Alzheimers Res Ther. 2026 May 7. doi: 10.1186/s13195-026-02043-2. Online ahead of print.
ABSTRACT
BACKGROUND: Brain endothelial dysfunction is an early pathological feature of Alzheimer disease (AD). We here investigate associations of the brain endothelial glycocalyx protein, syndecan-4 (SDC4), with amyloid and tau pathologies and cognitive impairment in a large longitudinal cohort of AD and controls.
METHODS: The study included n = 1,041 (n = 802 cognitively unimpaired and n = 239 cognitively impaired) participants who underwent biological classification using the NIA-AA “ATN” framework. Cognitive assessments included the Clinical Dementia Rating®-sum of boxes and the Knight- Preclinical Alzheimer’s Cognitive Composite. Cerebrospinal fluid (CSF) measures of SDC4 and emerging AD biomarkers were obtained using Olink Proteomics. 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. Pseudo-time models estimated CSF biomarker trajectories across the course of AD progression.
RESULTS: CSF SDC4 levels were elevated in even the earliest preclinical stages of AD compared to controls and were closely associated with other CSF and imaging biomarkers of AD. 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 follow-up (mean, 8 years). CSF 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. SDC4 was among the top 10 most important proteins in predicting the pseudo-time models of AD progression and predicted these models to a potentially better extent than other emerging AD biomarkers.
CONCLUSION: Findings from this large longitudinal study suggest that CSF SDC4 levels are increased in the earliest preclinical stages of AD and are closely associated with the progression of amyloid and tau pathologies and future rates of cognitive decline. We propose that SDC4 upregulation is an important early event in AD pathogenesis which predicts cognitive and pathological disease trajectories.
PMID:42098850 | DOI:10.1186/s13195-026-02043-2
