Basic Science and Pathogenesis

Area of Science:

• Proteomics
• Neuroscience
• Biomarker Discovery

Background:

• Alzheimer's disease (AD) exhibits significant molecular heterogeneity.
• Plasma proteomics offers a pathway to identify novel biomarkers and understand disease mechanisms.
• Classifying by amyloid and tau profiles refines the focus on distinct AD pathophysiology.

Purpose of the Study:

• To identify plasma protein signatures associated with amyloid and tau pathology in Alzheimer's disease.
• To characterize molecular subtypes of Alzheimer's disease based on protein expression.
• To evaluate LRRN1 as a diagnostic biomarker and potential therapeutic target.

Main Methods:

• Analyzed 3,635 plasma proteins from 973 participants using SOMAscan assay.
• Integrated cerebrospinal fluid (CSF) amyloid-beta (A) and phosphorylated tau (T) profiles.
• Applied linear regression and LightGBM for differential protein abundance and classification; used Non-negative Matrix Factorization (NMF) for subtype discovery.

Main Results:

• Identified 11 core differentially abundant proteins (DAPs) across AD spectrum, plus early and late DAPs.
• LRRN1 emerged as a robust predictor of AD (AUC = 0.757).
• Classified AD into four molecular subtypes based on 201 DAPs, linked to distinct pathways and clinical trajectories; subtype 4 showed strongest association with cognitive decline.

Conclusions:

• Protein signatures associated with amyloid and tau pathology were identified in clinical cohorts.
• LRRN1 is a promising candidate diagnostic biomarker and potential therapeutic target for specific AD subtypes.
• Distinct molecular subtypes of AD were revealed, offering insights into heterogeneity and personalized treatment strategies.