Profiling amyloid-β peptides as biomarkers for cerebral amyloid angiopathy

Emma van den Berg; Iris Kersten; Gunnar Brinkmalm; Kjell Johansson; Anna M de Kort; Catharina J M Klijn; Floris H B M Schreuder; Johan Gobom; Erik Stoops; Erik Portelius; Eleni Gkanatsiou; Henrik Zetterberg; Kaj Blennow; H Bea Kuiperij; Marcel M Verbeek

doi:10.1111/jnc.16074

Profiling amyloid-β peptides as biomarkers for cerebral amyloid angiopathy

J Neurochem. 2024 Feb 16. doi: 10.1111/jnc.16074. Online ahead of print.

Authors

Emma van den Berg¹, Iris Kersten¹, Gunnar Brinkmalm^{2

3}, Kjell Johansson³, Anna M de Kort¹, Catharina J M Klijn¹, Floris H B M Schreuder¹, Johan Gobom^{2

3}, Erik Stoops⁴, Erik Portelius³, Eleni Gkanatsiou^{2

3}, Henrik Zetterberg^{3

5

6

7

8

9}, Kaj Blennow^{2

3}, H Bea Kuiperij¹, Marcel M Verbeek^{1

10}

Affiliations

¹ Department of Neurology, Donders Institute for Brain, Cognition and Behaviour, Radboud University Medical Center, Nijmegen, The Netherlands.
² Institute of Neuroscience and Physiology, The Sahlgrenska Academy at the University of Gothenburg, Mölndal, Sweden.
³ Clinical Neurochemistry Laboratory, Sahlgrenska University Hospital, Mölndal, Sweden.
⁴ ADx NeuroSciences, Ghent, Belgium.
⁵ Department of Psychiatry and Neurochemistry, Institute of Neuroscience and Physiology, The Sahlgrenska Academy at the University of Gothenburg, Mölndal, Sweden.
⁶ UK Dementia Research Institute at UCL, London, UK.
⁷ Department of Neurodegenerative Disease, UCL Institute of Neurology, London, UK.
⁸ Hong Kong Center for Neurodegenerative Diseases, Clear Water Bay, Hong Kong, China.
⁹ Wisconsin Alzheimer's Disease Research Center, University of Wisconsin School of Medicine and Public Health, University of Wisconsin-Madison, Madison, Wisconsin, USA.
¹⁰ Department of Human Genetics, Radboud University Medical Center, Nijmegen, The Netherlands.

PMID: 38362804
DOI: 10.1111/jnc.16074

Abstract

Brain amyloid-β (Aβ) deposits are key pathological hallmarks of both cerebral amyloid angiopathy (CAA) and Alzheimer's disease (AD). Microvascular deposits in CAA mainly consist of the Aβ₄₀ peptide, whereas Aβ₄₂ is the predominant variant in parenchymal plaques in AD. The relevance in pathogenesis and diagnostic accuracy of various other Aβ isoforms in CAA remain understudied. We aimed to investigate the biomarker potential of various Aβ isoforms in cerebrospinal fluid (CSF) to differentiate CAA from AD pathology. We included 25 patients with probable CAA, 50 subjects with a CSF profile indicative of AD pathology (AD-like), and 23 age- and sex-matched controls. CSF levels of Aβ_1-34 , Aβ_1-37 , Aβ_1-38 , Aβ_1-39 , Aβ_1-40 , and Aβ_1-42 were quantified by liquid chromatography mass spectrometry. Lower CSF levels of all six Aβ peptides were observed in CAA patients compared with controls (p = 0.0005-0.03). Except for Aβ_1-42 (p = 1.0), all peptides were decreased in CAA compared with AD-like subjects (p = 0.007-0.03). Besides Aβ_1-42 , none of the Aβ peptides were decreased in AD-like subjects compared with controls. All Aβ peptides combined differentiated CAA from AD-like subjects better (area under the curve [AUC] 0.84) than individual peptide levels (AUC 0.51-0.75). Without Aβ_1-42 in the model (since decreased Aβ_1-42 served as AD-like selection criterion), the AUC was 0.78 for distinguishing CAA from AD-like subjects. CAA patients and AD-like subjects showed distinct disease-specific CSF Aβ profiles. Peptides shorter than Aβ_1-42 were decreased in CAA patients, but not AD-like subjects, which could suggest different pathological mechanisms between vascular and parenchymal Aβ accumulation. This study supports the potential use of this panel of CSF Aβ peptides to indicate presence of CAA pathology with high accuracy.

Keywords: Alzheimer's disease; amyloid-β; biomarkers; cerebral amyloid angiopathy; cerebrospinal fluid; mass spectrometry.

Abstract

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