Longitudinal association of shorter leukocyte telomere length with CSF biomarker dynamics across early Alzheimer's disease stages in at-risk individuals.

IF 10.8 1区医学 Q1 MEDICINE, RESEARCH & EXPERIMENTAL

EBioMedicine Pub Date : 2025-09-01 Epub Date: 2025-08-19 DOI:10.1016/j.ebiom.2025.105886

Blanca Rodríguez-Fernández, Armand González-Escalante, Patricia Genius, Tavia E Evans, Paula Ortiz-Romero, Carolina Minguillón, Gwendlyn Kollmorgen, Nicholas J Ashton, Henrik Zetterberg, Kaj Blennow, Juan Domingo Gispert, Arcadi Navarro, Marc Suárez-Calvet, Aleix Sala-Vila, Marta Crous-Bou, Natàlia Vilor-Tejedor

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引用次数: 0

Abstract

Background: Short telomere length (TL), a hallmark of biological ageing, has been associated with an increased risk of Alzheimer's disease (AD), but its pathophysiological role remains unclear. This study explored the relationship between blood leukocyte TL (LTL), cerebrospinal fluid (CSF) AD biomarkers changes, and brain structure across early stages of the AD continuum.

Methods: We included 346 cognitively unimpaired participants (aged 49-71) from the ALFA cohort, enriched for AD risk (53.2% APOE-ε4 carriers; 34% amyloid-positive). LTL was measured at baseline (visit 0) using quantitative PCR. Associations were assessed between baseline LTL and CSF biomarkers at visit 1 (mean follow-up from baseline = 3.98 years, SD = 1.02), and with changes in CSF biomarkers between visits 1 and 2 (mean interval = 3.45 years, SD = 0.58). Cortical thickness in ageing- and AD-vulnerable brain regions was evaluated by magnetic resonance imaging (MRI) at visit 1. Analyses were stratified by APOE-ε4 status and amyloid-tau (AT) profiles. Mediation models tested whether CSF biomarkers mediated LTL-cortical thickness associations.

Findings: Shorter LTL was associated with higher astrocytic reactivity at visit 1 and with increased synaptic dysfunction over time. Among APOE-ε4 carriers and AT-positive individuals, shorter LTL was associated with higher p-tau181 and neurodegeneration markers. Shorter LTL was associated with greater cortical thickness in ageing- and AD-vulnerable regions, partially mediated by astrocytic reactivity biomarkers.

Interpretation: These findings suggest that shorter telomeres are associated with early AD-related biological changes, potentially via mechanisms involving astrocytic reactivity and brain structural alterations. LTL may serve as an early marker of vulnerability to neurodegenerative processes in at-risk populations.

Funding: AARG-19-618265; PI19/00119; LCF/PR/GN17/10300004; TriBEKa-17-519007; # SLT002/16/00201.

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在高危人群中，较短的白细胞端粒长度与早期阿尔茨海默病阶段脑脊液生物标志物动态的纵向关联

背景：端粒长度短（TL）是生物衰老的标志，与阿尔茨海默病（AD）的风险增加有关，但其病理生理作用尚不清楚。本研究探讨了血液白细胞TL （LTL）、脑脊液（CSF） AD生物标志物变化与AD连续体早期阶段大脑结构之间的关系。方法：我们从ALFA队列中纳入了346名认知功能未受损的参与者（49-71岁），他们的AD风险增加（53.2%的APOE-ε4携带者，34%的淀粉样蛋白阳性）。使用定量PCR在基线（第0次访问）测量LTL。评估第一次就诊时基线LTL与脑脊液生物标志物之间的相关性（从基线开始的平均随访时间为3.98年，SD = 1.02），以及第一次和第二次就诊期间脑脊液生物标志物的变化（平均间隔时间为3.45年，SD = 0.58）。在就诊1时通过磁共振成像（MRI）评估衰老和ad易感脑区皮质厚度。根据APOE-ε4状态和淀粉样蛋白（AT）谱进行分层分析。中介模型测试脑脊液生物标志物是否介导ltl -皮质厚度关联。研究发现：较短的LTL与访问1时较高的星形细胞反应性和随着时间的推移突触功能障碍增加有关。在APOE-ε4携带者和at阳性个体中，较短的LTL与较高的p-tau181和神经变性标志物相关。较短的LTL与衰老和ad易感区域的较大皮质厚度相关，部分由星形细胞反应性生物标志物介导。解释：这些发现表明，较短的端粒与早期ad相关的生物学变化有关，可能通过涉及星形细胞反应性和大脑结构改变的机制。LTL可以作为高危人群神经退行性过程易感性的早期标志。资金:aarg - 19 - 618265;PI19/00119;LCF /公关/ GN17/10300004;tribeka - 17 - 519007;# SLT002/16/00201。

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来源期刊

EBioMedicine Biochemistry, Genetics and Molecular Biology-General Biochemistry,Genetics and Molecular Biology

CiteScore

17.70

自引率

0.90%

发文量

579

审稿时长

5 weeks

期刊介绍： eBioMedicine is a comprehensive biomedical research journal that covers a wide range of studies that are relevant to human health. Our focus is on original research that explores the fundamental factors influencing human health and disease, including the discovery of new therapeutic targets and treatments, the identification of biomarkers and diagnostic tools, and the investigation and modification of disease pathways and mechanisms. We welcome studies from any biomedical discipline that contribute to our understanding of disease and aim to improve human health.