CHIT1 and DDAH1 levels relate to amyloid-related imaging abnormalities risk profile in Alzheimer’s disease patients
Abstract Background Amyloid-related imaging abnormalities (ARIA) are a common and potentially dangerous side effect in anti-amyloid therapies, creating a need for tools to assess ARIA risk. Several patient factors have been linked to ARIA; namely the presence of microbleeds (MBL+), APOE E4 carriersh...
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BMC
2025-07-01
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| Series: | Alzheimer’s Research & Therapy |
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| Online Access: | https://doi.org/10.1186/s13195-025-01799-3 |
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| author | Marlies Oosthoek Everard G.B. Vijverberg Elena R. Blujdea Sjors G.J.G. In’t Veld Martín Pucheu Avilés Sára E. Zsadanyi Yanaika S. Hok-A-Hin Allerdien Visser Wiesje M. van der Flier Frederik Barkhof Marta del Campo Martijn C. Schut Alexandre Bejanin Daniel Alcolea Charlotte E. Teunissen Lisa Vermunt |
| author_facet | Marlies Oosthoek Everard G.B. Vijverberg Elena R. Blujdea Sjors G.J.G. In’t Veld Martín Pucheu Avilés Sára E. Zsadanyi Yanaika S. Hok-A-Hin Allerdien Visser Wiesje M. van der Flier Frederik Barkhof Marta del Campo Martijn C. Schut Alexandre Bejanin Daniel Alcolea Charlotte E. Teunissen Lisa Vermunt |
| author_sort | Marlies Oosthoek |
| collection | DOAJ |
| description | Abstract Background Amyloid-related imaging abnormalities (ARIA) are a common and potentially dangerous side effect in anti-amyloid therapies, creating a need for tools to assess ARIA risk. Several patient factors have been linked to ARIA; namely the presence of microbleeds (MBL+), APOE E4 carriership (APOE4+), and extremely low CSF Aβ42 concentrations (AL). We hypothesize that studying the CSF proteome of Alzheimer’s disease (AD) dementia patients from a high-risk group (MBL+APOE4+AL) can inform on the biological underpinnings of ARIA risk and aid the progress of ARIA risk biomarkers. Methods We utilized CSF proteomic data of AD (n = 156) and cognitively unimpaired individuals (CU n = 100) of the Amsterdam Dementia Cohort. The proteome of the defined high-risk (n = 13) was compared to low-risk AD group (n = 23), using age and sex corrected linear regressions followed by gene ontology analysis. For biomarker prioritization, we selected proteins that were abnormal in the high-risk group versus low-risk and CU patients. The biomarkers were validated in an independent cohort (high risk n = 14, low risk n = 9) analyzed using customized multiplex panels. Lastly, we assessed biomarker lead co-expression. Results Ninety-four proteins differentiated in the high-risk group compared to low-risk (p < 0.05), none surviving FDR correction. These proteins were enriched for synapse-related proteins and axonogenesis. CHIT1 (vs. low-risk AD: FC = 1.0, p = 0.014, vs. CU: FC = 2.4, p < 0.001) and DDAH1 (vs. low-risk AD: FC=-0.31, p = 0.046, vs. CU: FC = 0.5, p < 0.001) were prioritized as biomarker. DDAH1 protein changes replicated in an independent cohort (FC=-0.37, p = 0.010), and CHIT1 replicated on a trend level (FC = 0.70, p = 0.104). DDAH1 levels had the highest co-expression with synaptic process, energy utilization and RNA-binding cell signaling related proteins (R > 0.8). Conclusions The findings suggest that in the high risk group, there is a lack of upregulation in synapse and axonogenesis related proteins. High CSF CHIT1 and less increased CSF DDAH1 levels within AD relate to ARIA risk. From the literature, the link to ARIA risk for CHIT1 could be its contribution to innate immunity or vascular amyloid deposition, and for DDAH1 to blood-brain barrier integrity. Biomarker assays are available to assess the potential of CHIT1 and DDAH1 in trials and treatment studies in the clinical setting. |
| format | Article |
| id | doaj-art-a6cc71d9ac1e4d0bbe953046f346d7f7 |
| institution | Kabale University |
| issn | 1758-9193 |
| language | English |
| publishDate | 2025-07-01 |
| publisher | BMC |
| record_format | Article |
| series | Alzheimer’s Research & Therapy |
| spelling | doaj-art-a6cc71d9ac1e4d0bbe953046f346d7f72025-08-20T03:46:07ZengBMCAlzheimer’s Research & Therapy1758-91932025-07-0117111210.1186/s13195-025-01799-3CHIT1 and DDAH1 levels relate to amyloid-related imaging abnormalities risk profile in Alzheimer’s disease patientsMarlies Oosthoek0Everard G.B. Vijverberg1Elena R. Blujdea2Sjors G.J.G. In’t Veld3Martín Pucheu Avilés4Sára E. Zsadanyi5Yanaika S. Hok-A-Hin6Allerdien Visser7Wiesje M. van der Flier8Frederik Barkhof9Marta del Campo10Martijn C. Schut11Alexandre Bejanin12Daniel Alcolea13Charlotte E. Teunissen14Lisa Vermunt15Neurochemistry Laboratory, Department of Laboratory Medicine, Amsterdam Neuroscience, Vrije Universiteit Amsterdam, Amsterdam UMCAlzheimer Center, Department of Neurology, Vrije Universiteit AmsterdamNeurochemistry Laboratory, Department of Laboratory Medicine, Amsterdam Neuroscience, Vrije Universiteit Amsterdam, Amsterdam UMCNeurochemistry Laboratory, Department of Laboratory Medicine, Amsterdam Neuroscience, Vrije Universiteit Amsterdam, Amsterdam UMCNeurochemistry Laboratory, Department of Laboratory Medicine, Amsterdam Neuroscience, Vrije Universiteit Amsterdam, Amsterdam UMCSant Pau Memory Unit, Department of Neurology, Institut d’Investigacions Biomèdiques Sant Pau Hospital de Sant Pau, Universitat Autònoma de BarcelonaNeurochemistry Laboratory, Department of Laboratory Medicine, Amsterdam Neuroscience, Vrije Universiteit Amsterdam, Amsterdam UMCTranslational AI in Laboratory Medicine, Department of Laboratory Medicine, Vrije Universiteit Amsterdam, Amsterdam UMCAlzheimer Center, Department of Neurology, Vrije Universiteit AmsterdamDepartment of Neuroinflammation, Queen Square MS Centre, UCL Queen Square Institute of Neurology, Faculty of Brain Science, University College of LondonBarcelonaβeta Brain Research Center (BBRC), Pasqual Maragall FoundationTranslational AI in Laboratory Medicine, Department of Laboratory Medicine, Vrije Universiteit Amsterdam, Amsterdam UMCSant Pau Memory Unit, Department of Neurology, Institut d’Investigacions Biomèdiques Sant Pau Hospital de Sant Pau, Universitat Autònoma de BarcelonaSant Pau Memory Unit, Department of Neurology, Institut d’Investigacions Biomèdiques Sant Pau Hospital de Sant Pau, Universitat Autònoma de BarcelonaNeurochemistry Laboratory, Department of Laboratory Medicine, Amsterdam Neuroscience, Vrije Universiteit Amsterdam, Amsterdam UMCNeurochemistry Laboratory, Department of Laboratory Medicine, Amsterdam Neuroscience, Vrije Universiteit Amsterdam, Amsterdam UMCAbstract Background Amyloid-related imaging abnormalities (ARIA) are a common and potentially dangerous side effect in anti-amyloid therapies, creating a need for tools to assess ARIA risk. Several patient factors have been linked to ARIA; namely the presence of microbleeds (MBL+), APOE E4 carriership (APOE4+), and extremely low CSF Aβ42 concentrations (AL). We hypothesize that studying the CSF proteome of Alzheimer’s disease (AD) dementia patients from a high-risk group (MBL+APOE4+AL) can inform on the biological underpinnings of ARIA risk and aid the progress of ARIA risk biomarkers. Methods We utilized CSF proteomic data of AD (n = 156) and cognitively unimpaired individuals (CU n = 100) of the Amsterdam Dementia Cohort. The proteome of the defined high-risk (n = 13) was compared to low-risk AD group (n = 23), using age and sex corrected linear regressions followed by gene ontology analysis. For biomarker prioritization, we selected proteins that were abnormal in the high-risk group versus low-risk and CU patients. The biomarkers were validated in an independent cohort (high risk n = 14, low risk n = 9) analyzed using customized multiplex panels. Lastly, we assessed biomarker lead co-expression. Results Ninety-four proteins differentiated in the high-risk group compared to low-risk (p < 0.05), none surviving FDR correction. These proteins were enriched for synapse-related proteins and axonogenesis. CHIT1 (vs. low-risk AD: FC = 1.0, p = 0.014, vs. CU: FC = 2.4, p < 0.001) and DDAH1 (vs. low-risk AD: FC=-0.31, p = 0.046, vs. CU: FC = 0.5, p < 0.001) were prioritized as biomarker. DDAH1 protein changes replicated in an independent cohort (FC=-0.37, p = 0.010), and CHIT1 replicated on a trend level (FC = 0.70, p = 0.104). DDAH1 levels had the highest co-expression with synaptic process, energy utilization and RNA-binding cell signaling related proteins (R > 0.8). Conclusions The findings suggest that in the high risk group, there is a lack of upregulation in synapse and axonogenesis related proteins. High CSF CHIT1 and less increased CSF DDAH1 levels within AD relate to ARIA risk. From the literature, the link to ARIA risk for CHIT1 could be its contribution to innate immunity or vascular amyloid deposition, and for DDAH1 to blood-brain barrier integrity. Biomarker assays are available to assess the potential of CHIT1 and DDAH1 in trials and treatment studies in the clinical setting.https://doi.org/10.1186/s13195-025-01799-3ARIABiomarkerRisk |
| spellingShingle | Marlies Oosthoek Everard G.B. Vijverberg Elena R. Blujdea Sjors G.J.G. In’t Veld Martín Pucheu Avilés Sára E. Zsadanyi Yanaika S. Hok-A-Hin Allerdien Visser Wiesje M. van der Flier Frederik Barkhof Marta del Campo Martijn C. Schut Alexandre Bejanin Daniel Alcolea Charlotte E. Teunissen Lisa Vermunt CHIT1 and DDAH1 levels relate to amyloid-related imaging abnormalities risk profile in Alzheimer’s disease patients Alzheimer’s Research & Therapy ARIA Biomarker Risk |
| title | CHIT1 and DDAH1 levels relate to amyloid-related imaging abnormalities risk profile in Alzheimer’s disease patients |
| title_full | CHIT1 and DDAH1 levels relate to amyloid-related imaging abnormalities risk profile in Alzheimer’s disease patients |
| title_fullStr | CHIT1 and DDAH1 levels relate to amyloid-related imaging abnormalities risk profile in Alzheimer’s disease patients |
| title_full_unstemmed | CHIT1 and DDAH1 levels relate to amyloid-related imaging abnormalities risk profile in Alzheimer’s disease patients |
| title_short | CHIT1 and DDAH1 levels relate to amyloid-related imaging abnormalities risk profile in Alzheimer’s disease patients |
| title_sort | chit1 and ddah1 levels relate to amyloid related imaging abnormalities risk profile in alzheimer s disease patients |
| topic | ARIA Biomarker Risk |
| url | https://doi.org/10.1186/s13195-025-01799-3 |
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