A score or so different types of amyloid can form in the human body, each a protein that can become altered or misfolded in a way that encourages other molecules of the same protein to also alter or misfold. These broken proteins aggregate together into sheets and fibrils, forming solid deposits in and around cells that interfere with the normal function of tissues, or are actively toxic. Transthyretin is one such protein, and transthyretin amyloidosis is present to some degree in all older people. Evidence of recent years suggests that it is a factor in 10% of heart failure cases in old people in general, and it may be the dominant cause of cardiac mortality in supercentenarians, those aged 110 or older.
The open access paper noted here is an interesting overview of the mechanisms by which amyloidosis occurs in the case of transthyretin, in the context of trying to predict who is most at risk and should therefore be treated. Eidos Therapeutics has a treatment in the late stage of development that interfers enough with the mechanisms of transthyretin aggregation to be worth the effort, though as for most such lines of development it will initially be targeted at cases in which transthyretin is mutated in ways that accelerate amyloidosis, rather than as a preventative therapy for the entire population. More aggressive degradation of amyloid will likely be needed, such as via the use of catabodies, a line of work at an earlier stage of development at Covalent Bioscience, but nonetheless promising.
The rate of synthesis of transthyretin (TTR) is constant. For proteostasis, the rate of removal of TTR must equal the rate of synthesis. TTR in plasma is largely in the tetrameric form, (TTR)4, but dissociates to give very low, but significant concentrations of dimers and monomers. Removal of TTR from plasma proceeds via monomers.
Monomers undergo two processes that remove them from solution, proteolysis or aggregation. The combined rates of these two pathways equals the total rate of monomer removal, which is also equal to the rate of production of monomer via dissociation of tetramer. Depending on the relative rates, either of the two reaction pathways could account for anywhere from 100% to 0% of the rate of monomer removal. The critical monomer concentration for aggregation is unknown, however the cause of aggregation develops slowly over time. Once amyloidosis begins, the rate of development of amyloidosis is determined by the rate of monomer incorporation into various aggregates that lead to fibrils and amyloids.
Destabilizing tetramer by pleiotropic mutations leads to greater dissociation of monomer and a higher, variant-dependent concentration of TTR monomer in plasma. Mutations are not required for TTR amyloidosis formation; point mutations only modify the equilibrium concentrations. Amyloidosis caused by wild-type TTR follows the same mechanism as amyloidosis caused by variants of TTR and thus should be considered as variants of the same disease for purposes of clinical studies.
Amyloidosis begins when the rate of TTR proteolysis decreases relative to the rate of amyloid formation and monomer concentration increases sufficiently to allow significant oligomerization into fibrils and amyloids. The cause of a decrease in the rate of proteolysis of TTR remains to be identified. When the tetramer is stabilized by drugs or stabilizing mutations, the concentration of tetramer will increase in plasma to a steady-state level determined by the rate of proteolysis.
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