Giorgio Joseph, Jonson Caroline, Wang Yilin, Yokoyama Jennifer S, Wang Jingshen, Jagust William
Department of Neuroscience, University of California Berkeley, Berkeley, California, USA, 94720.
School of Psychological Sciences, College of Engineering, Science and the Environment, University of Newcastle, Newcastle, New South Wales, Australia, 2308.
Res Sq. 2024 Aug 9:rs.3.rs-4804430. doi: 10.21203/rs.3.rs-4804430/v1.
The canonical AD pathological cascade posits that the accumulation of amyloid beta ( ) is the initiating event, accelerating the accumulation of tau in the entorhinal cortex (EC), which subsequently spreads into the neocortex. Here in a sample of over 1300 participants with multimodal imaging and genetic information we queried how genetic variation affects these stages of the AD cascade. We observed that females and homozygotes are more susceptible to the effects of on the primary accumulation of tau, with greater EC tau for a given level of . Furthermore, we observed for individuals who have rare risk variants in Triggering Receptor Expressed on Myeloid Cells 2 () and/or homozygotes there was a greater spread of primary tau from the EC into the neocortex. These findings offer insights into the function of sex, APOE and microglia in AD progression, and have implications for determining personalised treatment with drugs targeting and tau.
经典的阿尔茨海默病（AD）病理级联假说认为，β淀粉样蛋白（Aβ）的积累是起始事件，加速了内嗅皮质（EC）中tau蛋白的积累，随后tau蛋白扩散到新皮质。在这个包含1300多名参与者的样本中，我们拥有多模态成像和基因信息，据此探究了基因变异如何影响AD级联反应的这些阶段。我们观察到，女性和APOE ε4纯合子更容易受到Aβ对tau蛋白初始积累的影响，在给定的Aβ水平下，内嗅皮质的tau蛋白含量更高。此外，我们还观察到，对于在髓样细胞2（TREM2）上表达的触发受体有罕见风险变异的个体和/或APOE ε4纯合子，初始tau蛋白从内嗅皮质扩散到新皮质的程度更大。这些发现为性别、载脂蛋白E（APOE）和小胶质细胞在AD进展中的作用提供了见解，并且对于确定针对Aβ和tau蛋白的个性化药物治疗具有重要意义。
