Levels and instability of transthyretin and correlations with core biomarkers in Alzheimer’s disease

Abstract Transthyretin (TTR) has gained attention due to its implication in Alzheimer’s Disease (AD) by modulating amyloid-beta (Aβ) pathology. This study aimed to establish associations between TTR and key AD biomarkers, to enhance our understanding of the role of TTR in AD pathogenesis. We evaluated TTR levels and tetrameric instability in plasma and CSF in mild cognitive impairment (MCI-AD) and Dementia-AD patients examining associations with clinical, biochemical and genetic data. Plasma TTR levels were lower in Dementia-AD, especially in women. In the MCI-AD group, CSF TTR levels inversely correlated with markers of amyloid pathology and neurodegeneration such as Aβ40, p-Tau181, t-Tau and NfL. CSF TTR instability was negatively associated with CSF Aβ42, indicating an association with increased amyloid burden. In the whole cohort, plasma TTR instability correlated with CSF TTR instability. In line with the strong association between CSF TTR instability and Aβ42, we showed increased TTR instability in samples incubated with Aβ42. No significant associations were observed in the Dementia-AD group. This study emphasizes that TTR is associated with Aβ clearance and neurodegeneration. We propose Aβ42 and its increase in the brain as a factor destabilizing the TTR tetrameric fold, impairing TTR function.