Plasma Synaptic Biomarkers and Clinical Progression in Mild-to-Moderate Alzheimer Disease

Abstract Background Blood-based biomarkers of amyloid and tau pathology are transforming Alzheimer disease (AD) diagnosis. However, biomarkers reflecting neurobiological processes associated with severity and progression remain less well established. Methods We measured 129 plasma proteins using NULISA-Seq™ in 307 individuals with mild-to-moderate AD. Clinical Dementia Rating – Sum of Boxes (CDR-Sb), Alzheimer Disease Assessment Scale – Cognitive Subscale (ADAS-Cog) and Disability Assessment for Dementia (DAD) were assessed at baseline, 12 and 18 months. Baseline and longitudinal associations were examined using linear and mixed-effects regression with multiple testing correction and adjustment for important clinical covariates. Complementary elastic-net analysis incorporated bootstrap stability selection and Bayesian Information Criterion based model refinement. Prioritised proteins identified were then evaluated in addition to established AD biomarkers including brain-derived phosphorylated tau-217 (BD-pTau217), glial fibrillary acidic protein (GFAP) and neurofilament light (NfL). Results Forty-four proteins were associated with baseline severity and 22 with progression. Synaptic and neuronal network proteins emerged consistently across analyses, in particular Neuronal Pentraxin Receptor (NPTXR). The highest vs lowest NPTXR tertile was associated with lower baseline CDR-Sb (β: -1.83; 95% confidence interval − 2.70 to -0.96; p < 0.001) and slower CDR-Sb progression (β: -0.51; 95% confidence interval − 0.99, -0.03; p = 0.04 per year). NPTXR increased explained variance beyond clinical variables, BD-pTau217, GFAP and NfL by up to 8.0% at baseline and 6.0% longitudinally. In addition to NPTXR, Neuronal Pentraxin 2 (NPTX2) was consistently associated with baseline disease severity whilst Fatty acid binding protein 3 (FABP3) provided additional information on clinical progression. Associations between β-synuclein and clinical progression were more modest and attenuated in sensitivity analyses. Conclusions Synaptic and neuronal network proteins were consistently associated with AD severity and progression. NPTXR provided complementary information beyond established biomarkers, supporting NPTXR as a marker of synaptic dysfunction in the clinical expression of AD. These findings warrant confirmation in independent cohorts and further evaluation of their potential to inform prognosis in established AD.