Platelets mirror changes in the frontal lobe antioxidant system in Alzheimer's disease

Alzheimers Dement. 2025 Apr;21(4):e70117. doi: 10.1002/alz.70117.

Abstract

Introduction: Blood biomarkers reflecting Alzheimer's disease (AD) pathophysiology can improve diagnosis and treatment.

Methods: We applied top-down proteomics to compare frontal lobe from 17 AD cases and 11 controls to blood platelets from a second independent study group of 124 AD patients, 61 with mild cognitive impairment (MCI), and 168 controls. Findings were immunologically validated.

Results: Sixty AD-associated proteoforms were identified in frontal lobe, with 26 identically represented in platelets. Validation in platelet samples confirmed elevated glutathione S-transferase omega 1 (GSTO1) levels linked to single nucleotide polymorphism (SNP) rs4925 and increased superoxide dismutase 1 (SOD1) levels in AD. Bioinformatics revealed copper chaperone for superoxide dismutase (CCS) and glutathione peroxidase 1 (GPX1) as integral partners of these antioxidant enzymes. Both were detected to be reduced in frontal lobes and platelets in AD. SOD1 and CCS are already changed in MCI.

Discussion: These four novel blood biomarkers, integrated with traditional AD biomarkers, may facilitate patient risk assessment and treatment, with SOD1 and CCS alterations in MCI offering early diagnostic potential.

Highlights: Platelets mirror several Alzheimer's disease (AD)-dependent neuronal changes, valuable for blood tests. As a start, 60 AD-associated frontal lobe proteins were identified by top-down proteomics. Fifty percent of these 60 AD-affected brain proteins are represented identically in platelets. Among these, glutathione S-transferase omega 1 (GSTO1), superoxide dismutase 1 (SOD1), copper chaperone for superoxide dismutase (CCS), and glutathione peroxidase 1 (GPX1) are identically AD related in brain and platelets. SOD1 and its crucial activating partner CCS are altered in the platelets of patients with mild cognitive impairment.

Keywords: Alzheimer's disease; antioxidant system; blood biomarker; frontal lobe; mild cognitive impairment; platelets.

MeSH terms

  • Aged
  • Aged, 80 and over
  • Alzheimer Disease* / blood
  • Alzheimer Disease* / genetics
  • Alzheimer Disease* / metabolism
  • Alzheimer Disease* / pathology
  • Antioxidants* / metabolism
  • Biomarkers / blood
  • Blood Platelets* / metabolism
  • Cognitive Dysfunction / blood
  • Cognitive Dysfunction / metabolism
  • Female
  • Frontal Lobe* / metabolism
  • Glutathione Peroxidase / blood
  • Glutathione Peroxidase / metabolism
  • Glutathione Peroxidase GPX1
  • Glutathione Transferase / metabolism
  • Humans
  • Male
  • Polymorphism, Single Nucleotide / genetics
  • Proteomics
  • Superoxide Dismutase / metabolism
  • Superoxide Dismutase-1 / metabolism

Substances

  • Superoxide Dismutase-1
  • Biomarkers
  • SOD1 protein, human
  • Glutathione Peroxidase
  • Glutathione Peroxidase GPX1
  • Superoxide Dismutase
  • GSTO1 protein, human
  • GPX1 protein, human
  • Glutathione Transferase
  • Antioxidants