Mengel David, Soter Ester, Ott Julia Maren, Wacker Madeleine, Leyva Alejandra, Peters Oliver, Hellmann-Regen Julian, Schneider Luisa-Sophie, Wang Xiao, Priller Josef, Spruth Eike, Altenstein Slawek, Schneider Anja, Fliessbach Klaus, Wiltfang Jens, Hansen Niels, Rostamzadeh Ayda, Düzel Emra, Glanz Wenzel, Incesoy Enise I, Buerger Katharina, Janowitz Daniel, Ewers Michael, Perneczky Robert, Rauchmann Boris, Teipel Stefan, Kilimann Ingo, Laske Christoph, Sodenkamp Sebastian, Spottke Annika, Brustkern Johanna, Brosseron Frederic, Wagner Michael, Stark Melina, Kleineidam Luca, Shao Kai, Lüsebrink Falk, Yakupov Renat, Schmid Matthias, Hetzer Stefan, Dechent Peter, Scheffler Klaus, Berron David, Jessen Frank, Synofzik Matthis
Division Translational Genomics of Neurodegenerative Diseases, Hertie-Institute for Clinical Brain Research and Center of Neurology, University of Tübingen, Hoppe-Seyler-Str. 3, 72076, Tübingen, Germany.
German Center for Neurodegenerative Diseases (DZNE), University of Tübingen, Otfried-Müller-Straße 27, 72076, Tübingen, Germany.
Mol Psychiatry. 2025 Apr 18. doi: 10.1038/s41380-025-03021-0.
Subjective cognitive decline (SCD) is proposed as an indicator of transitional disease stage 2 in the Alzheimer's disease (AD) continuum. However, molecular and particularly longitudinal fluid biomarker data for this stage are still limited. This study aimed to determine whether blood-based biomarkers in amyloid-positive individuals with SCD (A + SCD) support the notion of stage 2 as a distinct stage between stages 1 and 3 of AD and to identify those at high risk for clinical progression. In a prospective multicenter study (DELCODE) involving 457 participants across the AD continuum, we analyzed plasma phospho-tau 181 (p181) and neurofilament light chain (NfL) and assessed their association with longitudinal cognition, hippocampal atrophy, and AD clinical stage transition. The results showed that baseline plasma p181 levels were elevated and increased more rapidly in A + SCD individuals compared to amyloid-positive cognitively unimpaired (A + CU) individuals (stage 1). NfL levels rose across A + CU, A + SCD, and amyloid-positive mild cognitive impairment (A + MCI, stage 3). In A + SCD, but not in A + CU, higher p181 levels predicted cognitive decline (PACC5) and transition to MCI. In conclusion, plasma p181 provides molecular biomarker evidence supporting A + SCD as a pre-dementia AD stage (stage 2) distinct from A + CU (stage 1) and helps identify individuals at risk for cognitive decline early in the AD continuum.
主观认知衰退（SCD）被提议作为阿尔茨海默病（AD）连续体中过渡性疾病阶段2的一个指标。然而，该阶段的分子，尤其是纵向液体生物标志物数据仍然有限。本研究旨在确定淀粉样蛋白阳性的SCD个体（A+SCD）的血液生物标志物是否支持阶段2作为AD阶段1和阶段3之间一个独特阶段的概念，并识别出临床进展高风险个体。在一项涉及AD连续体中457名参与者的前瞻性多中心研究（DELCODE）中，我们分析了血浆磷酸化tau181（p181）和神经丝轻链（NfL），并评估了它们与纵向认知、海马萎缩和AD临床阶段转变的关联。结果显示，与淀粉样蛋白阳性认知未受损（A+CU）个体（阶段1）相比，A+SCD个体的基线血浆p181水平升高且升高速度更快。NfL水平在A+CU、A+SCD和淀粉样蛋白阳性轻度认知障碍（A+MCI，阶段3）个体中均有升高。在A+SCD个体中，而非A+CU个体中，较高的p181水平预测了认知衰退（PACC5）和向MCI的转变。总之，血浆p181提供了分子生物标志物证据，支持A+SCD作为一个不同于A+CU（阶段1）的痴呆前AD阶段（阶段2），并有助于在AD连续体早期识别出认知衰退风险个体。
