Argiris Georgette, Akinci Muge, Peña-Gómez Cleofé, Palpatzis Eleni, Garcia-Prat Marina, Shekari Mahnaz, Blennow Kaj, Zetterberg Henrik, Kollmorgen Gwendlyn, Quijano-Rubio Clara, Ashton Nicholas J, Karikari Thomas K, Brinkmalm-Westman Ann, Lantero-Rodriguez Juan, Fauria Karine, Sánchez-Benavides Gonzalo, Grau-Rivera Oriol, Suárez-Calvet Marc, Arenaza-Urquijo Eider M, Study For The Alfa
Department of Neuroscience, Columbia University, New York, NY, USA.
Barcelona Institute of Global Health (ISGlobal), Health and Environment Over the Lifecourse Programme, Barcelona, Spain.
Alzheimers Res Ther. 2024 Dec 23;16(1):274. doi: 10.1186/s13195-024-01629-y.
Cerebrospinal fluid (CSF) biomarkers of synaptic dysfunction, neuroinflammation, and glial response, complementing Alzheimer's disease (AD) core biomarkers, have improved the pathophysiological characterization of the disease. Here, we tested the hypothesis that the co-expression of multiple CSF biomarkers will help the identification of AD-like phenotypes when biomarker positivity thresholds are not met yet.
Two hundred and seventy cognitively unimpaired adults with family history (FH) of sporadic AD (mean age = 60.6 ± 4.85 years, 64.8% women) underwent lumbar puncture, magnetic resonance imaging (n = 266) and positron emission tomography imaging (n = 239) protocols, and clinical evaluations. CSF Aβ, Aβ, p-tau, p-tau p-tau NfL, neurogranin, sTREM2, YKL40, GFAP, S100, α-Synuclein, SYT1, and SNAP25 were measured. Participants were clustered based on CSF biomarker co-expression with an agglomerative algorithm. The predictive value of the classification against brain and cognitive outcomes was evaluated.
Three clusters (C) were identified. Higher Aβ burden and CSF p-tau was the hallmark of C1. The other two clusters showed lower Aβ burden but higher expression of glial (C2) or synaptic markers (C3). Participants in C1 showed an AD-like clinical phenotype, comprising participants with the overall highest percentage of two parent FH and APOE-ε4 carriers, in addition to comprising more females compared to C2. C3 displayed better vascular health compared to C1. C2 were older and comprised a lower percentage of females compared to C3. C1 showed an AD-like gray matter reduction in medial temporal (notably hippocampus) and frontal regions that were not observed in Aβ + compared with Aβ - . Furthermore, Aβ - participants in C1 showed GM reduction in inferior temporal areas compared with Aβ + participants overall. C1 membership also predicted cognitive decline in executive function, but not memory, beyond Aβ + status, overall suggesting a better prognosis in Aβ + participants without C1 membership. Additionally, C1 displayed a higher rate of conversion to Aβ + (25%) over time.
Our results suggest that examining multiple CSF biomarkers reflecting diverse pathological pathways may complement and/or outperform AD core biomarkers and thresholding approaches to identify individuals showing a clinical and cognitive AD-like phenotype, including higher conversion to Aβ + , GM reductions and cognitive decline. The clinical utility of this approach warrants further investigation and replication in other cohorts.
反映突触功能障碍、神经炎症和神经胶质反应的脑脊液（CSF）生物标志物，作为阿尔茨海默病（AD）核心生物标志物的补充，改善了该疾病的病理生理学特征描述。在此，我们检验了这样一个假设：当生物标志物阳性阈值尚未达到时，多种CSF生物标志物的共表达将有助于识别AD样表型。
270名有散发性AD家族史（FH）的认知未受损成年人（平均年龄=60.6±4.85岁，64.8%为女性）接受了腰椎穿刺、磁共振成像（n=266）和正电子发射断层扫描成像（n=239）检查以及临床评估。检测了CSF中的Aβ、Aβ、p-tau、p-tau p-tau、NfL、神经颗粒素、sTREM2、YKL40、GFAP、S100、α-突触核蛋白、SYT1和SNAP25。参与者基于CSF生物标志物共表达，采用凝聚算法进行聚类。评估了该分类对脑和认知结果的预测价值。
识别出三个聚类（C）。较高的Aβ负荷和CSF p-tau是C1的特征。另外两个聚类显示较低的Aβ负荷，但神经胶质（C2）或突触标志物（C3）表达较高。C1中的参与者表现出AD样临床表型，包括双亲FH和APOE-ε4携带者比例总体最高的参与者，此外与C2相比女性更多。与C1相比，C3显示出更好的血管健康状况。与C3相比，C
