From Analyte to Diagnosis: Fluid Biomarkers for Alzheimer's Disease. Reliability, Clinical Implementation, and Diagnostic Complexity
(2026) In Lund University, Faculty of Medicine Doctoral Dissertation Series- Abstract
- Alzheimer's disease (AD), the leading cause of dementia, is characterized by the accumulation of amyloid-β (Aβ) plaques and tau neurofibrillary tangles. Fluid biomarkers can accurately detect these.
Plasma biomarkers are of particular interest, given that they are minimally invasive and low-cost, with potential for large-scale implementation, particularly in settings where cerebrospinal fluid (CSF) and imaging are not accessible, such as primary and secondary care. Accordingly, plasma biomarkers increasingly support diagnosis in these settings, but current strategies trade off diagnostic accuracy against classifying all patients, leaving a proportion of intermediate results. Beyond AD pathology alone, co-occurring vascular and... (More) - Alzheimer's disease (AD), the leading cause of dementia, is characterized by the accumulation of amyloid-β (Aβ) plaques and tau neurofibrillary tangles. Fluid biomarkers can accurately detect these.
Plasma biomarkers are of particular interest, given that they are minimally invasive and low-cost, with potential for large-scale implementation, particularly in settings where cerebrospinal fluid (CSF) and imaging are not accessible, such as primary and secondary care. Accordingly, plasma biomarkers increasingly support diagnosis in these settings, but current strategies trade off diagnostic accuracy against classifying all patients, leaving a proportion of intermediate results. Beyond AD pathology alone, co-occurring vascular and α-synuclein pathologies contribute to the clinical presentation, and tools capable of capturing this complexity at scale remain limited.
Motivated by these challenges, this thesis aims to enhance the diagnosis of AD by addressing key factors that impact fluid biomarker performance and clinical utility. It does so by combining pre-analytical characterization, applied diagnostic workflows, and CSF and plasma biomarker profiling across three papers using the Swedish BioFINDER cohorts.
In Paper I, time-of-day at collection of CSF and plasma samples was assessed across established and emerging biomarkers. Sample timing generally had a small effect on biomarker levels, though this effect was more pronounced for a subset of biomarkers, supporting the need for standardized collection procedures as panels expand to less-characterized proteins.
In Paper II, repeated plasma testing was evaluated as a strategy to resolve intermediate plasma phosphorylated-tau (p-tau) 217 results in cognitively impaired participants. Retesting, particularly with a mass-spectrometry (MS)-based assay, improved classification of Aβ pathology and reduced the proportion of intermediate results, with performance similar to CSF confirmation. This indicates that selective plasma retesting may offer a scalable approach to improving classification where confirmatory testing is unavailable.
In Paper III, CSF and plasma were profiled using a large-scale biomarker panel to identify biomarker signatures associated with co-occurring pathology. Distinct CSF signatures were associated with vascular and α-synuclein pathology alongside AD, while the plasma signature remained largely AD-specific, representing an initial step toward multi-pathology biomarker panels.
Together, this work addressed key limitations in fluid biomarker-based AD diagnosis related to measurement variability, real-world diagnostic classification, and biomarker interpretation in the context of co-occurring pathology. In doing so, it advances AD diagnosis by expanding the biological scope of fluid biomarkers and supporting more accurate, accessible, and context-appropriate diagnostic practice. (Less)
Please use this url to cite or link to this publication:
https://lup.lub.lu.se/record/ff6a9d10-0761-4b2d-8ab7-98dbc37a87c3
- author
- Orduña Dolado, Anna LU
- supervisor
- opponent
-
- Associate Professor Andreasson, Ulf, Göteborg Universitet
- organization
- publishing date
- 2026
- type
- Thesis
- publication status
- published
- subject
- keywords
- Alzheimer’s diseaseAlzheimer’s disease, Diagnosis, Fluid biomarkers, amyloid-beta, Tau, co-pathology
- in
- Lund University, Faculty of Medicine Doctoral Dissertation Series
- issue
- 2026:138
- pages
- 117 pages
- publisher
- Lund University, Faculty of Medicine
- defense location
- Belfragesalen, BMC D15, Klinikgatan 32 i Lund. Join by Zoom: https://lu-se.zoom.us/j/66438925803?pwd=9qsmI7bUWiVxbbrtGTiBZ405ty7WX8.1
- defense date
- 2026-10-30 09:00:00
- ISSN
- 1652-8220
- ISBN
- 978-91-8021-937-2
- language
- English
- LU publication?
- yes
- id
- ff6a9d10-0761-4b2d-8ab7-98dbc37a87c3
- date added to LUP
- 2026-10-08 11:13:12
- date last changed
- 2026-10-08 13:05:15
@phdthesis{ff6a9d10-0761-4b2d-8ab7-98dbc37a87c3,
abstract = {{Alzheimer's disease (AD), the leading cause of dementia, is characterized by the accumulation of amyloid-β (Aβ) plaques and tau neurofibrillary tangles. Fluid biomarkers can accurately detect these.<br/>Plasma biomarkers are of particular interest, given that they are minimally invasive and low-cost, with potential for large-scale implementation, particularly in settings where cerebrospinal fluid (CSF) and imaging are not accessible, such as primary and secondary care. Accordingly, plasma biomarkers increasingly support diagnosis in these settings, but current strategies trade off diagnostic accuracy against classifying all patients, leaving a proportion of intermediate results. Beyond AD pathology alone, co-occurring vascular and α-synuclein pathologies contribute to the clinical presentation, and tools capable of capturing this complexity at scale remain limited.<br/>Motivated by these challenges, this thesis aims to enhance the diagnosis of AD by addressing key factors that impact fluid biomarker performance and clinical utility. It does so by combining pre-analytical characterization, applied diagnostic workflows, and CSF and plasma biomarker profiling across three papers using the Swedish BioFINDER cohorts.<br/>In Paper I, time-of-day at collection of CSF and plasma samples was assessed across established and emerging biomarkers. Sample timing generally had a small effect on biomarker levels, though this effect was more pronounced for a subset of biomarkers, supporting the need for standardized collection procedures as panels expand to less-characterized proteins.<br/>In Paper II, repeated plasma testing was evaluated as a strategy to resolve intermediate plasma phosphorylated-tau (p-tau) 217 results in cognitively impaired participants. Retesting, particularly with a mass-spectrometry (MS)-based assay, improved classification of Aβ pathology and reduced the proportion of intermediate results, with performance similar to CSF confirmation. This indicates that selective plasma retesting may offer a scalable approach to improving classification where confirmatory testing is unavailable.<br/>In Paper III, CSF and plasma were profiled using a large-scale biomarker panel to identify biomarker signatures associated with co-occurring pathology. Distinct CSF signatures were associated with vascular and α-synuclein pathology alongside AD, while the plasma signature remained largely AD-specific, representing an initial step toward multi-pathology biomarker panels.<br/>Together, this work addressed key limitations in fluid biomarker-based AD diagnosis related to measurement variability, real-world diagnostic classification, and biomarker interpretation in the context of co-occurring pathology. In doing so, it advances AD diagnosis by expanding the biological scope of fluid biomarkers and supporting more accurate, accessible, and context-appropriate diagnostic practice.}},
author = {{Orduña Dolado, Anna}},
isbn = {{978-91-8021-937-2}},
issn = {{1652-8220}},
keywords = {{Alzheimer’s diseaseAlzheimer’s disease; Diagnosis; Fluid biomarkers; amyloid-beta; Tau; co-pathology}},
language = {{eng}},
number = {{2026:138}},
publisher = {{Lund University, Faculty of Medicine}},
school = {{Lund University}},
series = {{Lund University, Faculty of Medicine Doctoral Dissertation Series}},
title = {{From Analyte to Diagnosis: Fluid Biomarkers for Alzheimer's Disease. Reliability, Clinical Implementation, and Diagnostic Complexity}},
url = {{https://lup.lub.lu.se/search/files/262740817/E-nailing_OrdunaDolado.pdf}},
year = {{2026}},
}