Gillespie Nathan A, Neale Michael C, Panizzon Matthew S, McKenzie Ruth E, Tu Xin M, Xian Hong, Reynolds Chandra A, Lyons Michael J, Rissman Robert A, Elman Jeremy A, Franz Carol, Kremen William S
Virginia Institute for Psychiatric and Behaviour Genetics, Department of Psychiatry, Virginia Commonwealth University, Box 980126, Richmond, VA 23298-0126, USA.
QIMR Berghofer Medical Research Institute, 300 Herston Road, Herston, Queensland 4006, Australia.
Aging Brain. 2025 May 17;7:100139. doi: 10.1016/j.nbas.2025.100139. eCollection 2025.
The amyloid cascade hypothesis predicts that amyloid-beta (Aβ) aggregation drives tau tangle accumulation. We tested competing causal and non-causal hypotheses regarding the direction of causation between Aβ40 and Aβ42 and total Tau (t-Tau) plasma biomarkers. Plasma Aβ40, Aβ42, t-Tau, and neurofilament light chain (NFL) were measured in 1,035 men (mean = 67.0 years) using Simoa immunoassays. Genetically informative twin modeling tested the direction of causation between Aβs and t-Tau. No clear evidence that Aβ40 or Aβ42 directly causes t-Tau was observed. Instead, the alternative causal hypotheses also fit the data well. In contrast, exploratory analyses suggested a causal impact of the Aβ biomarkers on NFL. Separately, reciprocal causation was observed between t-Tau and NFL. Plasma Aβ40 or Aβ42 do not appear to have a direct causal impact on t-Tau, though our use of total rather than phosphorylated tau was a limitation. In contrast, Aβ biomarkers appeared to causally impact NFL in cognitively unimpaired men in their late 60 s.
淀粉样蛋白级联假说预测，β淀粉样蛋白（Aβ）聚集会促使tau蛋白缠结的积累。我们测试了关于Aβ40和Aβ42与总tau蛋白（t-Tau）血浆生物标志物之间因果关系方向的相互竞争的因果和非因果假说。使用Simoa免疫测定法对1035名男性（平均年龄 = 67.0岁）的血浆Aβ40、Aβ42、t-Tau和神经丝轻链（NFL）进行了测量。具有遗传信息的双生子模型测试了Aβ与t-Tau之间的因果关系方向。未观察到Aβ40或Aβ42直接导致t-Tau的明确证据。相反，其他因果假说也与数据拟合良好。相比之下，探索性分析表明Aβ生物标志物对NFL有因果影响。另外，在t-Tau和NFL之间观察到了相互因果关系。血浆Aβ40或Aβ42似乎对t-Tau没有直接因果影响，不过我们使用的是总tau蛋白而非磷酸化tau蛋白，这是一个局限性。相比之下，Aβ生物标志物似乎对60多岁认知未受损男性的NFL有因果影响。
