Cerebrospinal fluid NPTX1 and NPTXR predict neurodegeneration and clinical progression in Alzheimer’s disease

Identifying biomarkers that precisely track the neurodegenerative component of Alzheimer's disease (AD) is essential for effective clinical management. Here we show that cerebrospinal fluid (CSF) levels of the synaptic proteins NPTX1 and NPTXR are robust indicators of disease severity and future clinical progression. In two independent, multi-ethnic cohorts spanning the AD continuum (n = 635), lower CSF NPTX levels correlate strongly with cognitive impairment and cortical thinning in AD-vulnerable regions. Longitudinally, baseline NPTX levels predict accelerated brain atrophy and the clinical transition from mild cognitive impairment to dementia, frequently outperforming or complementing established markers such as pTau181 and neurofilament light chain. These findings establish NPTX1 and NPTXR as sensitive, stage-specific markers of synaptic integrity and neurodegeneration. By accurately forecasting disease progression, these biomarkers offer significant potential to enhance patient stratification and provide a crucial tool for monitoring the efficacy of disease-modifying therapies in clinical trials.