Metabolomic and lipidomic signatures in autosomal dominant and late-onset Alzheimer's disease brains

for the Dominantly Inherited Alzheimer Network (DIAN) Study Group, The Alzheimer's Disease Neuroimaging Initiative, and the Alzheimer's Disease Metabolomics Consortium (ADMC)

Research output: Contribution to journalArticlepeer-review

7 Scopus citations

Abstract

Introduction: The identification of multiple genetic risk factors for Alzheimer's disease (AD) suggests that many pathways contribute to AD onset and progression. However, the metabolomic and lipidomic profiles in carriers of distinct genetic risk factors are not fully understood. The metabolome can provide a direct image of dysregulated pathways in the brain. Methods: We interrogated metabolomic signatures in the AD brain, including carriers of pathogenic variants in APP, PSEN1, and PSEN2 (autosomal dominant AD; ADAD), APOE ɛ4, and TREM2 risk variant carriers, and sporadic AD (sAD). Results: We identified 133 unique and shared metabolites associated with ADAD, TREM2, and sAD. We identified a signature of 16 metabolites significantly altered between groups and associated with AD duration. Discussion: AD genetic variants show distinct metabolic perturbations. Investigation of these metabolites may provide greater insight into the etiology of AD and its impact on clinical presentation. HIGHLIGHTS: APP/PSEN1/PSEN2 and TREM2 variant carriers show distinct metabolic changes. A total of 133 metabolites were differentially abundant in AD genetic groups. β-citrylglutamate is differentially abundant in autosomal dominant, TREM2, and sporadic AD. A 16-metabolite profile shows differences between Alzheimer's disease (AD) genetic groups. The identified metabolic profile is associated with duration of disease.

Original languageEnglish
Pages (from-to)1785-1799
Number of pages15
JournalAlzheimer's and Dementia
Volume19
Issue number5
DOIs
StatePublished - May 2023

Keywords

  • APOE
  • APP
  • PSEN1
  • PSEN2
  • TREM2
  • autosomal dominant Alzheimer's disease
  • lipidomics
  • metabolomics
  • β-citrylglutamate

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