APOE genotype and brain amyloid are associated with changes in the plasma proteome in elderly subjects without dementia
Abstract Objective Recent work has bolstered the possibility that peripheral changes may be relevant to Alzheimer's disease pathogenesis in the brain. While age‐associated blood‐borne proteins have been targeted to restore function to the aged brain, it remains unclear whether other dysfunction...
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| Format: | Article |
| Language: | English |
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Wiley
2025-02-01
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| Series: | Annals of Clinical and Translational Neurology |
| Online Access: | https://doi.org/10.1002/acn3.52250 |
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| author | Sarah M. Philippi Kailash BP Towfique Raj Joseph M. Castellano |
| author_facet | Sarah M. Philippi Kailash BP Towfique Raj Joseph M. Castellano |
| author_sort | Sarah M. Philippi |
| collection | DOAJ |
| description | Abstract Objective Recent work has bolstered the possibility that peripheral changes may be relevant to Alzheimer's disease pathogenesis in the brain. While age‐associated blood‐borne proteins have been targeted to restore function to the aged brain, it remains unclear whether other dysfunctional systemic states can be exploited for similar benefits. Here, we investigate whether APOE allelic variation or presence of brain amyloid are associated with plasma proteomic changes and the molecular processes associated with these changes. Methods Using the SOMAscan assay, we measured 1305 plasma proteins from 53 homozygous, APOE3 and APOE4 subjects without dementia. We investigated the relationship of either the APOE‐ε4 allele or amyloid positivity with plasma proteome changes by linear mixed effects modeling and ontology‐based pathway and module–trait correlation analyses. Results APOE4 is associated with plasma protein differences linked to atherosclerosis, tyrosine kinase activity, cholesterol transport, extracellular matrix, and synaptogenesis pathways. Independent of APOE4, we found that subjects likely harboring brain amyloid exhibit plasma proteome signatures associated with AD‐linked pathways, including neurovascular dysfunction. Interpretation Our results indicate that APOE4 status or presence of brain amyloid are associated with plasma proteomic shifts prior to the onset of symptoms, suggesting that systemic pathways in certain risk contexts may be plausible targets for disease modification. |
| format | Article |
| id | doaj-art-9db859136a874849b67cc95db2f87367 |
| institution | DOAJ |
| issn | 2328-9503 |
| language | English |
| publishDate | 2025-02-01 |
| publisher | Wiley |
| record_format | Article |
| series | Annals of Clinical and Translational Neurology |
| spelling | doaj-art-9db859136a874849b67cc95db2f873672025-08-20T02:56:58ZengWileyAnnals of Clinical and Translational Neurology2328-95032025-02-0112236638210.1002/acn3.52250APOE genotype and brain amyloid are associated with changes in the plasma proteome in elderly subjects without dementiaSarah M. Philippi0Kailash BP1Towfique Raj2Joseph M. Castellano3Nash Family Department of Neuroscience, Department of Neurology, Friedman Brain Institute Icahn School of Medicine at Mount Sinai New York New York USANash Family Department of Neuroscience, Department of Neurology, Friedman Brain Institute Icahn School of Medicine at Mount Sinai New York New York USANash Family Department of Neuroscience, Department of Neurology, Friedman Brain Institute Icahn School of Medicine at Mount Sinai New York New York USANash Family Department of Neuroscience, Department of Neurology, Friedman Brain Institute Icahn School of Medicine at Mount Sinai New York New York USAAbstract Objective Recent work has bolstered the possibility that peripheral changes may be relevant to Alzheimer's disease pathogenesis in the brain. While age‐associated blood‐borne proteins have been targeted to restore function to the aged brain, it remains unclear whether other dysfunctional systemic states can be exploited for similar benefits. Here, we investigate whether APOE allelic variation or presence of brain amyloid are associated with plasma proteomic changes and the molecular processes associated with these changes. Methods Using the SOMAscan assay, we measured 1305 plasma proteins from 53 homozygous, APOE3 and APOE4 subjects without dementia. We investigated the relationship of either the APOE‐ε4 allele or amyloid positivity with plasma proteome changes by linear mixed effects modeling and ontology‐based pathway and module–trait correlation analyses. Results APOE4 is associated with plasma protein differences linked to atherosclerosis, tyrosine kinase activity, cholesterol transport, extracellular matrix, and synaptogenesis pathways. Independent of APOE4, we found that subjects likely harboring brain amyloid exhibit plasma proteome signatures associated with AD‐linked pathways, including neurovascular dysfunction. Interpretation Our results indicate that APOE4 status or presence of brain amyloid are associated with plasma proteomic shifts prior to the onset of symptoms, suggesting that systemic pathways in certain risk contexts may be plausible targets for disease modification.https://doi.org/10.1002/acn3.52250 |
| spellingShingle | Sarah M. Philippi Kailash BP Towfique Raj Joseph M. Castellano APOE genotype and brain amyloid are associated with changes in the plasma proteome in elderly subjects without dementia Annals of Clinical and Translational Neurology |
| title | APOE genotype and brain amyloid are associated with changes in the plasma proteome in elderly subjects without dementia |
| title_full | APOE genotype and brain amyloid are associated with changes in the plasma proteome in elderly subjects without dementia |
| title_fullStr | APOE genotype and brain amyloid are associated with changes in the plasma proteome in elderly subjects without dementia |
| title_full_unstemmed | APOE genotype and brain amyloid are associated with changes in the plasma proteome in elderly subjects without dementia |
| title_short | APOE genotype and brain amyloid are associated with changes in the plasma proteome in elderly subjects without dementia |
| title_sort | apoe genotype and brain amyloid are associated with changes in the plasma proteome in elderly subjects without dementia |
| url | https://doi.org/10.1002/acn3.52250 |
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