epigenetic clocks, and Alzheimer's disease (AD) pathophysiology or risk. However, most prior analyses have not utilized longitudinal analyses or whole-brain neuroimaging biomarkers of AD. Herein, we employed longitudinal modeling and structural neuroimaging analyses to test the hypothesis that accelerated epigenetic aging would predict AD progression. Using survival analyses, we found that two second-generation epigenetic clocks, DNAmPhenoAge and DNAmGrimAge, predicted progression from cognitively normal aging to mild cognitive impairment or AD and worse longitudinal cognitive outcomes. Epigenetic age was also strongly associated with cortical thinning in AD-relevant regions and white matter disease burden. Thus, in contrast to earlier work suggesting limited applicability of blood-based epigenetic clocks in AD, our novel analytic framework suggests that second-generation epigenetic clocks have broad utility and may represent promising predictors of AD risk and pathophysiology.
横断面研究表明，源自表观遗传时钟的加速表观遗传衰老与阿尔茨海默病（AD）的病理生理学或风险之间的关系有限。然而，大多数先前的分析并未采用纵向分析或AD的全脑神经影像生物标志物。在此，我们采用纵向建模和结构神经影像分析来检验加速表观遗传衰老会预测AD进展这一假设。通过生存分析，我们发现两个第二代表观遗传时钟，即DNAmPhenoAge和DNAmGrimAge，可预测从认知正常衰老到轻度认知障碍或AD的进展以及更差的纵向认知结果。表观遗传年龄还与AD相关区域的皮质变薄和白质疾病负担密切相关。因此，与早期表明基于血液的表观遗传时钟在AD中的适用性有限的研究不同，我们新颖的分析框架表明第二代表观遗传时钟具有广泛的用途，可能是AD风险和病理生理学的有前景的预测指标。
