Serum proteomics revealsAPOEdependent and independent protein signatures in Alzheimer’s disease Article Swipe
Elisabet A. Frick
,
Valur Emilsson
,
Þórarinn Jónmundsson
,
Anna E. Steindorsdottir
,
Erik C. B. Johnson
,
Raquel Puerta
,
Eric B. Dammer
,
Anantharaman Shantaraman
,
Amanda Cano
,
Merçé Boada
,
Sergi Valero
,
Pablo García‐González
,
Elías F. Guðmundsson
,
Alexander Guðjónsson
,
Joseph Loureiro
,
Anthony P. Orth
,
Nicholas T. Seyfried
,
Allan I. Levey
,
Agustı́n Ruiz
,
Thor Aspelund
,
Lori L. Jennings
,
Lenore J. Launer
,
Valborg Guðmundsdóttir
,
Vilmundur Guðnason
·
YOU?
·
· 2023
· Open Access
·
· DOI: https://doi.org/10.1101/2023.11.08.23298251
YOU?
·
· 2023
· Open Access
·
· DOI: https://doi.org/10.1101/2023.11.08.23298251
Summary The current demand for early intervention, prevention, and treatment of late onset Alzheimer’s disease (LOAD) warrants deeper understanding of the underlying molecular processes which could contribute to biomarker and drug target discovery. Utilizing high-throughput proteomic measurements in serum from a prospective population-based cohort of older adults (n=5,294), we identified 303 unique proteins associated with incident LOAD (median follow-up 12.8 years). Over 40% of these proteins were associated with LOAD independently of APOE- ε 4 carrier status. These proteins were implicated in neuronal processes and overlapped with protein signatures of LOAD in brain and cerebrospinal fluid. We found 17 proteins which LOAD-association was strongly dependent on APOE- ε 4 carrier status. Most of them showed consistent associations with LOAD in cerebrospinal fluid and a third had brain-specific gene expression. Remarkably, four proteins in this group (TBCA, ARL2, S100A13 and IRF6) were downregulated by APOE- ε 4 yet upregulated as a consequence of LOAD as determined in a bi-directional Mendelian randomization analysis, reflecting a potential response to the disease onset. Accordingly, the direct association of these proteins to LOAD was reversed upon APOE- ε 4 genotype adjustment, a finding which we replicate in an external cohort (n=719). Our findings provide an insight into the dysregulated pathways that may lead to the development and early detection of LOAD, including those both independent and dependent on APOE- ε 4 . Importantly, many of the LOAD-associated proteins we find in the circulation have been found to be expressed - and have a direct link with AD - in brain tissue. Thus, the proteins identified here, and their upstream modulating pathways, provide a new source of circulating biomarker and therapeutic target candidates for LOAD.
Related Topics
Concepts
Apolipoprotein E
Mendelian randomization
Biomarker
Disease
Proteomics
Cerebrospinal fluid
Cohort
Alzheimer's disease
Population
Biology
Genotype
Bioinformatics
Neuroscience
Medicine
Gene
Internal medicine
Genetics
Genetic variants
Environmental health
Metadata
- Type
- preprint
- Language
- en
- Landing Page
- https://doi.org/10.1101/2023.11.08.23298251
- https://www.medrxiv.org/content/medrxiv/early/2023/11/09/2023.11.08.23298251.full.pdf
- OA Status
- green
- Cited By
- 3
- References
- 91
- Related Works
- 10
- OpenAlex ID
- https://openalex.org/W4388519437
All OpenAlex metadata
Raw OpenAlex JSON
- OpenAlex ID
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https://openalex.org/W4388519437Canonical identifier for this work in OpenAlex
- DOI
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https://doi.org/10.1101/2023.11.08.23298251Digital Object Identifier
- Title
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Serum proteomics revealsAPOEdependent and independent protein signatures in Alzheimer’s diseaseWork title
- Type
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preprintOpenAlex work type
- Language
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enPrimary language
- Publication year
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2023Year of publication
- Publication date
-
2023-11-09Full publication date if available
- Authors
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Elisabet A. Frick, Valur Emilsson, Þórarinn Jónmundsson, Anna E. Steindorsdottir, Erik C. B. Johnson, Raquel Puerta, Eric B. Dammer, Anantharaman Shantaraman, Amanda Cano, Merçé Boada, Sergi Valero, Pablo García‐González, Elías F. Guðmundsson, Alexander Guðjónsson, Joseph Loureiro, Anthony P. Orth, Nicholas T. Seyfried, Allan I. Levey, Agustı́n Ruiz, Thor Aspelund, Lori L. Jennings, Lenore J. Launer, Valborg Guðmundsdóttir, Vilmundur GuðnasonList of authors in order
- Landing page
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https://doi.org/10.1101/2023.11.08.23298251Publisher landing page
- PDF URL
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https://www.medrxiv.org/content/medrxiv/early/2023/11/09/2023.11.08.23298251.full.pdfDirect link to full text PDF
- Open access
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YesWhether a free full text is available
- OA status
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greenOpen access status per OpenAlex
- OA URL
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https://www.medrxiv.org/content/medrxiv/early/2023/11/09/2023.11.08.23298251.full.pdfDirect OA link when available
- Concepts
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Apolipoprotein E, Mendelian randomization, Biomarker, Disease, Proteomics, Cerebrospinal fluid, Cohort, Alzheimer's disease, Population, Biology, Genotype, Bioinformatics, Neuroscience, Medicine, Gene, Internal medicine, Genetics, Genetic variants, Environmental healthTop concepts (fields/topics) attached by OpenAlex
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3Total citation count in OpenAlex
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2025: 1, 2024: 2Per-year citation counts (last 5 years)
- References (count)
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91Number of works referenced by this work
- Related works (count)
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10Other works algorithmically related by OpenAlex
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| abstract_inverted_index.Mendelian | 158 |
| abstract_inverted_index.Utilizing | 33 |
| abstract_inverted_index.analysis, | 160 |
| abstract_inverted_index.biomarker | 28, 272 |
| abstract_inverted_index.dependent | 104, 221 |
| abstract_inverted_index.detection | 213 |
| abstract_inverted_index.expressed | 243 |
| abstract_inverted_index.follow-up | 58 |
| abstract_inverted_index.including | 216 |
| abstract_inverted_index.molecular | 22 |
| abstract_inverted_index.pathways, | 265 |
| abstract_inverted_index.potential | 163 |
| abstract_inverted_index.processes | 23, 83 |
| abstract_inverted_index.proteomic | 35 |
| abstract_inverted_index.replicate | 190 |
| abstract_inverted_index.treatment | 9 |
| abstract_inverted_index.(n=5,294), | 47 |
| abstract_inverted_index.associated | 53, 67 |
| abstract_inverted_index.candidates | 276 |
| abstract_inverted_index.consistent | 115 |
| abstract_inverted_index.contribute | 26 |
| abstract_inverted_index.determined | 154 |
| abstract_inverted_index.discovery. | 32 |
| abstract_inverted_index.identified | 49, 259 |
| abstract_inverted_index.implicated | 80 |
| abstract_inverted_index.modulating | 264 |
| abstract_inverted_index.overlapped | 85 |
| abstract_inverted_index.reflecting | 161 |
| abstract_inverted_index.signatures | 88 |
| abstract_inverted_index.underlying | 21 |
| abstract_inverted_index.Remarkably, | 129 |
| abstract_inverted_index.adjustment, | 185 |
| abstract_inverted_index.association | 172 |
| abstract_inverted_index.circulating | 271 |
| abstract_inverted_index.circulation | 237 |
| abstract_inverted_index.consequence | 150 |
| abstract_inverted_index.development | 210 |
| abstract_inverted_index.expression. | 128 |
| abstract_inverted_index.independent | 219 |
| abstract_inverted_index.prevention, | 7 |
| abstract_inverted_index.prospective | 41 |
| abstract_inverted_index.therapeutic | 274 |
| abstract_inverted_index.upregulated | 147 |
| abstract_inverted_index.Accordingly, | 169 |
| abstract_inverted_index.Importantly, | 227 |
| abstract_inverted_index.associations | 116 |
| abstract_inverted_index.dysregulated | 203 |
| abstract_inverted_index.measurements | 36 |
| abstract_inverted_index.Alzheimer’s | 13 |
| abstract_inverted_index.cerebrospinal | 94, 120 |
| abstract_inverted_index.downregulated | 141 |
| abstract_inverted_index.independently | 70 |
| abstract_inverted_index.intervention, | 6 |
| abstract_inverted_index.randomization | 159 |
| abstract_inverted_index.understanding | 18 |
| abstract_inverted_index.bi-directional | 157 |
| abstract_inverted_index.brain-specific | 126 |
| abstract_inverted_index.LOAD-associated | 231 |
| abstract_inverted_index.high-throughput | 34 |
| abstract_inverted_index.LOAD-association | 101 |
| abstract_inverted_index.population-based | 42 |
| cited_by_percentile_year.max | 96 |
| cited_by_percentile_year.min | 91 |
| corresponding_author_ids | https://openalex.org/A5002148586, https://openalex.org/A5000325789 |
| countries_distinct_count | 3 |
| institutions_distinct_count | 24 |
| corresponding_institution_ids | https://openalex.org/I165368041, https://openalex.org/I4210153238 |
| sustainable_development_goals[0].id | https://metadata.un.org/sdg/3 |
| sustainable_development_goals[0].score | 0.7799999713897705 |
| sustainable_development_goals[0].display_name | Good health and well-being |
| citation_normalized_percentile.value | 0.69942547 |
| citation_normalized_percentile.is_in_top_1_percent | False |
| citation_normalized_percentile.is_in_top_10_percent | False |