Metabolome in progression to Alzheimer's disease

Matej Orešič (Corresponding Author), Tuulia Hyötyläinen, S.-K. Herukka, Marko Sysi-Aho, Ismo Mattila, Tuulikki Seppänen-Laakso, V. Julkunen, Peddinti Gopalacharyulu, M. Hallikainen, Juha Koikkalainen, M. Kivipelto, S. Helisalmi, Jyrki Lötjönen, H. Soininen

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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.
Original languageEnglish
Article numbere57
Number of pages9
JournalTranslational Psychiatry
Volume1
DOIs
Publication statusPublished - 2011
MoE publication typeA1 Journal article-refereed

Fingerprint

Metabolome
Alzheimer Disease
Metabolomics
Phospholipid Ethers
Pentose Phosphate Pathway
Sphingomyelins
Phase Transition
Sterols
Membrane Lipids
Serum
Phosphatidylcholines
Cognition
Early Diagnosis
Oxidative Stress
Up-Regulation
Biomarkers
Prospective Studies

Keywords

  • Alzheimer's disease
  • hypoxia
  • lipidomics
  • metabolomics
  • mild cognitive impairment
  • pentose phosphate pathway

Cite this

Orešič, M., Hyötyläinen, T., Herukka, S-K., Sysi-Aho, M., Mattila, I., Seppänen-Laakso, T., ... Soininen, H. (2011). Metabolome in progression to Alzheimer's disease. Translational Psychiatry, 1, [e57]. https://doi.org/10.1038/tp.2011.55
Orešič, Matej ; Hyötyläinen, Tuulia ; Herukka, S.-K. ; Sysi-Aho, Marko ; Mattila, Ismo ; Seppänen-Laakso, Tuulikki ; Julkunen, V. ; Gopalacharyulu, Peddinti ; Hallikainen, M. ; Koikkalainen, Juha ; Kivipelto, M. ; Helisalmi, S. ; Lötjönen, Jyrki ; Soininen, H. / Metabolome in progression to Alzheimer's disease. In: Translational Psychiatry. 2011 ; Vol. 1.
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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.",
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Orešič, M, Hyötyläinen, T, Herukka, S-K, Sysi-Aho, M, Mattila, I, Seppänen-Laakso, T, Julkunen, V, Gopalacharyulu, P, Hallikainen, M, Koikkalainen, J, Kivipelto, M, Helisalmi, S, Lötjönen, J & Soininen, H 2011, 'Metabolome in progression to Alzheimer's disease', Translational Psychiatry, vol. 1, e57. https://doi.org/10.1038/tp.2011.55

Metabolome in progression to Alzheimer's disease. / Orešič, Matej (Corresponding Author); Hyötyläinen, Tuulia; Herukka, S.-K.; Sysi-Aho, Marko; Mattila, Ismo; Seppänen-Laakso, Tuulikki; Julkunen, V.; Gopalacharyulu, Peddinti; Hallikainen, M.; Koikkalainen, Juha; Kivipelto, M.; Helisalmi, S.; Lötjönen, Jyrki; Soininen, H.

In: Translational Psychiatry, Vol. 1, e57, 2011.

Research output: Contribution to journalArticleScientificpeer-review

TY - JOUR

T1 - Metabolome in progression to Alzheimer's disease

AU - Orešič, Matej

AU - Hyötyläinen, Tuulia

AU - Herukka, S.-K.

AU - Sysi-Aho, Marko

AU - Mattila, Ismo

AU - Seppänen-Laakso, Tuulikki

AU - Julkunen, V.

AU - Gopalacharyulu, Peddinti

AU - Hallikainen, M.

AU - Koikkalainen, Juha

AU - Kivipelto, M.

AU - Helisalmi, S.

AU - Lötjönen, Jyrki

AU - Soininen, H.

PY - 2011

Y1 - 2011

N2 - 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.

AB - 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.

KW - Alzheimer's disease

KW - hypoxia

KW - lipidomics

KW - metabolomics

KW - mild cognitive impairment

KW - pentose phosphate pathway

U2 - 10.1038/tp.2011.55

DO - 10.1038/tp.2011.55

M3 - Article

VL - 1

JO - Translational Psychiatry

JF - Translational Psychiatry

SN - 2158-3188

M1 - e57

ER -

Orešič M, Hyötyläinen T, Herukka S-K, Sysi-Aho M, Mattila I, Seppänen-Laakso T et al. Metabolome in progression to Alzheimer's disease. Translational Psychiatry. 2011;1. e57. https://doi.org/10.1038/tp.2011.55