Transthyretin (TTR) is secreted by hepatocytes, retinal pigment epithelial
cells, pancreatic and cells, choroid plexus epithelium, and
neurons under stress. The choroid plexus product is the main transporter of the
thyroid hormone thyroxine (T4) to the brain during early development. TTR is one
of three relatively abundant cerebrospinal fluid (CSF) proteins (Apolipoprotein J
[ApoJ] (also known as clusterin), Apolipoprotein E [ApoE], and TTR) that interact
with A peptides in vitro, in some instances inhibiting their
aggregation and toxicity. It is now clear that clusterin functions as an
extracellular, and perhaps intracellular, chaperone for many misfolded proteins
and that variation in its gene (Clu) is associated with susceptibility
to sporadic Alzheimer’s disease (AD). The function of ApoE in AD is not yet
completely understood, although the ApoE4 allele has the strongest
genetic association with the development of sporadic late onset AD. Despite
in vitro and in vivo evidence of the interaction between TTR
and A, genomewide association studies including large numbers of
sporadic Alzheimer’s disease patients have failed to show significant association
between variation in the TTR gene and disease prevalence. Early clinical
studies suggested an inverse relationship between CSF TTR levels and AD and the
possibility of using the reduced CSF TTR concentration as a biomarker. Later,
more extensive analyses indicated that CSF TTR concentrations may be increased in
some patients with AD. While the observed changes in TTR may be pathogenetically
or biologically interesting because of the inconsistency and lack of specificity,
they offered no benefit diagnostically or prognostically either independently or
when added to currently employed CSF biomarkers, i.e., decreased
A and increased Tau and phospho-Tau. While some clinical data
suggest that increases in CSF TTR may occur early in the disease with a
significant decrease late in the course, without additional, more granular data,
CSF TTR changes are neither consistent nor specific enough to warrant their use
as a specific AD biomarker.