Abstract
BACKGROUND: Recent studies have reported that Neuronal Pentraxin 2 (NPTX2), a synapse-associated protein, can significantly predict the progression of cognitive decline. However, the role of the NPTX protein family in the pathological progression of Alzheimer's Disease (AD) in humans remains unclear. METHODS: This study included 263 participants from the Alzheimer's Disease Neuroimaging Initiative, including cognitively normal, mild cognitive impairment, and AD individuals, with a mean age of 73.99 ± 7.43 years. Cerebrospinal fluid (CSF) NPTX proteins and Glial Fibrillary Acidic Protein (GFAP) were quantified by Mass spectrometry, Soluble Triggering Receptor Expressed on Myeloid Cells 2 (sTREM2) by a Meso Scale Discovery-based multiplex immunoassay, and amyloid-beta 42 (Aβ42), phosphorylated tau (P-tau), and total tau (T-tau) by Roche Elecsys immunoassays. We systematically evaluated the associations between NPTX proteins and baseline CSF AD biomarkers, as well as their relationships with longitudinal biomarker changes. Mediation models were applied to explore whether GFAP and sTREM2 mediate the associations between NPTX proteins and T-tau pathology. Additionally, subgroup analyses based on A/T/(N) classification were conducted to assess stage-specific effects, and sensitivity analyses were performed using 18 F-fluorodeoxyglucose Positron Emission Tomography in place of CSF AD biomarkers. RESULTS: We found that CSF NPTX proteins were significantly associated with CSF sTREM2 (β(NPTX1) = 0.293, p < 0.001; β(NPTX2) = 0.387, p < 0.001; β(NPR) = 0.382, p < 0.001), GFAP (β(NPTX1) = 0.274, p < 0.001; β(NPTX2) = 0.472, p < 0.001; β(NPR) = 0.444, p < 0.001), and core AD biomarkers at baseline. The association between NPTX2 and T-tau levels was significant and independent of Aβ42 (β = 0.619, p < 0.001). Mediation analyses indicated that sTREM2 and GFAP, individually or sequentially, partially mediated the associations between NPTX and T-tau pathology, with stronger effects observed in the suspected non-AD pathology and Stage 2 groups. Pathway analysis suggested that NPTX may influence tau pathology and cognitive function through the sequential sTREM2→GFAP→T-tau or P-tau pathway. CONCLUSIONS: NPTX proteins are associated with tau-related pathology in AD, and CSF GFAP and sTREM2 may mediate these associations, with their roles potentially differing across stages of disease progression.