Large-scale plasma proteomic analysis identifies proteins and pathways associated with dementia risk

Area of Science:

• Neuroscience
• Proteomics
• Biomarkers

Background:

• Plasma proteomic changes preceding dementia onset are not well understood.
• Identifying early biomarkers could improve dementia diagnosis and treatment.

Purpose of the Study:

• To identify plasma proteins associated with incident dementia risk.
• To investigate the causal role of specific proteins in Alzheimer's disease.
• To explore the biological pathways involved in dementia pathogenesis.

Main Methods:

• Quantified 4,877 plasma proteins in nondemented older adults.
• Performed a proteome-wide association study of dementia risk over five years.
• Utilized two-sample Mendelian randomization to assess causal relationships.

Main Results:

• Thirty-eight plasma proteins were associated with incident dementia.
• Sixteen proteins showed association with dementia risk in both mid-life and late-life samples.
• SVEP1 and angiostatin were causally implicated in Alzheimer's disease.
• SVEP1 levels correlated with brain atrophy in Alzheimer's-vulnerable regions.
• Pathway analyses highlighted immune, lipid, metabolic signaling, and hemostasis pathways.

Conclusions:

• Plasma proteomic profiling can identify early dementia risk markers.
• Specific proteins, including SVEP1, may play causal roles in Alzheimer's disease.
• Immune, metabolic, and lipid pathways are implicated in dementia pathogenesis.