Longer leukocyte telomere length is associated with lower markers of early Alzheimer's disease pathology, astrocytic reactivity, and synaptic dysfunction

Abstract Background Leukocyte telomere length (LTL) serves as a proxy for tissue‐specific TL and peripheral immune aging. Its association with aging‐related brain endophenotypes, cognitive functioning, and Alzheimer's disease (AD) risk is established, but the underlying molecular mechanisms remain elusive. Investigating LTL's association with AD biomarkers is crucial for identifying its role in brain resilience and disease progression. Method We included middle‐aged adults at risk of AD dementia from the ALFA+ study. In CSF, we measured Aβ42, Aβ40, NfL, GFAP, α‐synuclein, neurogranin, S100B, sTREM2, YKL40, and IL6 using the exploratory Roche NeuroToolKit robust prototype assays; p‐tau181 was measured using Elecsys ® ; GAP‐43 using an in‐house ELISA; and Synaptotagmin‐1 using mass spectrometry. In plasma, we measured Aβ42, Aβ40, p‐tau231, NfL, and GFAP using Simoa. LTL was determined by qPCR from DNA extracted from peripheral blood leukocytes. Multiple linear regression models were used to evaluate the association between LTL and both baseline and the change in CSF and plasma biomarker levels over a three‐year period. Models accounted for age, sex and APOE‐ε4 status, and time between measurements, when interrogating the change in biomarkers. Sensitivity analyses included models adjusted by CSF Aβ42/40, CSF p‐tau181. Sex‐, APOE‐ε4 and disease‐specific effects were explored through interaction and stratified models. Result In plasma, longer LTL was associated with lower plasma p‐tau231 at baseline [Figure 1A]. This association was mainly driven by women [Figure 1B]. In CSF, longer LTL was associated with reduced S100B at baseline [Figure 2A] and decreased α‐synuclein over time [Figure 2B], independently of CSF Aβ42/40 and p‐tau181 levels. Over time, longer LTL was associated with increasing CSF IL6 levels among A+T‐ individuals, while the opposite direction was observed among A+T+ individuals [Figure 3A‐3B]. Conclusion Longer LTL was associated with lower plasma p‐tau231, an early marker of AD pathology, specifically in women. Furthermore, longer LTL was independently associated with lower biomarkers of astrocytic and synaptic dysfunction, regardless of AD pathology. Nevertheless, an AT‐dependent shift in LTL's impact on CSF IL6 change emerged over time. These results collectively propose that peripheral immune aging could be related to the central nervous system along the AD continuum, either independently or in a sex‐ and disease‐specific manner.