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Apolipoprotein E4 and its later-life health effects on the multiple sclerosis population

Dean Zeldich1, Chia Hsin Cheng2, Yi Guan2

  • 1Department of Neurology, Thomas Jefferson University Hospital, Philadelphia, PA, USA.

Multiple Sclerosis Journal - Experimental, Translational and Clinical
|January 30, 2026
PubMed
Abstract

Insights

The apolipoprotein E4 (APOE4) allele worsens neuroinflammation and neurodegeneration in multiple sclerosis (MS) patients. This genetic factor exacerbates MS progression, impacting cognitive function and brain health, as shown by multi-domain biomarkers.

Area of Science:

  • Neuroimmunology
  • Genetics
  • Neurology

Background:

  • Multiple sclerosis (MS) is a chronic autoimmune disease characterized by neuroinflammation and neurodegeneration.
  • The apolipoprotein E4 (APOE4) allele is a significant genetic risk factor for Alzheimer's Disease, known to accelerate cognitive decline and neuroinflammatory processes.

Purpose of the Study:

  • To investigate the impact of the APOE4 allele on the health outcomes of multiple sclerosis patients.
  • To explore the role of APOE4 in exacerbating neurodegeneration and neuroinflammation in the context of MS.

Main Methods:

  • Utilized UK Biobank data, grouping MS patients by APOE4 carrier status (MS-E4 vs. MS-nonE4).
  • Included age- and sex-matched non-MS controls (control-E4 vs. control-nonE4).
  • Assessed retinal nerve fiber layer thickness (RNFL) via OCT, blood biomarkers (GFAP, NfL), cognitive performance, and brain MRI metrics.

Main Results:

  • MS patients with the APOE4 allele (MS-E4) showed poorer outcomes: thinner RNFL, elevated GFAP and NfL, slower cognitive reaction times, and increased white matter hyperintensities.
  • Glial fibrillary acidic protein (GFAP) levels demonstrated significant interactions between MS and APOE4 status, correlating with neurodegenerative markers.
  • Similar detrimental effects of APOE4 were observed in healthy control individuals.

Conclusions:

  • APOE4 significantly exacerbates neurodegeneration and neuroinflammation in MS patients.
  • Multi-domain biomarkers, including retinal OCT, cognitive tests, and MRI, are valuable for monitoring MS progression.
  • Less invasive biomarkers show promise for tracking disease advancement in MS.
Keywords:
APOE4Biomarkersmultiple sclerosisneurodegenerationneuroinflammation

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