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Reference proteins to improve Core 1 and Core 2 Alzheimer’s disease CSF and plasma biomarkers

Karlsson, Linda LU orcid ; Janelidze, Shorena LU ; Barthélemy, Nicolas R. ; Horie, Kanta ; Therriault, Joseph ; Gaetani, Lorenzo ; Bellomo, Giovanni ; Schindler, Suzanne E. ; Vogel, Jacob LU and Arvidsson, Ida LU orcid , et al. (2026) In Brain 149(4). p.1153-1167
Abstract

Concentration-based fluid biomarkers represent an informative and cost-effective way to detect and monitor Alzheimer’s disease (AD) pathology. However, non-AD-related interindividual variation in biofluids can also affect biomarker concentrations. Here, we investigated whether normalization of CSF and plasma biomarkers to reference proteins, such as amyloid-β40 (Aβ40) and non-phosphorylated mid-region tau (np-tau), improves their robustness and reliability of representing AD pathology load. Using the Swedish BioFINDER-2 cohort [n = 1702, 50.7% male, mean (standard deviation) age 68.4 (12.2) years], we compared the associations between tau/Aβ-PET load and fluid biomarkers alone versus biomarkers in a ratio with a reference protein (Aβ40... (More)

Concentration-based fluid biomarkers represent an informative and cost-effective way to detect and monitor Alzheimer’s disease (AD) pathology. However, non-AD-related interindividual variation in biofluids can also affect biomarker concentrations. Here, we investigated whether normalization of CSF and plasma biomarkers to reference proteins, such as amyloid-β40 (Aβ40) and non-phosphorylated mid-region tau (np-tau), improves their robustness and reliability of representing AD pathology load. Using the Swedish BioFINDER-2 cohort [n = 1702, 50.7% male, mean (standard deviation) age 68.4 (12.2) years], we compared the associations between tau/Aβ-PET load and fluid biomarkers alone versus biomarkers in a ratio with a reference protein (Aβ40 or np-tau) in univariate linear regression models. Fluid biomarkers included CSF and plasma measures of p-tau217, p-tau181, p-tau205, np-tau181-190, np-tau195–210, np-tau212–221, Aβ42 and Aβ40; CSF MTBR-tau243, SNAP-25, neurogranin, YKL-40 and sTREM2; and plasma eMTBR-tau243. Biomarkers were measured with mass spectrometry assays and/or immunoassays. In addition, we performed validation and extended analyses, comparing, for example, group-level diagnostic differences and longitudinal biomarker trajectories, in three independent prospective cohorts [BioFINDER-1, Knight Alzheimer Disease Research Center (ADRC) and Translational Biomarkers in Aging and Dementia (TRIAD)] and in an Italian multiple sclerosis cohort. CSF Aβ40 normalization significantly strengthened the associations of several core CSF AD biomarkers, including CSF MTBR-tau243, p-tau isoforms and synaptic biomarkers, with tau-PET (ΔR2 = 0.064–0.24) and Aβ-PET (ΔR2 = 0.016–0.28). Normalization to CSF np-tau mainly improved concordance with Aβ-PET (ΔR2 = −0.0059 to 0.19). The strongest association with tau-PET was observed for MTBR-tau243/Aβ40 (R2 = 0.78, compared with 0.65 for non-normalized MTBR-tau243), and with Aβ-PET for p-tau217/np-tau (R2 = 0.65, compared with 0.46 for non-normalized p-tau217). Plasma biomarker associations with tau-PET improved when using normalization to plasma Aβ40 or np-tau (ΔR2 = 0.004–0.14), with the strongest effect for eMTBR-tau243/np-tau (R2 = 0.72 versus 0.60). Associations with Aβ-PET were enhanced with np-tau normalization (ΔR2 = 0.018–0.16, strongest for p-tau217/np-tau: R2 = 0.62 versus 0.53). The results were replicated in Knight ADRC and TRIAD. Furthermore, longitudinal analyses showed that Aβ40 normalization typically reduced interindividual rather than intra-individual variability over time. Normalization did not enhance group-level differences in inflammatory CSF biomarkers in AD, nor did it improve biomarker associations in the multiple sclerosis cohort. In conclusion, normalization of CSF and plasma biomarkers to reference proteins, such as Aβ40 or np-tau, enhances their association with brain tau and Aβ pathology, making already high-performing AD fluid biomarkers even more accurate.

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organization
publishing date
type
Contribution to journal
publication status
published
subject
keywords
Alzheimer’s disease, Aβ40, CSF biomarkers, normalization, PET, plasma biomarkers
in
Brain
volume
149
issue
4
pages
15 pages
publisher
Oxford University Press
external identifiers
  • scopus:105035239495
  • pmid:41051312
ISSN
0006-8950
DOI
10.1093/brain/awaf375
language
English
LU publication?
yes
id
33816df4-3db6-493c-9bbc-46dbcf87b985
date added to LUP
2026-06-12 09:07:42
date last changed
2026-09-05 21:40:41
@article{33816df4-3db6-493c-9bbc-46dbcf87b985,
  abstract     = {{<p>Concentration-based fluid biomarkers represent an informative and cost-effective way to detect and monitor Alzheimer’s disease (AD) pathology. However, non-AD-related interindividual variation in biofluids can also affect biomarker concentrations. Here, we investigated whether normalization of CSF and plasma biomarkers to reference proteins, such as amyloid-β40 (Aβ40) and non-phosphorylated mid-region tau (np-tau), improves their robustness and reliability of representing AD pathology load. Using the Swedish BioFINDER-2 cohort [n = 1702, 50.7% male, mean (standard deviation) age 68.4 (12.2) years], we compared the associations between tau/Aβ-PET load and fluid biomarkers alone versus biomarkers in a ratio with a reference protein (Aβ40 or np-tau) in univariate linear regression models. Fluid biomarkers included CSF and plasma measures of p-tau217, p-tau181, p-tau205, np-tau181-190, np-tau195–210, np-tau212–221, Aβ42 and Aβ40; CSF MTBR-tau243, SNAP-25, neurogranin, YKL-40 and sTREM2; and plasma eMTBR-tau243. Biomarkers were measured with mass spectrometry assays and/or immunoassays. In addition, we performed validation and extended analyses, comparing, for example, group-level diagnostic differences and longitudinal biomarker trajectories, in three independent prospective cohorts [BioFINDER-1, Knight Alzheimer Disease Research Center (ADRC) and Translational Biomarkers in Aging and Dementia (TRIAD)] and in an Italian multiple sclerosis cohort. CSF Aβ40 normalization significantly strengthened the associations of several core CSF AD biomarkers, including CSF MTBR-tau243, p-tau isoforms and synaptic biomarkers, with tau-PET (ΔR2 = 0.064–0.24) and Aβ-PET (ΔR2 = 0.016–0.28). Normalization to CSF np-tau mainly improved concordance with Aβ-PET (ΔR2 = −0.0059 to 0.19). The strongest association with tau-PET was observed for MTBR-tau243/Aβ40 (R2 = 0.78, compared with 0.65 for non-normalized MTBR-tau243), and with Aβ-PET for p-tau217/np-tau (R2 = 0.65, compared with 0.46 for non-normalized p-tau217). Plasma biomarker associations with tau-PET improved when using normalization to plasma Aβ40 or np-tau (ΔR2 = 0.004–0.14), with the strongest effect for eMTBR-tau243/np-tau (R2 = 0.72 versus 0.60). Associations with Aβ-PET were enhanced with np-tau normalization (ΔR2 = 0.018–0.16, strongest for p-tau217/np-tau: R2 = 0.62 versus 0.53). The results were replicated in Knight ADRC and TRIAD. Furthermore, longitudinal analyses showed that Aβ40 normalization typically reduced interindividual rather than intra-individual variability over time. Normalization did not enhance group-level differences in inflammatory CSF biomarkers in AD, nor did it improve biomarker associations in the multiple sclerosis cohort. In conclusion, normalization of CSF and plasma biomarkers to reference proteins, such as Aβ40 or np-tau, enhances their association with brain tau and Aβ pathology, making already high-performing AD fluid biomarkers even more accurate.</p>}},
  author       = {{Karlsson, Linda and Janelidze, Shorena and Barthélemy, Nicolas R. and Horie, Kanta and Therriault, Joseph and Gaetani, Lorenzo and Bellomo, Giovanni and Schindler, Suzanne E. and Vogel, Jacob and Arvidsson, Ida and Åström, Kalle and Gordon, Brian A. and Raji, Cyrus A. and Benzinger, Tammie L.S. and Morris, John C. and Nilsson, Johanna and Brinkmalm, Ann and Palmqvist, Sebastian and Stomrud, Erik and Salvadó, Gemma and Pichet Binette, Alexa and Di Filippo, Massimiliano and Parnetti, Lucilla and Rosa-Neto, Pedro and Blennow, Kaj and Bateman, Randall J. and Mattsson-Carlgren, Niklas and Hansson, Oskar}},
  issn         = {{0006-8950}},
  keywords     = {{Alzheimer’s disease; Aβ40; CSF biomarkers; normalization; PET; plasma biomarkers}},
  language     = {{eng}},
  number       = {{4}},
  pages        = {{1153--1167}},
  publisher    = {{Oxford University Press}},
  series       = {{Brain}},
  title        = {{Reference proteins to improve Core 1 and Core 2 Alzheimer’s disease CSF and plasma biomarkers}},
  url          = {{http://dx.doi.org/10.1093/brain/awaf375}},
  doi          = {{10.1093/brain/awaf375}},
  volume       = {{149}},
  year         = {{2026}},
}