CHIT1 and DDAH1 levels relate to amyloid-related imaging abnormalities risk profile in Alzheimer's disease patients
Hok-A-Hin, Yanaika S. (Vrije Universiteit Amsterdam)
van der Flier, Wiesje M. (Vrije Universiteit Amsterdam)
Barkhof, Frederik (Vrije Universiteit Amsterdam)
del Campo, Marta (Fundació Pasqual Maragall)
Bejanin, Alexandre (Institut de Recerca Sant Pau)
Alcolea, Daniel (Institut de Recerca Sant Pau)
Teunissen, Charlotte E. (Amsterdam University Medical Center (UMC))
Vermunt, Lisa (Amsterdam University Medical Center (UMC))
Oosthoek, Marlies (Amsterdam University Medical Center (UMC))
Vijverberg, Everard G.B. (Vrije Universiteit Amsterdam)
Blujdea, Elena R. (Amsterdam University Medical Center (UMC))
Veld, Sjors G.J.G.In't (Amsterdam University Medical Center (UMC))
Pucheu Avilés, Martín (Amsterdam University Medical Center (UMC))
Zsadanyi, Sara E. (Institut de Recerca Sant Pau)
Visser, Allerdien (Amsterdam University Medical Center (UMC))
Schut, Martijn C. (Amsterdam University Medical Center (UMC))
Universitat Autònoma de Barcelona. Departament de Medicina

Data:	2025
Resum:	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 (A). We hypothesize that studying the CSF proteome of Alzheimer's disease (AD) dementia patients from a high-risk group (MBLAPOE4A) 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.
Ajuts:	Generalitat de Catalunya 2017-SGR-547 Instituto de Salud Carlos III PI18/00435 Instituto de Salud Carlos III PI17/01019 Instituto de Salud Carlos III PI22/00611 Ministerio de Economía y Competitividad PI13/01532 Instituto de Salud Carlos III PI21/00791 Ministerio de Economía y Competitividad PI16/01825 Instituto de Salud Carlos III AC19/00103 Ministerio de Economía y Competitividad PI14/01126 Instituto de Salud Carlos III PI19/00882 Instituto de Salud Carlos III PI20/01473 Instituto de Salud Carlos III PI22/00307 Instituto de Salud Carlos III PI18/00335 Instituto de Salud Carlos III PI17/01896
Drets:	Aquest document està subjecte a una llicència d'ús Creative Commons. Es permet la reproducció total o parcial, la distribució, i la comunicació pública de l'obra, sempre que no sigui amb finalitats comercials, i sempre que es reconegui l'autoria de l'obra original. No es permet la creació d'obres derivades.
Llengua:	Anglès
Document:	Article ; recerca ; Versió publicada
Matèria:	ARIA ; Biomarker ; Risk
Publicat a:	Alzheimer's research & therapy, Vol. 17, Num. 1 (December 2025) , p. 169, ISSN 1758-9193

DOI: 10.1186/s13195-025-01799-3
PMID: 40696469

12 p, 2.9 MB

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