Plasma Alzheimer's disease biomarker variability: Amyloid-independent and amyloid-dependent factors

Eun Hye Lee; Sung Hoon Kang; Daeun Shin; Young Ju Kim; Henrik Zetterberg; Kaj Blennow; Fernando Gonzalez-Ortiz; Nicholas J Ashton; Bo Kyoung Cheon; Heejin Yoo; Hongki Ham; Jihwan Yun; Jun Pyo Kim; Hee Jin Kim; Duk L Na; Hyemin Jang; Sang Won Seo; K‐ROAD study group

doi:10.1002/alz.14368

Plasma Alzheimer's disease biomarker variability: Amyloid-independent and amyloid-dependent factors

Alzheimers Dement. 2024 Nov 13. doi: 10.1002/alz.14368. Online ahead of print.

Authors

Eun Hye Lee¹, Sung Hoon Kang^{1

2}, Daeun Shin¹, Young Ju Kim^{1

3}, Henrik Zetterberg^{4

5

6

7

8

9}, Kaj Blennow^{4

5

10

11}, Fernando Gonzalez-Ortiz^{4

5}, Nicholas J Ashton^{4

12

13

14}, Bo Kyoung Cheon^{1

3}, Heejin Yoo^{1

3}, Hongki Ham^{3

15}, Jihwan Yun¹⁶, Jun Pyo Kim¹, Hee Jin Kim^{1

3

15

17}, Duk L Na^{1

3}, Hyemin Jang¹⁸, Sang Won Seo^{1

3

15

19

20}; K‐ROAD study group

Affiliations

¹ Department of Neurology, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, South Korea.
² Department of Neurology, Korea University Guro Hospital, Korea University College of Medicine, Seoul, South Korea.
³ Alzheimer's Disease Convergence Research Center, Samsung Medical Center, Seoul, South Korea.
⁴ Department of Psychiatry and Neurochemistry, Institute of Neuroscience and Physiology, the Sahlgrenska Academy at the University of Gothenburg, Göteborg, Sweden.
⁵ Clinical Neurochemistry Laboratory, Sahlgrenska University Hospital, Göteborg, Sweden.
⁶ Department of Neurodegenerative Disease, UCL Institute of Neurology, London, UK.
⁷ UK Dementia Research Institute at UCL, London, UK.
⁸ Hong Kong Center for Neurodegenerative Diseases, Hong Kong, P.R. 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 Paris Brain Institute, ICM, Pitié-Salpêtrière Hospital, Sorbonne University, Paris, France.
¹¹ 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 USTC, Hefei, P.R. China.
¹² King's College London, Institute of Psychiatry, Psychology and Neuroscience, Maurice Wohl Clinical Neuroscience Institute, London, UK.
¹³ NIHR Biomedical Research Centre for Mental Health and Biomedical Research Unit for Dementia at South London and Maudsley NHS Foundation, London, UK.
¹⁴ Centre for Age-Related Medicine, Stavanger University Hospital, Stavanger, Norway.
¹⁵ Neuroscience Center, Samsung Medical Center, Seoul, South Korea.
¹⁶ Department of Neurology, Soonchunhyang University Bucheon Hospital, Bucheon-si, South Korea.
¹⁷ Department of Digital Health, SAIHST, Sungkyunkwan University, Seoul, South Korea.
¹⁸ Department of Neurology, Seoul National University Hospital, Seoul National University School of Medicine, Seoul, South Korea.
¹⁹ Department of Health Sciences and Technology, SAIHST, Sungkyunkwan University, Seoul, South Korea.
²⁰ Department of Intelligent Precision Healthcare Convergence, Sungkyunkwan University, Suwon, South Korea.

PMID: 39535473
DOI: 10.1002/alz.14368

Abstract

Introduction: We aimed to investigate which factors affect plasma biomarker levels via amyloid beta (Aβ)-independent or Aβ-dependent effects and improve the predictive performance of these biomarkers for Aβ positivity on positron emission tomography (PET).

Methods: A total of 2935 participants underwent blood sampling for measurements of plasma Aβ42/40 ratio, phosphorylated tau 217 (p-tau217; ALZpath), glial fibrillary acidic protein (GFAP), and neurofilament light chain (NfL) levels using single-molecule array and Aβ PET. Laboratory findings were collected using a routine blood test battery.

Results: Aβ-independent factors included hemoglobin and estimated glomerular filtration rate (eGFR) for p-tau217 and hemoglobin, eGFR, and triiodothyronine (T₃) for GFAP and NfL. Aβ-dependent factors included apolipoprotein E genotypes, body mass index status for Aβ42/40, p-tau217, GFAP, and NfL. However, these factors exhibited negligible or modest effects on Aβ positivity on PET.

Discussion: Our findings highlight the importance of accurately interpreting plasma biomarkers for predicting Aβ uptake in real-world settings.

Highlights: We investigated factor-Alzheimer's disease plasma biomarker associations in a large Korean cohort. Hemoglobin and estimated glomerular filtration rate affect the biomarkers independently of brain amyloid beta (Aβ). Apolipoprotein E genotypes and body mass index status affect the biomarkers dependent on brain Aβ. Addition of Aβ-independent factors shows negligible effect in predicting Aβ positivity. Adjusting for Aβ-dependent factors shows a modest effect in predicting Aβ positivity.

Keywords: Alzheimer's disease; amyloid beta–dependent variability; amyloid beta–independent variability; biomarker application; biomarker variability; comorbidity; plasma biomarkers; subcortical vascular cognitive impairment.

Abstract

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