title: Metabolome in progression to Alzheimer's disease.
abstract: Mild cognitive impairment (MCI) is considered as a transition phase between normal aging and Alzheimer's disease (AD). MCI confers an increased risk of developing AD, although the state is heterogeneous with several possible outcomes, including even improvement back to normal cognition. We sought to determine the serum metabolomic profiles associated with progression to and diagnosis of AD in a prospective study. At the baseline assessment, the subjects enrolled in the study were classified into three diagnostic groups: healthy controls (n=46), MCI (n=143) and AD (n=47). Among the MCI subjects, 52 progressed to AD in the follow-up. Comprehensive metabolomics approach was applied to analyze baseline serum samples and to associate the metabolite profiles with the diagnosis at baseline and in the follow-up. At baseline, AD patients were characterized by diminished ether phospholipids, phosphatidylcholines, sphingomyelins and sterols. A molecular signature comprising three metabolites was identified, which was predictive of progression to AD in the follow-up. The major contributor to the predictive model was 2,4-dihydroxybutanoic acid, which was upregulated in AD progressors (P=0.0048), indicating potential involvement of hypoxia in the early AD pathogenesis. This was supported by the pathway analysis of metabolomics data, which identified upregulation of pentose phosphate pathway in patients who later progressed to AD. Together, our findings primarily implicate hypoxia, oxidative stress, as well as membrane lipid remodeling in progression to AD. Establishment of pathogenic relevance of predictive biomarkers such as ours may not only facilitate early diagnosis, but may also help identify new therapeutic avenues.
authors: VTT Technical Research Centre of Finland, Espoo, Finland. matej.oresic@vtt.fi
authors: M
authors: M
authors: Orešič
authors: T
authors: T
authors: Hyötyläinen
authors: S-K
authors: SK
authors: Herukka
authors: M
authors: M
authors: Sysi-Aho
authors: I
authors: I
authors: Mattila
authors: T
authors: T
authors: Seppänan-Laakso
authors: V
authors: V
authors: Julkunen
authors: P V
authors: PV
authors: Gopalacharyulu
authors: M
authors: M
authors: Hallikainen
authors: J
authors: J
authors: Koikkalainen
authors: M
authors: M
authors: Kivipelto
authors: S
authors: S
authors: Helisalmi
authors: J
authors: J
authors: Lötjönen
authors: H
authors: H
authors: Soininen
mesh_terms: D000368:Aged; D000544:Alzheimer Disease / Q000175:diagnosis / Q000378:metabolism* / Q000473:pathology; D015415:Biomarkers / Q000097:blood / Q000378:metabolism; D060825:Cognitive Dysfunction / Q000175:diagnosis / Q000378:metabolism* / Q000473:pathology; D018450:Disease Progression; D005260:Female; D005500:Follow-Up Studies; D006801:Humans; D008297:Male; D055442:Metabolome / Q000502:physiology; D010427:Pentose Phosphate Pathway / Q000502:physiology*; D011237:Predictive Value of Tests
chemical_list: D015415:Biomarkers