Early Syndecan-4 Upregulation Predicts Cognitive and Pathological Trajectories in Alzheimer Disease

Objective: Brain endothelial dysfunction is an early pathological feature of Alzheimer disease (AD). Syndecan-4 (SDC4) is a heparan sulfate proteoglycan which is an important component of the brain endothelial glycocalyx. In this study, we investigate SDC4 associations with amyloid and tau pathologies and cognitive impairment in a large longitudinal cohort of AD, including preclinical AD, and controls. Methods: The study included n=1,041 (n=802 cognitively unimpaired and n=239 cognitively impaired) participants. Biological classification using the National Institute of Aging- Alzheimer's Association (ATN) framework was performed in all participants. Cognitive assessments included the Clinical Dementia Rating-sum of boxes and the Knight- Preclinical Alzheimer's Cognitive Composite which includes episodic memory, language, and executive function scores. Cerebrospinal fluid (CSF) total tau, p-tau181, and Abeta42/Abeta40 levels were measured using Lumipulse assays. CSF measures of SDC4 and established AD biomarkers were obtained using the Explore HT Olink Proteomics platform. Amyloid-PET (n=719) and tau-PET (n=302) scans were performed in subsets of participants. Partial correlations and linear mixed models, respectively, examined cross-sectional and longitudinal associations of CSF SDC4 levels with amyloid-PET and tau-PET burden and cognition adjusting for co-variates. CSF biomarker trajectories across the course of AD progression were estimated using pseudo-time models. Results: CSF SDC4 levels were elevated in AD, including the earliest preclinical stages, compared to controls and were closely associated with CSF and imaging biomarkers of amyloid and tau, and CSF biomarkers of neuronal and synaptic injury, astrocytic reactivity and microglial dysregulation. Higher CSF SDC4 levels correlated with higher global and regional amyloid-PET and tau-PET burden and worse baseline cognition. Higher baseline CSF SDC4 levels predicted more rapid progression of brain amyloid and tau, and faster decline in global cognition, episodic memory, language, and executive functions over a mean follow-up period of 8 years. SDC4 associations with cognition were mainly mediated by global tau-PET burden. Importantly, our pseudo-time models estimate that SDC4 upregulation begins very early in AD pathogenesis near the point of amyloid-positivity and increases more robustly following the point of tau-positivity. In our cohort, SDC4 was among the top 10 most important proteins (of >5,000 examined proteins) in predicting the pseudo-time models of AD progression and predicted these models to a potentially better extent than established AD biomarkers. Interpretation: Findings from this large translational longitudinal study suggest close associations of SDC4 upregulation with the progression of brain amyloid and tau pathologies in AD including the early preclinical stages. Further, we here demonstrate the ability of early increases in CSF SDC4 levels to predict trajectories of future cognitive decline over a mean follow-up period of 8 years. Therefore, we propose that SDC4 upregulation, as a potential surrogate of brain endothelial dysfunction, is an early event in AD pathogenesis which can reliably predict cognitive and pathological disease trajectories.