Peripheral Syndecan-3 and Neurofilament Light Chain as Complementary Blood Biomarkers for Alzheimer's Disease

Reliable and disease-specific blood biomarkers are critically needed for Alzheimer's disease (AD), particularly in early stages when interventions are most effective. Although phosphorylated tau and neurofilament light chain (NfL) are widely used, their diagnostic specificity has been reported to decrease in elderly populations with multimorbidities. Syndecan-3 (SDC3), a heparan sulfate proteoglycan implicated in amyloid and tau aggregation, has recently emerged as a mechanistically relevant biomarker candidate. In this clinically realistic cohort study, we examined 46 participants, including 23 clinically diagnosed AD patients and 23 age-matched non-AD individuals with psychiatric and/or metabolic comorbidities. SDC3 expression was quantified in peripheral blood mononuclear cells (PBMCs), while soluble SDC3 and NfL were measured in plasma. Both PBMC-expressed and plasma SDC3 levels were elevated in AD compared with non-AD participants and showed a strong intercorrelation, whereas plasma NfL was likewise increased in AD. Individually, PBMC-SDC3, plasma SDC3, and NfL demonstrated moderate discriminatory performance. However, multivariable models integrating SDC3 (PBMC or plasma), NfL, and age achieved substantially improved discrimination (AUC > 0.8). SDC3 did not correlate with NfL, consistent with a biological signal distinct from neuroaxonal injury and reflective of peripheral immune-metabolic remodeling. Together, these findings identify SDC3 as a blood-based biomarker associated with systemic immune remodeling that complements established neuronal markers in a clinically realistic AD versus non-AD comparison. While exploratory, this study supports further investigation of SDC3 within integrated, multi-domain biomarker strategies in larger and independent cohorts.