Department of Epidemiology and Biostatistics, George Washington University Milken Institute School of Public Health, Washington, DC.
Department of Neurology, Massachusetts General Hospital, Harvard Medical School, Boston, MA.
Ann Neurol. 2018 Jul;84(1):10-22. doi: 10.1002/ana.25246. Epub 2018 Jun 26.
Our objectives were to characterize the inter-relation of known dementia-related neuropathologies in one comprehensive model and quantify the extent to which accumulation of neuropathologies accounts for the association between age and dementia.
We used data from 1,362 autopsied participants of three community-based clinicopathological cohorts: the Religious Orders Study, the Rush Memory and Aging Project, and the Minority Aging Research Study. We estimated a series of structural equation models summarizing a priori hypothesized neuropathological pathways between age and dementia risk individually and collectively.
At time of death (mean age, 89 years), 44% of our sample had a clinical dementia diagnosis. When considered individually, our vascular, amyloid/tau, neocortical Lewy body, and TAR DNA-binding protein 43 (TDP-43)/hippocampal sclerosis pathology pathways each accounted for a substantial proportion of the association between age and dementia. When considered collectively, the four pathways fully accounted for all variance in dementia risk previously attributable to age. Pathways involving amyloid/tau, neocortical Lewy bodies, and TDP-43/hippocampal sclerosis were interdependent, attributable to the importance of amyloid beta plaques in all three. The importance of the pathways varied, with the vascular pathway accounting for 32% of the association between age and dementia, wheraes the remaining three inter-related degenerative pathways together accounted for 68% (amyloid/tau, 24%; the Lewy body, 1%; and TDP-43/hippocampal sclerosis, 43%).
Age-related increases in dementia risk can be attributed to accumulation of multiple pathologies, each of which contributes to dementia risk. Multipronged approaches may be necessary if we are to develop effective therapies. Ann Neurol 2018;84:10-22.
我们的目的是在一个综合模型中描述已知与痴呆相关的神经病理学之间的相互关系，并量化神经病理学的积累在多大程度上解释了年龄与痴呆之间的关联。
我们使用了来自三个基于社区的临床病理队列的 1362 名尸检参与者的数据：宗教秩序研究、拉什记忆和衰老项目以及少数族裔衰老研究。我们估计了一系列结构方程模型，这些模型单独和集体总结了年龄与痴呆风险之间预先假设的神经病理学途径。
在死亡时（平均年龄 89 岁），我们样本的 44%有临床痴呆诊断。当单独考虑时，我们的血管、淀粉样蛋白/tau、新皮质路易体和 TAR DNA 结合蛋白 43（TDP-43）/海马硬化病理学途径各自解释了年龄与痴呆之间关联的很大一部分。当集体考虑时，这四个途径完全解释了以前归因于年龄的痴呆风险的所有差异。涉及淀粉样蛋白/tau、新皮质路易体和 TDP-43/海马硬化的途径是相互依存的，这归因于淀粉样β斑块在所有三种途径中的重要性。途径的重要性各不相同，血管途径占年龄与痴呆之间关联的 32%，而其余三个相互关联的退行性途径共同占 68%（淀粉样蛋白/tau，24%；路易体，1%；TDP-43/海马硬化，43%）。
痴呆风险的年龄相关性增加可归因于多种病理学的积累，每种病理学都有助于痴呆风险。如果我们要开发有效的治疗方法，可能需要采取多管齐下的方法。
Ann Neurol 2018;84:10-22.
