Predictive metabolic networks reveal sex- and APOE genotype-specific metabolic signatures and drivers for precision medicine in Alzheimer's disease

for the Alzheimer's Disease Neuroimaging Initiative and the Alzheimer's Disease Metabolomics Consortium

Research output: Contribution to journalArticlepeer-review

14 Scopus citations

Abstract

Introduction: Late-onset Alzheimer's disease (LOAD) is a complex neurodegenerative disease characterized by multiple progressive stages, glucose metabolic dysregulation, Alzheimer's disease (AD) pathology, and inexorable cognitive decline. Discovery of metabolic profiles unique to sex, apolipoprotein E (APOE) genotype, and stage of disease progression could provide critical insights for personalized LOAD medicine. Methods: Sex- and APOE-specific metabolic networks were constructed based on changes in 127 metabolites of 656 serum samples from the Alzheimer's Disease Neuroimaging Initiative cohort. Results: Application of an advanced analytical platform identified metabolic drivers and signatures clustered with sex and/or APOE ɛ4, establishing patient-specific biomarkers predictive of disease state that significantly associated with cognitive function. Presence of the APOE ɛ4 shifts metabolic signatures to a phosphatidylcholine-focused profile overriding sex-specific differences in serum metabolites of AD patients. Discussion: These findings provide an initial but critical step in developing a diagnostic platform for personalized medicine by integrating metabolomic profiling and cognitive assessments to identify targeted precision therapeutics for AD patient subgroups through computational network modeling.

Original languageEnglish (US)
Pages (from-to)518-531
Number of pages14
JournalAlzheimer's and Dementia
Volume19
Issue number2
DOIs
StatePublished - Feb 2023

Keywords

  • Alzheimer's Disease Neuroimaging Initiative
  • apolipoprotein E ε4
  • computational systems biology
  • late-onset Alzheimer's disease
  • metabolic biomarkers
  • metabolic network
  • metabolomics
  • precision medicine
  • sex-specific metabolic changes

ASJC Scopus subject areas

  • Epidemiology
  • Health Policy
  • Developmental Neuroscience
  • Clinical Neurology
  • Geriatrics and Gerontology
  • Cellular and Molecular Neuroscience
  • Psychiatry and Mental health

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