Blood-based (BB) biomarkers for Aβ and tau can indicate pathological processes in the brain, in the early pathological, even pre-symptomatic stages in Alzheimer’s disease. However, the relation between BB biomarkers and AD-related processes in the brain in the earliest pre-pathology stage before amyloid pathology develops, and their relation with total brain concentrations of Aβ and tau, is poorly understood. This stage presents a critical window for the earliest prevention of AD. Preclinical models with well-defined temporal progression to robust amyloid and tau pathology provide a unique opportunity to study this relation and were used here to study the link between BB biomarkers with AD-related processes in pre- and pathological stages. We performed a cross-sectional study at different ages assessing the link between BB concentrations and AD-related processes in the brain. This was complemented with a longitudinal analysis and with analysis of age-related changes in a small cohort of human subjects. We found that BB-tau concentrations increased in serum, correlating with progressive development of tau pathology and with increasing tau aggregates and p-tau concentrations in brain in TauP301S mice (PS19) developing tauopathy. BB-Aβ42 concentrations in serum decreased between 4.5 and 9 months of age, correlating with the progressive development of robust amyloid pathology in APP/PS1 (5xFAD) mice, in line with previous findings. Most importantly, BB-Aβ42 concentrations significantly increased between 1.5 and 4.5 months, i.e., in the earliest pre-pathological stage, before robust amyloid pathology develops in the brain, indicating biphasic BB-Aβ42 dynamics. Furthermore, increasing BB-Aβ42 in the pre-pathological phase, strongly correlated with increasing Aβ42 concentrations in brain. Our subsequent longitudinal analysis of BB-Aβ42 in 5xFAD mice, confirmed biphasic BB-Aβ42, with an initial increase, before decreasing with progressive robust pathology. Furthermore, in human samples, BB-Aβ42 concentrations were significantly higher in old (> 60 years) compared to young (< 50 years) subjects, as well as to age-matched AD patients, further supporting age-dependent increase of Aβ42 concentrations in the earliest pre-pathological phase, before amyloid pathology. Also BB-Aβ40 concentrations were found to increase in the earliest pre-pathological phase both in preclinical models and human subjects, while subsequent significantly decreasing concentrations in the pathological phase were characteristic for BB-Aβ42. Together our data indicate that BB biomarkers reflect pathological processes in brain of preclinical models with amyloid and tau pathology, both in the pathological and pre-pathological phase. Our data indicate a biphasic pattern of BB-Aβ42 in preclinical models and a human cohort. And most importantly, we here show that BB-Aβ increased and correlated with increasing concentrations of Aβ in the brain, in the earliest pre-pathological stage in a preclinical model. Our data thereby identify a novel critical window for prevention, using BB-Aβ as marker for accumulating Aβ in the brain, in the earliest pre-pathological stage, opening new avenues for personalized early preventive strategies against AD, even before amyloid pathology develops.

Aβ 和 tau 的基于血液 (BB) 的生物标志物可以指示大脑中的病理过程，在阿尔茨海默病的早期病理阶段，甚至是症状前阶段。然而，在淀粉样蛋白病理发展之前的最早的病理前阶段，BB 生物标志物与大脑中 AD 相关过程之间的关系，以及它们与 Aβ 和 tau 总脑浓度的关系知之甚少。这一阶段为尽早预防 AD 提供了一个关键窗口。具有明确时间进展到稳健的淀粉样蛋白和 tau 病理学的临床前模型为研究这种关系提供了独特的机会，并在此用于研究 BB 生物标志物与前期和病理阶段的 AD 相关过程之间的联系。我们在不同年龄进行了一项横断面研究，评估了大脑中 BB 浓度与 AD 相关过程之间的联系。这与纵向分析和对一小群人类受试者年龄相关变化的分析相辅相成。我们发现血清中的 BB-tau 浓度增加，与 tau 病理的进行性发展以及 TauP301S 小鼠 (PS19) 发展为 tau 病变的脑中 tau 聚集体和 p-tau 浓度增加相关。血清中的 BB-Aβ42 浓度在 4.5 到 9 个月之间下降，这与 APP/PS1 (5xFAD) 小鼠中稳健的淀粉样蛋白病理的逐渐发展相关，这与之前的研究结果一致。最重要的是，BB-Aβ42 浓度在 1.5 到 4.5 个月之间显着增加，即在最早的病理前阶段，在大脑中出现强大的淀粉样蛋白病理之前，表明双相 BB-Aβ42 动力学。此外，在病理前期增加 BB-Aβ42 与脑中 Aβ42 浓度的增加密切相关。我们随后对 5xFAD 小鼠中的 BB-Aβ42 进行纵向分析，证实了双相 BB-Aβ42，最初增加，然后随着进行性强健病理而降低。此外，在人体样本中，与年轻（< 50 岁）受试者以及年龄匹配的 AD 患者相比，老年人（> 60 岁）的 BB-Aβ42 浓度显着更高，这进一步支持了 Aβ42 浓度的年龄依赖性增加。最早的病理前阶段，在淀粉样蛋白病理之前。在临床前模型和人类受试者中，发现 BB-Aβ40 浓度在最早的病理前阶段增加，而随后在病理阶段显着降低的浓度是 BB-Aβ42 的特征。我们的数据共同表明，BB 生物标志物反映了具有淀粉样蛋白和 tau 病理学的临床前模型大脑中的病理过程，无论是在病理阶段还是病理前阶段。我们的数据表明 BB-Aβ42 在临床前模型和人类队列中的双相模式。最重要的是，我们在这里表明，在临床前模型中最早的病理前阶段，BB-Aβ 增加并与脑中 Aβ 浓度增加相关。因此，我们的数据确定了一个新的预防关键窗口，使用 BB-Aβ 作为在最早的病理前阶段在大脑中积累 Aβ 的标志物，为针对 AD 的个性化早期预防策略开辟了新途径，