Rodríguez-Fernández Blanca, González-Escalante Armand, Genius Patricia, E Evans Tavia, Ortiz-Romero Paula, Minguillón Carolina, Kollmorgen Gwendlyn, Ashton Nicholas J, Zetterberg Henrik, Blennow Kaj, Gispert Juan Domingo, Navarro Arcadi, Suárez-Calvet Marc, Sala-Vila Aleix, Crous-Bou Marta, Vilor-Tejedor Natàlia
Barcelonaβeta Brain Research Center (BBRC), Pasqual Maragall Foundation, 30 Wellington Street, Barcelona, 08005, Spain; Centre for Genomic Regulation (CRG), The Barcelona Institute for Science and Technology, 88 Doctor Aiguader Street, Ciutat Vella, Barcelona, 08003, Spain; Hospital del Mar Research Institute, 88 Doctor Aiguader Street, Ciutat Vella, Barcelona, 08003, Spain; Universitat Autònoma de Barcelona (UAB), Plaça Cívica, Bellaterra (Cerdanyola del Vallès), Barcelona, 08193, Spain.
Barcelonaβeta Brain Research Center (BBRC), Pasqual Maragall Foundation, 30 Wellington Street, Barcelona, 08005, Spain; Hospital del Mar Research Institute, 88 Doctor Aiguader Street, Ciutat Vella, Barcelona, 08003, Spain; Universitat Pompeu Fabra (UPF), 10-12 Plaça de la Mercè, Barcelona, 08002, Spain.
EBioMedicine. 2025 Aug 19;119:105886. doi: 10.1016/j.ebiom.2025.105886.
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.
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.
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.
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.
AARG-19-618265; PI19/00119; LCF/PR/GN17/10300004; TriBEKa-17-519007; # SLT002/16/00201.
短端粒长度（TL）是生物衰老的一个标志，与阿尔茨海默病（AD）风险增加有关，但其病理生理作用仍不清楚。本研究探讨了AD连续体早期阶段血液白细胞TL（LTL）、脑脊液（CSF）AD生物标志物变化与脑结构之间的关系。
我们纳入了来自ALFA队列的346名认知未受损参与者（年龄49 - 71岁），这些参与者AD风险较高（53.2%为APOE-ε4携带者；34%为淀粉样蛋白阳性）。在基线（访视0）时使用定量PCR测量LTL。评估基线LTL与访视1时CSF生物标志物之间的关联（从基线开始的平均随访时间 = 3.98年，标准差 = 1.02），以及与访视1和访视2之间CSF生物标志物变化的关联（平均间隔 = 3.45年，标准差 = 0.58）。在访视1时通过磁共振成像（MRI）评估衰老和AD易损脑区的皮质厚度。分析按APOE-ε4状态和淀粉样蛋白 - tau（AT）谱分层。中介模型测试CSF生物标志物是否介导LTL - 皮质厚度关联。
较短的LTL与访视1时较高的星形胶质细胞反应性以及随时间增加的突触功能障碍相关。在APOE-ε4携带者和AT阳性个体中，较短的LTL与较高的p - tau181和神经退行性变标志物相关。较短的LTL与衰老和AD易损区域更大的皮质厚度相关，部分由星形胶质细胞反应性生物标志物介导。
这些发现表明，较短的端粒可能通过涉及星形胶质细胞反应性和脑结构改变的机制与早期AD相关生物变化有关。LTL可能作为高危人群神经退行性变过程易感性的早期标志物。
AARG - 19 - 618265；PI19/00119；LCF/PR/GN17/10300004；TriBEKa - 17 - 519007；# SLT002/16/00201。
