Biological variation estimates of Alzheimer's disease plasma biomarkers in healthy individuals

Wagner S. Brum (Lead / Corresponding author), Nicholas J. Ashton, Joel Simrén, Guiglielmo di Molfetta, Thomas K. Karikari, Andrea L. Benedet, Eduardo R. Zimmer, Laia Montoliu-Gaya, Andreas Jeromin, Aasne Karine Aarsand, Bill Bartlett, Pilar Fernández-Calle, Abdurrahman Coşkun, Jorge Díaz-Garzón, Niels Jonker, Henrik Zetterberg, Sverre Sandberg, Anna Carobene (Lead / Corresponding author), Kaj Blennow (Lead / Corresponding author)

Research output: Contribution to journalArticlepeer-review

3 Citations (Scopus)
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Blood biomarkers have proven useful in Alzheimer's disease (AD) research. However, little is known about their biological variation (BV), which improves the interpretation of individual-level data.

We measured plasma amyloid beta (Aβ42, Aβ40), phosphorylated tau (p-tau181, p-tau217, p-tau231), glial fibrillary acidic protein (GFAP), and neurofilament light chain (NfL) in plasma samples collected weekly over 10 weeks from 20 participants aged 40 to 60 years from the European Biological Variation Study. We estimated within- (CVI) and between-subject (CVG) BV, analytical variation, and reference change values (RCV).

Biomarkers presented considerable variability in CVI and CVG. Aβ42/Aβ40 had the lowest CVI (≈ 3%) and p-tau181 the highest (≈ 16%), while others ranged from 6% to 10%. Most RCVs ranged from 20% to 30% (decrease) and 25% to 40% (increase).

BV estimates for AD plasma biomarkers can potentially refine their clinical and research interpretation. RCVs might be useful for detecting significant changes between serial measurements when monitoring early disease progression or interventions.

·Plasma amyloid beta (Aβ42/Aβ40) presents the lowest between- and within-subject biological variation, but also changes the least in Alzheimer's disease (AD) patients versus controls.
·Plasma phosphorylated tau variants significantly vary in their within-subject biological variation, but their substantial fold-changes in AD likely limits the impact of their variability.
·Plasma neurofilament light chain and glial fibrillary acidic protein demonstrate high between-subject variation, the impact of which will depend on clinical context.
·Reference change values can potentially be useful in monitoring early disease progression and the safety/efficacy of interventions on an individual level.
·Serial sampling revealed that unexpectedly high values in heathy individuals can be observed, which urges caution when interpreting AD plasma biomarkers based on a single test result.
Original languageEnglish
Pages (from-to)1284-1297
Number of pages14
JournalAlzheimer's and Dementia
Issue number2
Early online date20 Nov 2023
Publication statusPublished - 21 Feb 2024


  • amyloid
  • analytical variation
  • biological variation
  • glial fibrillary acidic protein
  • neurofilament light
  • phosphorylated tau
  • plasma biomarkers
  • reference change values

ASJC Scopus subject areas

  • Clinical Neurology
  • Geriatrics and Gerontology
  • Psychiatry and Mental health
  • Cellular and Molecular Neuroscience
  • Health Policy
  • Developmental Neuroscience
  • Epidemiology


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