Proteome-wide association study identifies novel Alzheimer's disease-associated proteins

Area of Science:

• Neuroscience
• Genetics
• Biochemistry

Background:

• Alzheimer's disease (AD) is a progressive neurodegenerative disorder with limited therapeutic interventions.
• Identifying factors influencing AD risk and progression is crucial for developing effective strategies.

Purpose of the Study:

• To identify plasma proteins with genetically regulated levels associated with Alzheimer's disease (AD) and related cognitive phenotypes.
• To explore the mechanistic links between these proteins, AD risk, and brain structure.

Main Methods:

• Proteome-wide association study (PWAS) using UK Biobank plasma proteomic data (N=45,540).
• Genome-wide association study for AD (N=487,511).
• Longitudinal analyses of AD and mild cognitive disorder (MCD), cross-sectional hippocampal volume studies, and protein-protein interaction network analysis.

Main Results:

• Identified 30 AD-associated plasma proteins, including 13 novel candidates (e.g., FES, LRP11, HDGF).
• PILRB and FES showed associations with AD and/or MCD in longitudinal studies.
• LRP11 levels correlated with increased hippocampal volume and reduced AD risk, while HDGF levels correlated with decreased hippocampal volume and increased AD risk.

Conclusions:

• Discovered 13 novel plasma protein candidates associated with AD risk and hippocampal volume.
• Established potential mechanistic links between identified proteins (PILRA, PILRB, FES, LRP11) and AD pathology.
• Findings provide novel insights into AD pathogenesis and potential biomarkers.