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Quantification of total apolipoprotein e and its isoforms in cerebrospinal fluid from patients with neurodegenerative diseases

Minta, K. ; Brinkmalm, G. ; Janelidze, S. LU ; Sjödin, S. ; Portelius, E. ; Stomrud, E. LU orcid ; Zetterberg, H. LU ; Blennow, K. LU ; Hansson, O. LU orcid and Andreasson, U. (2020) In Alzheimer's Research and Therapy 12(1).
Abstract

Background: The human APOE gene, which codes for apolipoprotein E (apoE), has three major polymorphic alleles: ϵ2, ϵ3, and ϵ4 that give rise to amino acid substitutions. APOE-ϵ4 is a strong risk factor of sporadic Alzheimer's disease (AD) but the reason why is still unknown despite intense research for more than 20 years. The aim of the study was to investigate if the concentrations of total apoE and the specific apoE isoforms in cerebrospinal fluid (CSF) differ between various neurodegenerative diseases and control individuals, as well as among the APOE genotypes. Methods: Quantification of total apoE and specific apoE isoforms (E2, E3, and E4) in CSF was performed using high-resolution parallel reaction monitoring mass spectrometry.... (More)

Background: The human APOE gene, which codes for apolipoprotein E (apoE), has three major polymorphic alleles: ϵ2, ϵ3, and ϵ4 that give rise to amino acid substitutions. APOE-ϵ4 is a strong risk factor of sporadic Alzheimer's disease (AD) but the reason why is still unknown despite intense research for more than 20 years. The aim of the study was to investigate if the concentrations of total apoE and the specific apoE isoforms in cerebrospinal fluid (CSF) differ between various neurodegenerative diseases and control individuals, as well as among the APOE genotypes. Methods: Quantification of total apoE and specific apoE isoforms (E2, E3, and E4) in CSF was performed using high-resolution parallel reaction monitoring mass spectrometry. In total, 1820 individuals were involved in the study including clinically diagnosed AD patients (n = 228), cognitively unimpaired (CU) patients (n = 896), and patients with other neurodegenerative disorders (n = 696). Follow-up data was available for 100 individuals, assessed at two time points. Subjects were dichotomized based on an Aβ42/40 CSF concentration ratio cut-off into Aβ positive (Aβ+, < 0.091) and Aβ negative (Aβ-, > 0.091) groups. Results: Even though there was a significant increase of total apoE in the amyloid β-positive (Aβ+) group compared with amyloid β-negative (Aβ-) individuals (p < 0.001), the magnitude of the effect was very small (AUC = 0.55). Moreover, CSF total apoE concentrations did not differ between Aβ- CU controls and clinically diagnosed AD patients. There was a difference in concentration between isoforms in heterozygous individuals in an isoform-dependent manner (E2 < E3 < E4) (p < 0.001, AUC = 0.64-0.69), and these associations remained when dichotomizing the samples into Aβ+ and Aβ- groups (p < 0.01, AUC = 0.63-0.74). In the cohort with follow-up samples, neither total apoE nor isoform-specific apoE concentrations differed between the two time points (p > 0.05). Conclusions: The results indicate that neither the concentrations of total apoE nor the different apoE isoforms in CSF are associated with APOE-ϵ4 carrier status, Aβ status, or clinical dementia diagnoses.

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; ; ; ; ; ; ; ; and
organization
publishing date
type
Contribution to journal
publication status
published
subject
keywords
Alzheimer's disease, Apolipoprotein E, Cerebrospinal fluid, Mass spectrometry
in
Alzheimer's Research and Therapy
volume
12
issue
1
article number
19
publisher
BioMed Central (BMC)
external identifiers
  • scopus:85079335762
  • pmid:32054532
ISSN
1758-9193
DOI
10.1186/s13195-020-00585-7
language
English
LU publication?
yes
id
d3f7fcc5-9122-4d29-a451-c52fc249cfb3
date added to LUP
2021-01-13 10:42:10
date last changed
2024-06-27 06:17:56
@article{d3f7fcc5-9122-4d29-a451-c52fc249cfb3,
  abstract     = {{<p>Background: The human APOE gene, which codes for apolipoprotein E (apoE), has three major polymorphic alleles: ϵ2, ϵ3, and ϵ4 that give rise to amino acid substitutions. APOE-ϵ4 is a strong risk factor of sporadic Alzheimer's disease (AD) but the reason why is still unknown despite intense research for more than 20 years. The aim of the study was to investigate if the concentrations of total apoE and the specific apoE isoforms in cerebrospinal fluid (CSF) differ between various neurodegenerative diseases and control individuals, as well as among the APOE genotypes. Methods: Quantification of total apoE and specific apoE isoforms (E2, E3, and E4) in CSF was performed using high-resolution parallel reaction monitoring mass spectrometry. In total, 1820 individuals were involved in the study including clinically diagnosed AD patients (n = 228), cognitively unimpaired (CU) patients (n = 896), and patients with other neurodegenerative disorders (n = 696). Follow-up data was available for 100 individuals, assessed at two time points. Subjects were dichotomized based on an Aβ<sub>42/40</sub> CSF concentration ratio cut-off into Aβ positive (Aβ+, &lt; 0.091) and Aβ negative (Aβ-, &gt; 0.091) groups. Results: Even though there was a significant increase of total apoE in the amyloid β-positive (Aβ+) group compared with amyloid β-negative (Aβ-) individuals (p &lt; 0.001), the magnitude of the effect was very small (AUC = 0.55). Moreover, CSF total apoE concentrations did not differ between Aβ- CU controls and clinically diagnosed AD patients. There was a difference in concentration between isoforms in heterozygous individuals in an isoform-dependent manner (E2 &lt; E3 &lt; E4) (p &lt; 0.001, AUC = 0.64-0.69), and these associations remained when dichotomizing the samples into Aβ+ and Aβ- groups (p &lt; 0.01, AUC = 0.63-0.74). In the cohort with follow-up samples, neither total apoE nor isoform-specific apoE concentrations differed between the two time points (p &gt; 0.05). Conclusions: The results indicate that neither the concentrations of total apoE nor the different apoE isoforms in CSF are associated with APOE-ϵ4 carrier status, Aβ status, or clinical dementia diagnoses.</p>}},
  author       = {{Minta, K. and Brinkmalm, G. and Janelidze, S. and Sjödin, S. and Portelius, E. and Stomrud, E. and Zetterberg, H. and Blennow, K. and Hansson, O. and Andreasson, U.}},
  issn         = {{1758-9193}},
  keywords     = {{Alzheimer's disease; Apolipoprotein E; Cerebrospinal fluid; Mass spectrometry}},
  language     = {{eng}},
  number       = {{1}},
  publisher    = {{BioMed Central (BMC)}},
  series       = {{Alzheimer's Research and Therapy}},
  title        = {{Quantification of total apolipoprotein e and its isoforms in cerebrospinal fluid from patients with neurodegenerative diseases}},
  url          = {{http://dx.doi.org/10.1186/s13195-020-00585-7}},
  doi          = {{10.1186/s13195-020-00585-7}},
  volume       = {{12}},
  year         = {{2020}},
}