Basic Science and Pathogenesis.

Area of Science:

• Neuroscience
• Genetics
• Proteomics

Background:

• Apolipoprotein E ε4 (APOE4) is the primary genetic risk factor for Alzheimer's disease (AD).
• APOE4 carriers also exhibit increased risk and altered disease progression in frontotemporal dementia (FTD) and Parkinson's disease (PD).
• Underlying mechanisms linking APOE4 to these neurodegenerative diseases remain largely unknown.

Purpose of the Study:

• To identify APOE4-specific molecular mechanisms across plasma, cerebrospinal fluid (CSF), and brain.
• To investigate unifying pathways affected by APOE4 carriage in neurodegenerative diseases.

Main Methods:

• Machine learning-based proteome profiling was performed on samples from APOE4 carriers and non-carriers across different neurodegenerative disease states (NI, AD, FTD, PD).
• Utilized SomaScan 7k assay and mass spectrometry for proteomic data acquisition.
• Employed mutual information, classification and regression trees, and network analyses to identify APOE4-associated proteins and their relationships with clinical variables.

Main Results:

• APOE4 carriers, irrespective of diagnosis, displayed a shared proteome signature in plasma and CSF, linked to immune dysregulation, inflammation, and nucleic acid processes.
• Brain proteome profiling confirmed these altered pathways in APOE4 carriers.
• Disease-specific correlations were observed between APOE4-associated proteins and clinical factors like lifestyle and comorbidities.

Conclusions:

• APOE4 carriage is associated with systemic biological alterations extending beyond the central nervous system.
• These systemic changes are a crucial, but not sufficient, factor in neurodegenerative disease development.
• Interactions between the APOE4 proteomic signature and lifestyle/clinical factors are disease-specific.