Proteome profiling of cerebrospinal fluid using machine learning shows a unique protein signature associated with APOE4 genotype.

Journal: Aging cell
PMID: 39722190

Abstract

Proteome changes associated with APOE4 variant carriage that are independent of Alzheimer's disease (AD) pathology and diagnosis are unknown. This study investigated APOE4 proteome changes in people with AD, mild cognitive impairment, and no impairment. Clinical, APOE genotype, and cerebrospinal fluid (CSF) proteome and AD biomarker data was sourced from the Alzheimer's Disease Neuroimaging Initiative (ADNI) database. Proteome profiling was done using supervised machine learning. We found an APOE4-specific proteome signature that was independent of cognitive diagnosis and AD pathological biomarkers, and increased the risk of progression to cognitive impairment. Proteins were enriched in brain regions including the caudate and cortex and cells including endothelial cells, oligodendrocytes, and astrocytes. Enriched peripheral immune cells included T cells, macrophages, and B cells. APOE4 carriers have a unique CSF proteome signature associated with a strong brain and peripheral immune and inflammatory phenotype that likely underlies APOE4 carriers' vulnerability to cognitive decline and AD as they age.

Authors

  • Artur Shvetcov
    Translational Dementia Research Group, Centre for Immunology and Allergy Research, Westmead Institute for Medical Research, Sydney, NSW, Australia.
  • Shannon Thomson
    Translational Dementia Research Group, Centre for Immunology and Allergy Research, Westmead Institute for Medical Research, Sydney, NSW, Australia.
  • Ann-Na Cho
    Human Brain Microphysiology Systems Group, School of Biomedical Engineering, Faculty of Engineering, The University of Sydney, Sydney, NSW, Australia.
  • Heather M Wilkins
    University of Kansas Alzheimer's Disease Research Centre, Kansas City, KS, USA.
  • Joanne H Reed
    School of Medical Sciences, Faculty of Medicine and Health, The University of Sydney, Sydney, NSW, Australia.
  • Russell H Swerdlow
    University of Kansas Alzheimer's Disease Research Centre, Kansas City, KS, USA.
  • David A Brown
    Department of Physical Therapy, University of Alabama at Birmingham, 1720 2nd Avenue South, Birmingham, AL, 35294, USA.
  • Caitlin A Finney
    Translational Dementia Research Group, Centre for Immunology and Allergy Research, Westmead Institute for Medical Research, Sydney, NSW, Australia.

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