Bilgel Murat, Wong Dean F, Moghekar Abhay R, Ferrucci Luigi, Resnick Susan M
Brain Aging and Behavior Section, Laboratory of Behavioral Neuroscience, National Institute on Aging, Baltimore, MD 21224, USA.
Mallinckrodt Institute of Radiology, Washington University School of Medicine, St. Louis, MO 63110, USA.
Brain Commun. 2022 Jul 25;4(4):fcac193. doi: 10.1093/braincomms/fcac193. eCollection 2022.
Amyloid- pathology is associated with greater tau pathology and facilitates tau propagation from the medial temporal lobe to the neocortex, where tau is closely associated with local neurodegeneration. The degree of the involvement of amyloid- versus existing tau pathology in tau propagation and neurodegeneration has not been fully elucidated in human studies. Careful quantification of these effects can inform the development and timing of therapeutic interventions. We conducted causal mediation analyses to investigate the relative contributions of amyloid- and existing tau to tau propagation and neurodegeneration in two longitudinal studies of individuals without dementia: the Baltimore Longitudinal Study of Aging ( = 103, age range 57-96) and the Alzheimer's Disease Neuroimaging Initiative ( = 122, age range 56-92). As proxies of neurodegeneration, we investigated cerebral blood flow, glucose metabolism, and regional volume. We first confirmed that amyloid- moderates the association between tau in the entorhinal cortex and in the inferior temporal gyrus, a neocortical region exhibiting early tau pathology (amyloid group × entorhinal tau interaction term = 0.488, standard error [SE] = 0.126, < 0.001 in the Baltimore Longitudinal Study of Aging; = 0.619, SE = 0.145, < 0.001 in the Alzheimer's Disease Neuroimaging Initiative). In causal mediation analyses accounting for this facilitating effect of amyloid, amyloid positivity had a statistically significant direct effect on inferior temporal tau as well as an indirect effect via entorhinal tau (average direct effect =0.47, < 0.001 and average causal mediation effect =0.44, = 0.0028 in Baltimore Longitudinal Study of Aging; average direct effect =0.43, = 0.004 and average causal mediation effect =0.267, = 0.0088 in Alzheimer's Disease Neuroimaging Initiative). Entorhinal tau mediated up to 48% of the total effect of amyloid on inferior temporal tau. Higher inferior temporal tau was associated with lower colocalized cerebral blood flow, glucose metabolism, and regional volume, whereas amyloid had only an indirect effect on these measures via tau, implying tau as the primary driver of neurodegeneration (amyloid-cerebral blood flow average causal mediation effect =-0.28, = 0.021 in Baltimore Longitudinal Study of Aging; amyloid-volume average causal mediation effect =-0.24, < 0.001 in Alzheimer's Disease Neuroimaging Initiative). Our findings suggest targeting amyloid or medial temporal lobe tau might slow down neocortical spread of tau and subsequent neurodegeneration, but a combination therapy may yield better outcomes.
淀粉样蛋白病理与更严重的tau蛋白病理相关，并促进tau蛋白从内侧颞叶向新皮质传播，而tau蛋白在新皮质中与局部神经退行性变密切相关。在人类研究中，淀粉样蛋白与现有tau蛋白病理在tau蛋白传播和神经退行性变中的参与程度尚未完全阐明。对这些效应进行仔细量化可为治疗干预的开发和时机提供依据。我们进行了因果中介分析，以研究在两项针对无痴呆个体的纵向研究中，淀粉样蛋白和现有tau蛋白对tau蛋白传播和神经退行性变的相对贡献：巴尔的摩衰老纵向研究（n = 103，年龄范围57 - 96岁）和阿尔茨海默病神经影像学计划（n = 122，年龄范围56 - 92岁）。作为神经退行性变的指标，我们研究了脑血流量、葡萄糖代谢和区域体积。我们首先证实，淀粉样蛋白调节内嗅皮质和颞下回（一个表现出早期tau蛋白病理的新皮质区域）中tau蛋白之间的关联（在巴尔的摩衰老纵向研究中，淀粉样蛋白组×内嗅tau蛋白交互项β = 0.488，标准误[SE] = 0.126，p < 0.001；在阿尔茨海默病神经影像学计划中，β = 0.619，SE = 0.145，p < 0.001）。在考虑淀粉样蛋白这种促进作用的因果中介分析中，淀粉样蛋白阳性对内颞叶tau蛋白有统计学显著的直接效应，以及通过内嗅tau蛋白的间接效应（在巴尔的摩衰老纵向研究中，平均直接效应 = 0.47，p < 0.001，平均因果中介效应 = 0.44，p = 0.0028；在阿尔茨海默病神经影像学计划中，平均直接效应 = 0.43，p = 0.004，平均因果中介效应 = 0.267，p = 0.0088）。内嗅tau蛋白介导了淀粉样蛋白对内颞叶tau蛋白总效应的高达48%。较高的内颞叶tau蛋白与较低的共定位脑血流量、葡萄糖代谢和区域体积相关，而淀粉样蛋白仅通过tau蛋白对这些指标有间接效应，这意味着tau蛋白是神经退行性变的主要驱动因素（在巴尔的摩衰老纵向研究中，淀粉样蛋白 - 脑血流量平均因果中介效应 = -0.28，p = 0.021；在阿尔茨海默病神经影像学计划中，淀粉样蛋白 - 体积平均因果中介效应 = -0.24，p < 0.001）。我们的研究结果表明，针对淀粉样蛋白或内侧颞叶tau蛋白可能会减缓tau蛋白在新皮质中的传播以及随后的神经退行性变，但联合治疗可能会产生更好的效果。
