Transthyretin Levels and Instability in Alzheimer’s Disease: Correlations with AD Biomarkers in a Cohort Study

In the last few decades, Transthyretin (TTR) has gained attention due to its implication in brain functions and neurodegenerative conditions, such as Alzheimer’s Disease (AD) by modulating amyloid-beta (Aβ) pathology. This study aims to assess TTR levels and tetrameric instability in both plasma and cerebrospinal fluid (CSF) across the clinical continuum of AD, and to establish associations between TTR and key AD biomarkers, to enhance our understanding of the role of TTR in AD pathogenesis.

Methods

We conducted an evaluation of TTR levels and tetrameric instability in plasma and CSF in mild cognitive impairment (MCI-AD, n=29) and Dementia-AD (n=37) patients and examined the association with clinical, biochemical and genetic data.

Results

Key findings revealed a substantial decrease in plasma TTR levels in the Dementia-AD patients compared to the MCI-AD group, with a pronounced gender-specific effect identified in women, while no differences were detected in the CSF. The search for associations identified several correlations amongst MCI-AD patients where CSF TTR levels inversely correlated with markers of amyloid pathology and neurodegeneration such as Aβ40 (r=-0.43, p < 0.02), p-Tau181 (r=-0.54, p < 0.03), t-Tau (r=-0.57, p< 0.001) and NfL (r=-0.49, p<0.006). CSF TTR instability also correlated negatively with CSF Aβ42 (r=-0.6, p<0.001) and Aβ42/Aβ40 ratio (r=-0.58, p<0.001), indicating an association with increased amyloid burden. In the Dementia-AD group, plasma TTR levels correlated negatively with GFAP (r=-0.4, p<0.014), reflecting potential links with neuroinflammation. Additionally, plasma TTR instability correlated with CSF TTR instability (r=0.42, p < 0.009) and tau pathology markers (p-Tau181 (r=0.38, p < 0.02) and t-Tau (r=0.42, p<0.09)). Given the strong association between CSF TTR instability and Aβ42, we investigated the effect of the peptide on TTR tetrameric instability and showed a clear increase in TTR instability in samples incubated with Aβ42 for 24 hours (p<0.05).

Conclusions

This study emphasizes several associations between TTR and other key indicators of AD and suggests TTR is associated with Aβ clearance, neurodegeneration, and neuroinflammation across different stages of the disease. We propose Aβ42 and its increase in the brain as a factor destabilizing the TTR tetrameric fold, resulting in TTR impaired function.