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Publications

Journal Article Research Support, Non-U.S. Gov't Epublish 7 citations

PubMed: 40343697 DOI: 10.1001/jamanetworkopen.2025.8842

Cerebral Amyloid Angiopathy and Downstream Alzheimer Disease Plasma Biomarkers.

JAMA Netw Open 8(5):e258842

Authors: Sung Hoon Kang, Eun Hye Lee, Young Ju Kim, Hyemin Jang, Daeun Shin, Henrik Zetterberg, Kaj Blennow, Fernando Gonzalez-Ortiz, Nicholas J Ashton, Jihwan Yun, Hee Jin Kim, Duk L Na, Jun Pyo Kim, Sang Won Seo

Affiliations

  • Department of Neurology, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Republic of Korea. Department of Neurology, Korea University Guro Hospital, Korea University College of Medicine, Seoul, Republic of Korea.
  • Department of Neurology, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Republic of Korea. Department of Radiology and Imaging Sciences, Indiana University School of Medicine, Indianapolis. Indiana Alzheimer Disease Research Center, Indiana University School of Medicine, Indianapolis.
  • Department of Neurology, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Republic of Korea. Alzheimer's Disease Convergence Research Center, Samsung Medical Center, Seoul, Republic of Korea.
  • Department of Neurology, Seoul National University Hospital, Seoul National University School of Medicine, Seoul, Republic of Korea.
  • Department of Neurology, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Republic of Korea.
  • Department of Psychiatry and Neurochemistry, Institute of Neuroscience and Physiology, the Sahlgrenska Academy at the University of Gothenburg, Gothenburg, Sweden. Clinical Neurochemistry Laboratory, Sahlgrenska University Hospital, Gothenburg, Sweden. Department of Neurodegenerative Disease, UCL Queen Square Institute of Neurology, London, United Kingdom. UK Dementia Research Institute at UCL, London, United Kingdom. Hong Kong Center for Neurodegenerative Diseases, Hong Kong, People's Republic of China. Wisconsin Alzheimer's Disease Research Center, University of Wisconsin School of Medicine and Public Health, University of Wisconsin-Madison.
  • Department of Psychiatry and Neurochemistry, Institute of Neuroscience and Physiology, the Sahlgrenska Academy at the University of Gothenburg, Gothenburg, Sweden.
  • Clinical Neurochemistry Laboratory, Sahlgrenska University Hospital, Gothenburg, Sweden.
  • Paris Brain Institute, Pitié-Salpêtrière Hospital, Sorbonne University, Paris, France.
  • Neurodegenerative Disorder Research Center, Division of Life Sciences and Medicine, and Department of Neurology, Institute on Aging and Brain Disorders, University of Science and Technology of China and First Affiliated Hospital of University of Science and Technology of China, Hefei, People's Republic of China.
  • Department of Psychiatry and Neurochemistry, Institute of Neuroscience and Physiology, the Sahlgrenska Academy at the University of Gothenburg, Gothenburg, Sweden. Institute of Psychiatry, Psychology and Neuroscience, Maurice Wohl Clinical Neuroscience Institute, King's College London, London, United Kingdom. National Institute of Health Research Biomedical Research Centre for Mental Health and Biomedical Research Unit for Dementia at South London and Maudsley NHS Foundation, London, United Kingdom. Centre for Age-Related Medicine, Stavanger University Hospital, Stavanger, Norway.
  • Department of Neurology, Soonchunhyang University Bucheon Hospital, Gyeonggi-do, Republic of Korea.
  • Department of Neurology, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Republic of Korea. Alzheimer's Disease Convergence Research Center, Samsung Medical Center, Seoul, Republic of Korea. Department of Digital Health, Samsung Advanced Institute of Health Sciences and Technology, Sungkyunkwan University, Seoul, Republic of Korea. Department of Health Sciences and Technology, Samsung Advanced Institute of Health Sciences and Technology, Sungkyunkwan University, Seoul, Republic of Korea. Department of Intelligent Precision Healthcare Convergence, Sungkyunkwan University, Suwon, Republic of Korea.

Abstract

Importance

As amyloid-targeted therapies have become commercially available, the monitoring of cerebral amyloid angiopathy (CAA), which is an important risk factor for amyloid-related imaging abnormalities, has received increasing attention. However, comprehensive evidence on the association between Alzheimer disease (AD) plasma biomarkers and various CAA imaging markers is still lacking.

Objective

To examine the association of CAA imaging markers with downstream AD plasma biomarkers in relation to amyloid-β (Aβ) uptake on positron emission tomography (PET) and whether their interplay is associated with cognitive changes.

Design, Setting, and Participants

This registry-based cohort study in 25 hospitals across South Korea recruited participants aged 45 years or older who were registered between January 1, 2016, and December 31, 2023. Participants were categorized as having no cognitive impairment, mild cognitive impairment, or dementia of the Alzheimer type.

Exposures

Cerebral amyloid angiopathy imaging markers assessed by magnetic resonance imaging, including cerebral microbleeds (CMBs), cortical superficial siderosis, white matter hyperintensities, lacunes, and enlarged perivascular spaces.

Main Outcomes and Measures

Plasma phosphorylated tau-217 (p-tau217) was measured using a commercial assay. Glial fibrillary acidic protein (GFAP) and neurofilament light chain (NfL) were measured using a single-molecule assay on a single platform. All participants underwent amyloid PET imaging. Associations of CAA and vascular imaging markers with downstream AD plasma biomarkers were investigated using linear regression.

Results

A total of 1708 participants were included (mean [SD] age, 71.2 [8.4] years; 1044 female [61.1%]). The mean (SD) follow-up period was 4.3 (3.1) years. Lobar CMB counts and the presence of CAA were associated with downstream AD plasma biomarkers, including p-tau217 (β = 0.12 [95% CI, 0.05-0.18] and 0.29 [95% CI, 0.12-0.47], respectively), GFAP (β = 0.07 [95% CI, 0.03-0.12] and 0.20 [95% CI, 0.09-0.31], respectively), and NfL (β = 0.07 [95% CI, 0.03-0.11] and 0.16 [95% CI, 0.06-0.25], respectively) with and without the mediation of Aβ uptake on PET (indirect effect: lobar CMBs-p-tau217, 59.8% [β = 0.07 (95% CI, 0.03-0.11)]; lobar CMBs-GFAP, 49.3% [β = 0.04 (95% CI, 0.01-0.06)]; lobar CMBs-NfL, 20.9% [β = 0.01 (95% CI, 0.01-0.03)]; CAA-p-tau217, 50.9% [β = 0.15 (95% CI, 0.06-0.24)]; CAA-GFAP, 39.2% [β = 0.08 (95% CI, 0.03-0.13)]; CAA-NfL, 19.2% [β = 0.03 (95% CI, 0.01-0.05)]). Amyloid-β uptake fully mediated the associations between cortical superficial siderosis and downstream AD plasma markers. In contrast, hypertensive arteriosclerotic vascular imaging markers, including lacunes, deep CMBs, and enlarged perivascular spaces in basal ganglia, were associated with only NfL levels (β = 0.07 [95% CI, 0.01-0.13], 0.20 [95% CI, 0.08-0.32], and 0.14 [95% CI, 0.06-0.23], respectively), regardless of Aβ uptake on PET. Finally, there were interactive associations of lobar CMBs in conjunction with p-tau217 levels (β = -0.56 [95% CI, -0.79 to -0.34]) and GFAP levels (β = -0.44 [95% CI, -0.70 to -0.17]) with annual Mini-Mental State Examination changes.

Conclusions and Relevance

In this cohort study of participants with no cognitive impairment, mild cognitive impairment, or dementia of the Alzheimer type, a novel association was found among CAA imaging markers, downstream AD plasma biomarkers, and cognitive declines in relation to brain Aβ burdens. The findings emphasize the importance of understanding the clinical effects of amyloid-related imaging abnormality-like CAA imaging markers in light of upcoming amyloid-targeted therapies.

MeSH

Dementia, Alzheimer Disease, Positron-Emission Tomography, Cohort Studies, Cognitive Dysfunction, Siderosis, Biomarkers, Clinical Medicine, Cognition Disorders, Therapeutics, Amyloid, Cerebral Amyloid Angiopathy, Plasma