See the published version of this article at Alzheimer's Research and Therapy.
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Anna Månberg
KTH Royal Institute of Technology
Corresponding Author
ORCiD: https://orcid.org/0000-0002-0056-1313
License:
This work is licensed under a CC BY 4.0 License. Read Full License
View the published article at Alzheimer's Research and Therapy.
Background
Increased knowledge of the evolution of molecular changes in neurodegenerative disorders such as Alzheimer’s disease (AD) is important for the understanding of disease pathophysiology and also crucial to be able to identify and validate disease biomarkers. While several biological changes that occur early in the disease development have already been recognised, the need for further characterization of the pathophysiological mechanisms behind AD still remains.
Methods
In this study, we investigated cerebrospinal fluid (CSF) levels of 104 proteins in 307 asymptomatic 70-year-olds from the H70 Gothenburg Birth Cohort Studies using a multiplexed antibody- and bead-based technology.
Results
The protein levels were first correlated with the core AD CSF biomarker concentrations of total tau, phospho-tau and amyloid beta (Aβ42) in all individuals. Sixty-three proteins showed significant correlations to either total tau, phospho-tau or Aβ42. Thereafter, individuals were divided based on CSF Aβ42/Aβ40 ratio and Clinical Dementia Rating (CDR) score to determine if early changes in pathology and cognition had an effect on the correlations. We compared the associations of the analysed proteins with CSF markers between groups and found 33 proteins displaying significantly different associations for amyloid-positive individuals and amyloid-negative individuals, as defined by the CSF Aβ42/Aβ40 ratio. No differences in the associations could be seen for individuals divided by CDR score.
Conclusions
We identified a series of transmembrane proteins, proteins associated with or anchored to the plasma membrane, and proteins involved in or connected to synaptic vesicle transport to be associated with CSF biomarkers of amyloid and tau pathology in AD. Further studies are needed to explore these proteins’ role in AD pathophysiology.
Keywords
Preclinical Alzheimer’s disease, Affinity proteomics, CSF markers, brain-enriched proteins, multidisciplinary epidemiological studies, AD pathophysiology
Figure 1
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Figure 4
This is a list of supplementary files associated with this preprint. Click to download.
- SupplementaryFilesFigure1.pdf
Supplementary Figure 1. Dichotomization of individuals into groups based on NfL concentration and APOE ε4 carrier status.
- SupplementaryFilesFigure2.pdf
Supplementary Figure 2. Correlation scatterplots between suggested markers for AD, neurodegeneration or synaptic dysfunction. All correlations with a Spearman rho value>0.6 are displayed in red.
- SupplementaryFilesFigure3.pdf
Supplementary Figure 3. Range of CSF markers in individuals divided by CSF Aβ42/Aβ40 ratio or CDR score. Significant differences are indicated with stars, *** p<0.001.
- SupplementaryFilesFigure4.pdf
Supplementary Figure 4. Boxplots of proteins displaying significant differences between A+ individuals and A- individuals.
- SupplementaryFilesFigure5.pdf
Supplementary Figure 5. T-tau association with GAP43 levels for individuals divided by CDR score. (A) Scatterplot of GAP43 levels and t-tau concentration. Both individuals with CDR≥0.5 and CDR=0 display significant associations of GAP43 levels with t-tau concentration (CDR≥0.5: Spearman rho=0.72; p=3E-08; CDR=0: Spearman rho=0.81; p=4E-56). (B) Linear regression revealed no significant difference between slopes of CDR≥0.5 and CDR=0 individuals for the association of GAP43 with t-tau concentration.
- SupplementaryFilesFigure6.pdf
Supplementary Figure 6. Sex differences for RIMS3 and VCAM1. Significant differences between female and male protein levels could be identified using the Wilcoxon rank sum test. However, sex showed no significant interaction with the CSF markers.
- SupplementaryFilesFigure7.pdf
Supplementary Figure 7. Boxplots of proteins displaying significant differences between individuals divided by NfL concentration and CSF Aβ42/Aβ40. Upon stratification of individuals based on both CSF Aβ42/Aβ40 ratio and NfL concentration two trends in protein profiles could be identified; higher protein levels in Nf+ individuals, independently of Aβ42/Aβ40 ratio and higher protein levels in the Nf+A+ group.
- SupplementaryFilesFigure8.pdf
Supplementary Figure 8. Correlations to NRGN concentration and comparison of NRGN levels between A+ and A- individuals. (A) Visualisation of Pearson R for correlations between NRGN concentration and the 104 measured proteins. Thirty-seven proteins displayed a Pearson R>0.5 and are annotated by their HGNC ID. (B) Higher concentration of NRGN was observed in A+ individuals compared to the A- individuals.
- SupplementaryFilesFigure9.pdf
Supplementary Figure 9. Heatmap of tissue expression for all studied proteins across 37 human tissues. When comparing the expression profiles of the 104 analysed proteins across 37 different human tissues, the responding genes could be divided into four clusters. The first cluster showed a general expression in all tissue types (Cluster 1) and the second cluster displayed elevated expression in the liver compared to other tissues (Cluster 2). A third cluster had higher expression in the brain (Cluster 3) and the last was a mixed group with high expression in brain or other tissue types (Cluster 4).
- SupplementaryFilesTables.xlsx
Supplementary Table 1. Rho values and linear regression results for total-tau correlations in all individuals and with individuals divided by Aβ42/Aβ40 ratio Supplementary Table 2. Rho values and linear regression results for phospho-tau correlations in all individuals and with individuals divided by Aβ42/Aβ40 ratio Supplementary Table 3. Rho values and linear regression results for Aβ42 correlations in all individuals and with individuals divided by Aβ42/Aβ40 ratio Supplementary Table 4. Rho values and linear regression results for total-tau correlations in all individuals and with individuals divided by CDR score Supplementary Table 5. Rho values and linear regression results for phospho-tau correlations in all individuals and with individuals divided by CDR score Supplementary Table 6. Rho values and linear regression results for Aβ42 correlations in all individuals and with individuals divided by CDR score Supplementary Table 7. P-values for linear regressions and Wilcoxon rank sum tests regarding sex differences
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CURRENT STATUS: Published
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Published
On 02 Mar, 2021
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Editorial decision: Accept
On 18 Jan, 2021
Editor assigned
On 17 Jan, 2021
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On 17 Jan, 2021
Editor invited
On 17 Jan, 2021
No comments provided
Editorial decision: Minor Revision
On 19 Dec, 2020
Review #2 received
Received 13 Dec, 2020
Reviewer #2 agreed
On 29 Nov, 2020
Reviewer #1 agreed
On 28 Nov, 2020
Review #1 received
Received 28 Nov, 2020
Reviewers invited
Invitations sent on 27 Nov, 2020
Editor assigned
On 25 Nov, 2020
Submission checks complete
On 25 Nov, 2020
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This preprint is under consideration at Alzheimer's Research and Therapy. A preprint is a preliminary version of a manuscript that has not completed peer review at a journal. Research Square does not conduct peer review prior to posting preprints. The posting of a preprint on this server should not be interpreted as an endorsement of its validity or suitability for dissemination as established information or for guiding clinical practice.
Learn more about In Review
Research
Anna Månberg
KTH Royal Institute of Technology
Corresponding Author
ORCiD: https://orcid.org/0000-0002-0056-1313
Badges
Prescreen
This manuscript passed our Prescreen assessment
Complete author information
Appropriate declaration statements
Potential risks to human health
Prescreen
Peer Review Timeline
CURRENT STATUS: Published
Version 2
Posted 26 Jan, 2021
Published
On 02 Mar, 2021
No community comments so far
Editorial decision: Accept
On 18 Jan, 2021
Editor assigned
On 17 Jan, 2021
Submission checks complete
On 17 Jan, 2021
Editor invited
On 17 Jan, 2021
No comments provided
Editorial decision: Minor Revision
On 19 Dec, 2020
Review #2 received
Received 13 Dec, 2020
Reviewer #2 agreed
On 29 Nov, 2020
Reviewer #1 agreed
On 28 Nov, 2020
Review #1 received
Received 28 Nov, 2020
Reviewers invited
Invitations sent on 27 Nov, 2020
Editor assigned
On 25 Nov, 2020
Submission checks complete
On 25 Nov, 2020
Editor invited
On 25 Nov, 2020
First submitted
On 24 Nov, 2020
Metrics
Comments: 0
PDF Downloads: ...
HTML Views: ...
Subject Areas
Cognitive Neuroscience
License:
This work is licensed under a CC BY 4.0 License. Read Full License
View the published article at Alzheimer's Research and Therapy.
Background
Increased knowledge of the evolution of molecular changes in neurodegenerative disorders such as Alzheimer’s disease (AD) is important for the understanding of disease pathophysiology and also crucial to be able to identify and validate disease biomarkers. While several biological changes that occur early in the disease development have already been recognised, the need for further characterization of the pathophysiological mechanisms behind AD still remains.
Methods
In this study, we investigated cerebrospinal fluid (CSF) levels of 104 proteins in 307 asymptomatic 70-year-olds from the H70 Gothenburg Birth Cohort Studies using a multiplexed antibody- and bead-based technology.
Results
The protein levels were first correlated with the core AD CSF biomarker concentrations of total tau, phospho-tau and amyloid beta (Aβ42) in all individuals. Sixty-three proteins showed significant correlations to either total tau, phospho-tau or Aβ42. Thereafter, individuals were divided based on CSF Aβ42/Aβ40 ratio and Clinical Dementia Rating (CDR) score to determine if early changes in pathology and cognition had an effect on the correlations. We compared the associations of the analysed proteins with CSF markers between groups and found 33 proteins displaying significantly different associations for amyloid-positive individuals and amyloid-negative individuals, as defined by the CSF Aβ42/Aβ40 ratio. No differences in the associations could be seen for individuals divided by CDR score.
Conclusions
We identified a series of transmembrane proteins, proteins associated with or anchored to the plasma membrane, and proteins involved in or connected to synaptic vesicle transport to be associated with CSF biomarkers of amyloid and tau pathology in AD. Further studies are needed to explore these proteins’ role in AD pathophysiology.
Figure 1
Figure 2
Figure 3
Figure 4
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