Barcelonaβeta Brain Research Center (BBRC), Pasqual Maragall Foundation, Barcelona, Spain.
IMIM (Hospital del Mar Medical Research Institute), Barcelona, Spain.
Alzheimers Dement. 2020 Oct;16(10):1358-1371. doi: 10.1002/alz.12131. Epub 2020 Jun 23.
The biological pathways involved in the preclinical stage of the Alzheimer's continuum are not well understood.
We used NeuroToolKit and Elecsys immunoassays to measure cerebrospinal fluid (CSF) amyloid-β (Aβ)42, Aβ40, phosphorylated tau (p-tau), total tau (t-tau), neurofilament light (NfL), neurogranin, sTREM2, YKL40, GFAP, IL6, S100, and α-synuclein in cognitively unimpaired participants of the ALFA+ study, many within the Alzheimer's continuum.
CSF t-tau, p-tau, and neurogranin increase throughout aging only in Aβ-positive individuals, whereas NfL and glial biomarkers increase with aging regardless of Aβ status. We modelled biomarker changes as a function of CSF Aβ42/40, p-tau and p-tau/Aβ42 as proxies of disease progression. The first change observed in the Alzheimer's continuum was a decrease in the CSF Aβ42/40 ratio. This is followed by a steep increase in CSF p-tau; t-tau; neurogranin; and, to a lesser extent, in NfL and glial biomarkers.
Multiple biological pathways are altered and could be targeted very early in the Alzheimer's continuum.
阿尔茨海默病连续体的临床前阶段涉及的生物学途径尚不清楚。
我们使用 NeuroToolKit 和 Elecsys 免疫测定法测量认知正常的 ALFA+研究参与者的脑脊液（CSF）中的淀粉样蛋白-β（Aβ）42、Aβ40、磷酸化 tau（p-tau）、总 tau（t-tau）、神经丝轻链（NfL）、神经颗粒蛋白、sTREM2、YKL40、GFAP、IL6、S100 和α-突触核蛋白，其中许多人处于阿尔茨海默病连续体中。
CSF t-tau、p-tau 和神经颗粒蛋白仅在 Aβ 阳性个体中随着年龄的增长而增加，而 NfL 和神经胶质生物标志物则无论 Aβ 状态如何随着年龄的增长而增加。我们将生物标志物的变化建模为 CSF Aβ42/40、p-tau 和 p-tau/Aβ42 的函数，作为疾病进展的替代物。在阿尔茨海默病连续体中观察到的第一个变化是 CSF Aβ42/40 比值的降低。随后，CSF p-tau、t-tau、神经颗粒蛋白急剧增加；在一定程度上，NfL 和神经胶质生物标志物也会增加。
多个生物学途径发生改变，并且可能在阿尔茨海默病连续体的早期阶段得到靶向治疗。
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