An essential and highly conserved tetrameric protein

// What is TTR?

Transthyretin (TTR), also known as prealbumin, is a plasma protein mainly produced in the liver that circulates as a tetramer in the blood. It is evolutionarily conserved among multiple species and plays a crucial role in processes vital to human health and bodily functions.

• TTR is the key transport protein for thyroxine and vitamin A and has additional roles in memory, neuroprotection and cognitive function
• Recent research has highlighted the potential neuroprotective functions of TTR in the setting of Alzheimer’s disease
• The substantial metabolic effort needed to sustain transthyretin's relatively high plasma concentration, given its 2-day half-life, implies that serum TTR may possess significant, yet not fully understood, functions

// Why TTR matters

TTR destabilisation is the root cause of ATTR-CM

Factors such as ageing or mutations in the TTR gene can initiate structural changes that destabilise the configuration of TTR protein tetramers. This destabilisation may cause:

• TTR protein tetramers to dissociate into monomers
• Monomers to misfold and aggregate into amyloid fibrils
   

The deposition of these amyloid fibrils in tissues, particularly in the myocardium, leads to the clinical manifestations of transthyretin cardiac amyloidosis (ATTR-CM).

This process of amyloidogenesis is primarily governed by the rate of TTR tetramer dissociation.

^{Adapted from Hood CJ, et al. 2022, Taylor AIP, et al. 2022.}

Stabilising TTR is crucial to slow disease progression
 

Several points support the rationale for using serum TTR as an in vivo biomarker of TTR stability:

• Serum TTR has a half-life of approximately 2 days in healthy adults, with hepatic secretion influenced by nutritional status but unaffected by intrinsic stability
• Destabilising variants of TTR drive below normal serum TTR concentrations in patients with variant ATTR amyloidosis reflecting lower tetrameric stability. Similarly, patients with wild-type ATTR amyloidosis often exhibit low-normal to below-normal levels
• Serum TTR is an independent predictor of survival in patients with ATTRwt-CM
• Treatment with TTR stabilisers enhances TTR tetramer stability, leading to increased serum TTR levels in patients with ATTR-CM
• Heterozygous carriers of the TTR variant T119M, which confers increased tetramer stability, exhibit approximately 20% higher serum TTR levels than the general population

Higher serum TTR levels are associated with favourable clinical outcomes:

• In the general population, data from two prospective cohort studies showed that higher plasma TTR levels are linked to a decreased risk of incident heart failure, highlighting the potential of serum TTR as a marker of tetramer stability

^{Adapted from Greve AM, et al. 2021.}

• Similarly, in patients with biopsy-proven ATTR-CM, higher baseline serum TTR levels (≥18 mg/dL) were associated with significantly longer survival compared to levels below the normal limit (4.1 years vs 2.8 years; p=0.03)

^{Patients untreated for the duration of the follow-up (n=101) were stratified by baseline TTR threshold value of 18 mg/dL. Adapted from Hanson JLS, et al. 2018.}

Increased life expectancy and a reduced risk of vascular disease was also found in a large observational study in carriers of a TTR stabilising variant (T119M) when compared to noncarriers. The TTR gene has over 200 known variants, most of which destabilise the TTR protein tetramer, promoting amyloid formation. The T119M variant is a key exception, which enhances the stability of the tetramer by 37-fold compared to wild-type TTR. According to the study, T119M carriers compared to noncarriers:

• Had a ~20% increase in plasma TTR levels
• Experienced a 15% reduced risk of cardiovascular disease
• Showed a median increase in life expectancy of 7 years for death from vascular disease
   

Moreover, serum TTR levels are now emerging as a robust prognostic marker:

• Declining TTR levels are linked to worsening cardiac function, suggesting their utility for monitoring disease progression
• When combined with markers of cardiac function, serum TTR levels offer a sensitive tool for assessing disease progression, evaluating treatment response and refining risk assessment strategies