Afshar Shiva, Dammer Eric B, Bian Shijia, Bennett David A, Mohs Richard, Beauregard Doug, Dwyer John, Hales Chadwick M, Goldstein Felicia C, Parker Monica W, Trammell Antoine R, Watson Caroline M, Golde Todd E, Seyfried Nicholas T, Roberts Blaine R, Manzanares Cecelia M, Lah James J, Levey Allan I, Johnson Erik C B
Goizueta Alzheimer's Disease Research Center, Emory University School of Medicine, Atlanta, GA, USA.
Department of Biochemistry, Emory University School of Medicine, Atlanta, GA, USA.
Nat Aging. 2025 Sep 10. doi: 10.1038/s43587-025-00965-4.
Clinical Alzheimer's disease is currently characterized by cerebral β-amyloidosis associated with cognitive impairment. However, most cases of Alzheimer's disease are associated with multiple neuropathologies at autopsy. The peripheral protein changes associated with these disease endophenotypes are poorly understood. In this study, we analyzed the plasma proteomes of individuals from four cohorts (n = 2,139 participants) to identify proteins and pathways associated with cerebral β-amyloidosis and other neuropathologies, including tau, Lewy bodies, TDP43, cerebral amyloid angiopathy, atherosclerosis, arteriolosclerosis and infarcts as well as cognitive function. Analyses in a cohort with paired brain data showed that known neuropathologies could account for only half of proteins associated with cognitive function and that many plasma proteins associated with these neuropathologies are not strongly correlated to levels in brain, suggesting a potential contribution of peripheral factors to the development of Alzheimer's disease endophenotypes. Targeting pathways represented by these peripheral proteins may modify Alzheimer's disease risk or disease progression.
临床阿尔茨海默病目前的特征是与认知障碍相关的脑β淀粉样变性。然而，大多数阿尔茨海默病病例在尸检时与多种神经病理学相关。与这些疾病内表型相关的外周蛋白变化了解甚少。在本研究中，我们分析了来自四个队列（n = 2139名参与者）个体的血浆蛋白质组，以鉴定与脑β淀粉样变性和其他神经病理学相关的蛋白质和通路，包括tau、路易小体、TDP43、脑淀粉样血管病、动脉粥样硬化、小动脉硬化和梗死以及认知功能。对一个具有配对脑数据的队列进行的分析表明，已知的神经病理学仅能解释与认知功能相关蛋白质的一半，并且许多与这些神经病理学相关的血浆蛋白与脑内水平的相关性不强，这表明外周因素对阿尔茨海默病内表型的发展可能有贡献。以这些外周蛋白所代表的通路为靶点可能会改变阿尔茨海默病的风险或疾病进展。
