Transthyretin Decrease in Plasma of MCI and AD Patients: Investigation of Mechanisms for Disease Modulation

Abstract

Different authors described that transthyretin (TTR) is decreased in the cerebrospinal fluid (CSF) of Alzheimer's disease (AD) patients and thus TTR is a potential CSF biomarker in AD. However, descriptions of what happens to TTR in plasma of these patients are lacking in the literature. We investigated TTR levels in plasma samples from 55 patients with mild-cognitive impairment (MCI), 56 patients with AD and 41 non-demented controls, and found that TTR is decreased in both MCI and AD groups, suggesting that TTR might be used for staging early AD. In MCI and AD groups, women showed significantly lower plasma TTR levels when compared to MCI and AD men, respectively, and to women control group. In the AD women group, TTR levels correlated with disease stage, reflecting disease severity. Although MCI and AD men groups presented TTR levels lower than men in the control group, the difference was not statistically significant. Genetic analysis for ApoE revealed no relationship between TTR levels and the presence of the ε4 allele, for both men and women, in both patient groups. Importantly, we assessed thyroxine binding to TTR in plasma and found, in both MCI and AD groups, that TTR had reduced capacity to carry the hormone. Finally, we measured plasma estradiol levels in women and showed a reduction in both groups. Thus, this study prompts TTR as an early plasma biomarker in AD indicating that disease modulation by TTR is gender dependent; this study provides hypotheses into the mechanisms involved.

Transthyretin: a multifaceted protein

“…Recently, with the use of powerful tools, a 2-fold decrease in TTR levels in CSF of AD patients was demonstrated (92,104). As observed in CSF, TTR plasma levels are decreased in AD patients and mild-cognitive impairment (MCI) when compared with non-demented controls, suggesting TTR as an early AD biomarker (105,106).…”

Blood–brain-barriers in aging and in Alzheimer’s disease

“…Studies in humans found decreased TTR levels in the CSF of AD patients [64], which may result from the decreased CP secretory activity described to occur with aging [26]. Furthermore, TTR is also decreased in the blood of individuals with mild cognitive impairment and with AD [65]. These observations suggested that mutated forms of TTR, with decreased affinity to Aβ, could be associated with AD; however, no mutations in TTR were found associated with the disease [66].…”

Transthyretin stability is critical in assisting beta amyloid clearance– Relevance of transthyretin stabilization in Alzheimer's disease

“…In fact, it has also been shown that plasma TTR from patients with AD presents impaired ability to carry T4 hormone. As T4 binding to TTR implies tetrameric conformation, this indicates TTR instability and supports the idea that the TTR tetramer is the main Aβ‐binding species . Furthermore, studies using TTR mutants showed that the lower the stability of TTR variant (and the higher its amyloidogenic potential), the weaker its affinity toward Aβ42; thus, the highly unstable TTR with a leucine substituted by a proline at position 55 (L55P TTR) was shown to bind weakly to Aβ …”