Sex differences in CSF biomarkers profile of accelerated biological aging individuals at risk of Alzheimer’s disease

Abstract

AbstractBackgroundPrevalence of Alzheimer’s disease (AD) is higher in women than in men; however, underlying biological mechanisms remain unknown. Being aging the major risk factor for AD, sex dimorphism in biological aging could explain sex‐specific patterns of disease manifestation across the Alzheimer’s continuum. This study aimed to explore whether there are sex‐specific differences in specific biological pathways among individuals at accelerated or decelerated biological aging.MethodsThis study included 370 middle‐aged cognitively unimpaired participants at risk of AD from the Alzheimer’s and Families (ALFA) cohort (61.9% women). Telomere length (TL) was determined by qPCR from DNA extracted from peripheral blood leukocytes [Figure 1A]. TL values were normalized by computing z‐scores. Delta‐age was calculated as the residuals from regressing TL z‐scores on chronological age separately in women and men. Accelerated and decelerated aging groups were defined as those individuals in the 10th and 90th percentiles of delta‐age, respectively [Figure 1B]. Aβ42, Aβ40, CCL2, p‐tau, t‐tau, NfL, neurogranin, SNAP25, GAP43, synaptotagmin1, sTREM2, YKL40, GFAP, S100B, IL6, sVCAM1, sICAM1, and α‐synuclein were measured in CSF. Biomarker measurements were performed using immunoassays (colorimetric ELISA, MSD, Elecsys®, Simoa and the exploratory Roche NeuroToolKit robust prototype assays) and mass spectrometry. Differences on CSF biomarkers levels were assessed using non‐parametric tests for equality of means. P‐values <0.05 were considered significant. Multiple comparisons corrections were performed.ResultsLevels of CSF t‐tau, p‐tau, GAP43 and α‐synuclein were significantly higher in accelerated aging females compared to males (q‐values = 0.030, 0.031, 0.022, 0.041, respectively) [Figure 1C]. These differences were not observed when comparing the whole sample of women and men. Intra sex‐specific differences showed that the cytokine CCL2 was significantly higher in men at accelerated aging compared to men at decelerated aging (p‐value = 0.028) [Figure 1D].ConclusionsAccelerated aging women present higher levels of CSF biomarkers for tau‐pathology and synaptic dysfunction compared to their male counterparts. Accelerated biological aging could be associated with neuroinflammatory processes in cognitively unimpaired men at risk of AD. Biological aging based on TL determination could provide useful insights in tracking sex‐specific patterns of disease progression across the AD continuum.