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

Wagner S.  Brum; 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; Kaj Blennow

doi:10.1002/alz.13518

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)

Biomedical Engineering

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Abstract

INTRODUCTION
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.

METHODS
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).

RESULTS
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).

DISCUSSION
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.

Highlights
·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 language	English
Pages (from-to)	1284-1297
Number of pages	14
Journal	Alzheimer's and Dementia
Volume	20
Issue number	2
Early online date	20 Nov 2023
DOIs	https://doi.org/10.1002/alz.13518
Publication status	Published - 21 Feb 2024

Keywords

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

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

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10.1002/alz.13518Licence: CC BY

Final Published Version Final published version, 1.33 MBLicence: CC BY

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Brum, W. S., Ashton, N. J., Simrén, J., di Molfetta, G., Karikari, T. K., Benedet, A. L., Zimmer, E. R., Montoliu-Gaya, L., Jeromin, A., Aarsand, A. K., Bartlett, B., Fernández-Calle, P., Coşkun, A., Díaz-Garzón, J., Jonker, N., Zetterberg, H., Sandberg, S., Carobene, A., & Blennow, K. (2024). Biological variation estimates of Alzheimer's disease plasma biomarkers in healthy individuals. Alzheimer's and Dementia, 20(2), 1284-1297. https://doi.org/10.1002/alz.13518

@article{ec93fb907c4b4896bd784f41c55cb94e,

title = "Biological variation estimates of Alzheimer's disease plasma biomarkers in healthy individuals",

abstract = "INTRODUCTIONBlood 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.METHODSWe 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).RESULTSBiomarkers 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).DISCUSSIONBV 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.Highlights·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.",

keywords = "amyloid, analytical variation, biological variation, glial fibrillary acidic protein, neurofilament light, phosphorylated tau, plasma biomarkers, reference change values",

author = "Brum, {Wagner S.} and Ashton, {Nicholas J.} and Joel Simr{\'e}n and {di Molfetta}, Guiglielmo and Karikari, {Thomas K.} and Benedet, {Andrea L.} and Zimmer, {Eduardo R.} and Laia Montoliu-Gaya and Andreas Jeromin and Aarsand, {Aasne Karine} and Bill Bartlett and Pilar Fern{\'a}ndez-Calle and Abdurrahman Co{\c s}kun and Jorge D{\'i}az-Garz{\'o}n and Niels Jonker and Henrik Zetterberg and Sverre Sandberg and Anna Carobene and Kaj Blennow",

year = "2024",

month = feb,

day = "21",

doi = "10.1002/alz.13518",

language = "English",

volume = "20",

pages = "1284--1297",

journal = "Alzheimer's and Dementia",

issn = "1552-5260",

publisher = "Wiley",

number = "2",

}

Brum, WS, Ashton, NJ, Simrén, J, di Molfetta, G, Karikari, TK, Benedet, AL, Zimmer, ER, Montoliu-Gaya, L, Jeromin, A, Aarsand, AK, Bartlett, B, Fernández-Calle, P, Coşkun, A, Díaz-Garzón, J, Jonker, N, Zetterberg, H, Sandberg, S, Carobene, A & Blennow, K 2024, 'Biological variation estimates of Alzheimer's disease plasma biomarkers in healthy individuals', Alzheimer's and Dementia, vol. 20, no. 2, pp. 1284-1297. https://doi.org/10.1002/alz.13518

TY - JOUR

T1 - Biological variation estimates of Alzheimer's disease plasma biomarkers in healthy individuals

AU - Brum, Wagner S.

AU - Ashton, Nicholas J.

AU - Simrén, Joel

AU - di Molfetta, Guiglielmo

AU - Karikari, Thomas K.

AU - Benedet, Andrea L.

AU - Zimmer, Eduardo R.

AU - Montoliu-Gaya, Laia

AU - Jeromin, Andreas

AU - Aarsand, Aasne Karine

AU - Bartlett, Bill

AU - Fernández-Calle, Pilar

AU - Coşkun, Abdurrahman

AU - Díaz-Garzón, Jorge

AU - Jonker, Niels

AU - Zetterberg, Henrik

AU - Sandberg, Sverre

AU - Carobene, Anna

AU - Blennow, Kaj

PY - 2024/2/21

Y1 - 2024/2/21

N2 - INTRODUCTIONBlood 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.METHODSWe 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).RESULTSBiomarkers 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).DISCUSSIONBV 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.Highlights·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.

AB - INTRODUCTIONBlood 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.METHODSWe 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).RESULTSBiomarkers 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).DISCUSSIONBV 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.Highlights·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.

KW - amyloid

KW - analytical variation

KW - biological variation

KW - glial fibrillary acidic protein

KW - neurofilament light

KW - phosphorylated tau

KW - plasma biomarkers

KW - reference change values

U2 - 10.1002/alz.13518

DO - 10.1002/alz.13518

M3 - Article

C2 - 37985230

SN - 1552-5260

VL - 20

SP - 1284

EP - 1297

JO - Alzheimer's and Dementia

JF - Alzheimer's and Dementia

IS - 2

ER -

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

Abstract

Keywords

ASJC Scopus subject areas

UN SDGs

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