Identification of plasma proteins relating to brain neurodegeneration and vascular pathology in cognitively normal individuals

Liu Shi, Colin Buchanan, Simon R. Cox, Robert Hillary, Riccardo E Marioni, Archie Campbell, Caroline Hayward, Aleks Stolicyn, Heather Whalley, Mat Harris, Jennifer MJ Waymont, Gordon Waiter, Ellen Backhouse, Joanna M. Wardlaw, Douglas Steele, Andrew M McIntosh, Simon Lovestone, Noel J Buckley, Alejo J Nevado-Holgado

Research output: Contribution to journalArticlepeer-review


INTRODUCTION: This study aims to first discover plasma proteomic biomarkers relating to neurodegeneration (N) and vascular (V) damage in cognitively normal individuals and second to discover proteins mediating sex-related difference in N and V pathology.
METHODS: 5032 plasma proteins were measured in 1061 cognitively normal individuals (628 females and 433 males), nearly 90% of whom had magnetic resonance imaging measures of hippocampal volume (as N) and white matter hyperintensities (as V).
RESULTS: Differential protein expression analysis and co-expression network analysis revealed different proteins and modules associated with N and V respectively. Furthermore, causal mediation analysis revealed four proteins mediated sex-related difference in neurodegeneration and one protein mediated such difference in vascular damage.
DISCUSSION: Once validated, the identified proteins could help to select cognitively normal individuals with N and V pathology for Alzheimer’s disease clinical trials and provide targets for further mechanistic studies on brain sex-differences, leading to sex-specific therapeutic strategies.
Original languageEnglish
JournalAlzheimer's & Dementia: Diagnosis, Assessment & Disease Monitoring
Early online date27 Sep 2021
Publication statusPublished - 2021


  • plasma proteomics
  • neurodegeneration
  • vascular damage
  • sex-related difference
  • mediation


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