Shorter leukocyte telomere length is associated with distinct CSF biomarker dynamics across early AD stages in at‐risk individuals

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BACKGROUND: Shorter telomeres are a hallmark of biological aging and have been associated with an increased risk of Alzheimer's disease (AD). However, their role in AD pathophysiology remains unclear. This study investigates the relationship between telomere length (TL), longitudinal cerebrospinal fluid (CSF) AD biomarkers, and brain structure at early stages of the AD continuum. METHOD: We included 346 cognitively unimpaired participants from the ALFA+ cohort, aged 49-71 years, at increased risk for AD (53.2% APOE-ε4 carriers, 34% CSF amyloid-positive). Participants had available CSF biomarker data, structural MRI, and leukocyte TL (LTL) measured by qPCR. AD-related CSF biomarkers were assessed at baseline and longitudinally after a mean follow-up of 3.45 years (SD = 0.58) with Elecsys® and NeuroToolKit CSF immunoassays (Roche Diagnostics International Ltd). Brain signatures were derived from the average cortical thickness in aging and AD-vulnerable regions. Stratified models by APOE-ε4 status and CSF amyloid-tau (AT) classification were computed. Linear structural equation modeling was applied to assess the mediating role of CSF biomarkers in the association between LTL and cortical thickness. RESULT: Shorter LTL was associated with higher astrocytic reactivity and with longitudinal synaptic dysfunction increases. In APOE-ε4 carriers and AT-positive individuals, shorter LTL was associated with higher p-tau181 and neurodegeneration markers [Figure 1]. APOE-ε4 carriership modified the association between LTL and CSF YKL-40 and longitudinal CSF sTREM2 changes over time [Figure 2]. Additionally, shorter LTL was associated with thicker cortex in aging and AD-vulnerable regions [Figure 3A-B], with astrocytic reactivity biomarkers partially mediating this association [Figure 3C-D]. CONCLUSION: These findings suggest that shorter telomeres may contribute to early AD progression, potentially through effects on astrocytic reactivity and brain structure.

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