Short-term variability of Alzheimer’s disease plasma biomarkers in a mixed memory clinic cohort
Abstract Background For clinical implementation of Alzheimer’s disease (AD) blood-based biomarkers (BBMs), knowledge of short-term variability, is crucial to ensure safe and correct biomarker interpretation, i.e., to capture changes or treatment effects that lie beyond that of expected short-term va...
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BMC
2025-01-01
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| Series: | Alzheimer’s Research & Therapy |
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| Online Access: | https://doi.org/10.1186/s13195-024-01658-7 |
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| author | Frederikke Kragh Clemmensen Mathias Holsey Gramkow Anja Hviid Simonsen Nicholas J. Ashton Hanna Huber Kaj Blennow Henrik Zetterberg Gunhild Waldemar Steen Gregers Hasselbalch Kristian Steen Frederiksen |
| author_facet | Frederikke Kragh Clemmensen Mathias Holsey Gramkow Anja Hviid Simonsen Nicholas J. Ashton Hanna Huber Kaj Blennow Henrik Zetterberg Gunhild Waldemar Steen Gregers Hasselbalch Kristian Steen Frederiksen |
| author_sort | Frederikke Kragh Clemmensen |
| collection | DOAJ |
| description | Abstract Background For clinical implementation of Alzheimer’s disease (AD) blood-based biomarkers (BBMs), knowledge of short-term variability, is crucial to ensure safe and correct biomarker interpretation, i.e., to capture changes or treatment effects that lie beyond that of expected short-term variability and considered clinically relevant. In this study we investigated short-term intra- and inter-individual variability of AD biomarkers in the intended use population, memory clinic patients. Methods In a consecutive sample of memory clinic patients (AD n = 27, non-AD n = 20), blood samples were collected on three separate days within a period of 36 days and analysed for plasma Aβ40, Aβ42, p-tau181, p-tau217, p-tau231, T-tau, neurofilament light (NfL), and glial fibrillary acidic protein (GFAP). We measured intra- and inter-individual variability and explored if the variability could be affected by confounding factors. Secondly, we established the minimum change required to detect a difference between two given blood samples that exceeds intra-individual variability and analytical variation (reference change value, RCV). Finally, we tested if classification accuracy varied across the three visits. Results Intra-individual variability ranged from ~ 3% (Aβ42/40) to ~ 12% (T-tau). Inter-individual variability ranged from ~ 7% (Aβ40) to ~ 39% (NfL). Adjusting the models for time, eGFR, Hba1c, and BMI did not affect the variation. RCV was lowest for Aβ42/Aβ40 (- ~ 15%/ + ~ 17%) and highest in p-tau181 (- ~ 30/ + ~ 42%). No variation in classification accuracies was found across visits. Conclusion We found low intra-individual variability, robust to various factors, appropriate to capture individual changes in AD BBMs, while moderate inter-individual variability may give rise to caution in diagnostic contexts. High RCVs may pose challenges for AD BBMs with low fold changes and consequently, short-term variability is important to take into consideration when, e.g., estimating intervention effect and longitudinal changes of AD BBM levels. Trial registration Clinicaltrials.gov (NCT05175664), date of registration 2021–12-01. |
| format | Article |
| id | doaj-art-55c024e32e134c2d95f70da10782a61a |
| institution | Kabale University |
| issn | 1758-9193 |
| language | English |
| publishDate | 2025-01-01 |
| publisher | BMC |
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| series | Alzheimer’s Research & Therapy |
| spelling | doaj-art-55c024e32e134c2d95f70da10782a61a2025-01-26T12:18:56ZengBMCAlzheimer’s Research & Therapy1758-91932025-01-0117111410.1186/s13195-024-01658-7Short-term variability of Alzheimer’s disease plasma biomarkers in a mixed memory clinic cohortFrederikke Kragh Clemmensen0Mathias Holsey Gramkow1Anja Hviid Simonsen2Nicholas J. Ashton3Hanna Huber4Kaj Blennow5Henrik Zetterberg6Gunhild Waldemar7Steen Gregers Hasselbalch8Kristian Steen Frederiksen9Danish Dementia Research Centre, Department of Neurology, Copenhagen University Hospital - RigshospitaletDanish Dementia Research Centre, Department of Neurology, Copenhagen University Hospital - RigshospitaletDanish Dementia Research Centre, Department of Neurology, Copenhagen University Hospital - RigshospitaletDepartment of Psychiatry and Neurochemistry, Institute of Neuroscience and Physiology, Lab Hus V3, The Sahlgrenska Academy at the University of GothenburgDepartment of Psychiatry and Neurochemistry, Institute of Neuroscience and Physiology, Lab Hus V3, The Sahlgrenska Academy at the University of GothenburgDepartment of Psychiatry and Neurochemistry, Institute of Neuroscience and Physiology, Lab Hus V3, The Sahlgrenska Academy at the University of GothenburgDepartment of Psychiatry and Neurochemistry, Institute of Neuroscience and Physiology, Lab Hus V3, The Sahlgrenska Academy at the University of GothenburgDanish Dementia Research Centre, Department of Neurology, Copenhagen University Hospital - RigshospitaletDanish Dementia Research Centre, Department of Neurology, Copenhagen University Hospital - RigshospitaletDanish Dementia Research Centre, Department of Neurology, Copenhagen University Hospital - RigshospitaletAbstract Background For clinical implementation of Alzheimer’s disease (AD) blood-based biomarkers (BBMs), knowledge of short-term variability, is crucial to ensure safe and correct biomarker interpretation, i.e., to capture changes or treatment effects that lie beyond that of expected short-term variability and considered clinically relevant. In this study we investigated short-term intra- and inter-individual variability of AD biomarkers in the intended use population, memory clinic patients. Methods In a consecutive sample of memory clinic patients (AD n = 27, non-AD n = 20), blood samples were collected on three separate days within a period of 36 days and analysed for plasma Aβ40, Aβ42, p-tau181, p-tau217, p-tau231, T-tau, neurofilament light (NfL), and glial fibrillary acidic protein (GFAP). We measured intra- and inter-individual variability and explored if the variability could be affected by confounding factors. Secondly, we established the minimum change required to detect a difference between two given blood samples that exceeds intra-individual variability and analytical variation (reference change value, RCV). Finally, we tested if classification accuracy varied across the three visits. Results Intra-individual variability ranged from ~ 3% (Aβ42/40) to ~ 12% (T-tau). Inter-individual variability ranged from ~ 7% (Aβ40) to ~ 39% (NfL). Adjusting the models for time, eGFR, Hba1c, and BMI did not affect the variation. RCV was lowest for Aβ42/Aβ40 (- ~ 15%/ + ~ 17%) and highest in p-tau181 (- ~ 30/ + ~ 42%). No variation in classification accuracies was found across visits. Conclusion We found low intra-individual variability, robust to various factors, appropriate to capture individual changes in AD BBMs, while moderate inter-individual variability may give rise to caution in diagnostic contexts. High RCVs may pose challenges for AD BBMs with low fold changes and consequently, short-term variability is important to take into consideration when, e.g., estimating intervention effect and longitudinal changes of AD BBM levels. Trial registration Clinicaltrials.gov (NCT05175664), date of registration 2021–12-01.https://doi.org/10.1186/s13195-024-01658-7Alzheimer’s disease biomarkersBlood-based biomarkersMemory clinic cohortShort-term variabilityIntra- and Inter-individual variability, Reference change value (RCV), Plasma Aβ42/Aβ40 ratio, Phosphorylated tau (p-tau), Neurofilament light (NfL), Glial fibrillary acidic protein (GFAP) |
| spellingShingle | Frederikke Kragh Clemmensen Mathias Holsey Gramkow Anja Hviid Simonsen Nicholas J. Ashton Hanna Huber Kaj Blennow Henrik Zetterberg Gunhild Waldemar Steen Gregers Hasselbalch Kristian Steen Frederiksen Short-term variability of Alzheimer’s disease plasma biomarkers in a mixed memory clinic cohort Alzheimer’s Research & Therapy Alzheimer’s disease biomarkers Blood-based biomarkers Memory clinic cohort Short-term variability Intra- and Inter-individual variability, Reference change value (RCV), Plasma Aβ42/Aβ40 ratio, Phosphorylated tau (p-tau), Neurofilament light (NfL), Glial fibrillary acidic protein (GFAP) |
| title | Short-term variability of Alzheimer’s disease plasma biomarkers in a mixed memory clinic cohort |
| title_full | Short-term variability of Alzheimer’s disease plasma biomarkers in a mixed memory clinic cohort |
| title_fullStr | Short-term variability of Alzheimer’s disease plasma biomarkers in a mixed memory clinic cohort |
| title_full_unstemmed | Short-term variability of Alzheimer’s disease plasma biomarkers in a mixed memory clinic cohort |
| title_short | Short-term variability of Alzheimer’s disease plasma biomarkers in a mixed memory clinic cohort |
| title_sort | short term variability of alzheimer s disease plasma biomarkers in a mixed memory clinic cohort |
| topic | Alzheimer’s disease biomarkers Blood-based biomarkers Memory clinic cohort Short-term variability Intra- and Inter-individual variability, Reference change value (RCV), Plasma Aβ42/Aβ40 ratio, Phosphorylated tau (p-tau), Neurofilament light (NfL), Glial fibrillary acidic protein (GFAP) |
| url | https://doi.org/10.1186/s13195-024-01658-7 |
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