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Linda Karlsson1, Shorena Janelidze1, Nicolas R Barthélemy2

  • 1Clinical Memory Research Unit, Department of Clinical Sciences, Lund University, Lund, Sweden.

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Summary
This summary is machine-generated.

Normalizing Alzheimer's disease (AD) fluid biomarkers with reference proteins like Aβ40 or non-phosphorylated tau (np-tau) significantly improves their association with brain amyloid and tau pathology. This enhances the precision of both cerebrospinal fluid (CSF) and plasma AD biomarkers.

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Area of Science:

  • Biomarker discovery and validation
  • Neurodegenerative disease diagnostics
  • Alzheimer's disease (AD) research

Background:

  • Fluid biomarkers are cost-effective for Alzheimer's disease (AD) detection, but inter-individual variation can affect accuracy.
  • Previous work identified reference proteins improving concordance between CSF Aβ42/PET and CSF p-tau181/PET.
  • The impact of reference proteins on CSF AD biomarker associations with brain pathology and plasma biomarker improvement remains unclear.

Purpose of the Study:

  • To investigate the effect of reference proteins on the relationship between cerebrospinal fluid (CSF) AD biomarkers and brain tau/amyloid-β (Aβ) PET load.
  • To determine if plasma AD biomarkers can be improved by incorporating reference proteins.
  • To assess the impact of normalization using CSF Aβ40 or non-phosphorylated tau (np-tau) on biomarker-pathology associations.

Main Methods:

  • Utilized the Swedish BioFINDER-2 cohort (n=1702) for analysis.
  • Compared associations between tau/Aβ-PET load and CSF biomarkers (e.g., MTBR-tau243, p-tau isoforms, SNAP-25) alone versus normalized to reference proteins (Aβ40, np-tau) using univariate linear regression.
  • Extended the analysis to plasma biomarkers and validated findings in Knight ADRC and TRIAD cohorts.

Main Results:

  • CSF Aβ40 normalization significantly strengthened associations between CSF biomarkers (MTBR-tau243, p-tau isoforms, synaptic biomarkers) and tau/Aβ-PET.
  • Normalization to CSF np-tau primarily improved concordance between CSF biomarkers and Aβ-PET.
  • Plasma biomarker associations with tau/Aβ-PET were enhanced by normalization with plasma Aβ40 or np-tau, with findings replicated across cohorts.

Conclusions:

  • Normalization to reference proteins (Aβ40 or np-tau) enhances associations between CSF and plasma AD biomarkers with brain tau and Aβ pathology.
  • This normalization strategy increases the precision of established AD and synaptic fluid biomarkers.
  • Reference protein normalization improves the accuracy and interpretability of fluid biomarkers for Alzheimer's disease.