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Basic Science and Pathogenesis.

Hanjun Zhao1, Liu Shi1, Rashmi Maurya1

  • 1Department of Psychiatry, University of Oxford, Oxford, United Kingdom.

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|December 24, 2025
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Summary
This summary is machine-generated.

This study identifies novel Alzheimer's disease (AD) protein biomarkers in plasma, revealing distinct molecular subtypes and highlighting LRRN1 as a potential diagnostic and therapeutic target for AD.

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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.