D016 Alix as a potential biomarker for disease progression in Huntington’s disease

<h3>Background</h3> Impairment of the endosomal/lysosomal system is present in HD. Indeed, we previously described reduced levels of Alix, a protein associated with this system and neuronal death, in postmortem HD brains. <h3>Aims</h3> Here, we investigated whether alterations in Alix protein levels could be detected in cerebrospinal fluid (CSF) of HD mutation carriers, potentially serving as a novel disease biomarker. <h3>Methods</h3> In a cross-sectional study, we analyzed CSF from HD mutation carriers and controls. Alix was measured by ELISA, displaying linearity (37–530 pg/mL) and low intra- and interplate coefficients of variation (5%). <h3>Results</h3> Our data show reduced Alix expression in CSF from presymptomatic HD mutation carriers, with increased levels in symptomatic individuals (figure 1). Given that our data in the brain mirrored the decrease of Alix seen in premanifest individuals, correlations were firstly performed considering only this subgroup of HD carriers. Notably, Alix positively correlated with striatal volume (r=0.45, p&lt;0.05) (figure 2). Subsequently, we examined the entire cohort collectively. Alix expression inversely correlated with CAG age product (r=0.43, p&lt;0.01) (figure 3), indicating a close association with disease progression. Furthermore, Alix expression correlated with standardized clinical scales for HD, including the composite Unified Huntington9s Disease Rating Scale (r=-0.38, p&lt;0.05) (figure 4). Correlations were also observed between Alix and CSF biomarkers of neuronal cell damage, including tau (r=0.62, p&lt;0.001) and neurofilament light chain (r=0.40, p&lt;0.01) (figure 5). <h3>Conclusions</h3> Our findings suggest Alix as a potential peripheral biomarker for HD progression, warranting further exploration into its roles in HD pathogenesis.