CSF proteomics identifies early changes in autosomal dominant Alzheimer's disease

Area of Science:

• Neuroscience
• Proteomics
• Biomarker Discovery

Background:

• Autosomal dominant Alzheimer's disease (ADAD) requires early diagnostic and monitoring tools.
• Cerebrospinal fluid (CSF) proteomic profiling offers potential for identifying novel Alzheimer's disease biomarkers.

Purpose of the Study:

• To identify early-stage cerebrospinal fluid (CSF) proteomic biomarkers for autosomal dominant Alzheimer's disease (ADAD).
• To develop predictive models for disease monitoring and therapeutic strategy development in ADAD.

Main Methods:

• High-throughput proteomic analysis of CSF from 286 ADAD mutation carriers (MCs) and 177 non-carriers (NCs).
• Development of a multi-layer regression model to identify proteins with distinct trajectories.
• Validation using independent ADAD and sporadic AD datasets, coupled with machine learning for predictive model construction.

Main Results:

• Identified 137 proteins with differential trajectories between MCs and NCs.
• Discovered eight proteins exhibiting changes preceding traditional Alzheimer's disease biomarkers.
• Characterized proteomic changes into three stages: early (stress response, metabolism), middle (neuronal death), and late presymptomatic (microglial activity).
• Developed a predictive model using a six-protein subset superior to conventional biomarkers in differentiating MCs from NCs.

Conclusions:

• Novel CSF proteomic signatures can detect early pathological changes in ADAD.
• The identified protein panels and predictive models show promise for early diagnosis and monitoring of ADAD.
• These findings pave the way for targeted interventions and treatment strategies in preclinical ADAD stages.