Transthyretin Amyloidosis is More Prevalent than Thought

Evidence suggests that transthyretin (TTR) amyloidosis, also known as senile systemic amyloidosis, is the condition that kills the oldest people, those who have survived every other aspect of aging to reach ages of 110 and greater. Here, I'll note a review paper in which the authors point out that TTR amyloidosis in aging is very likely much more prevalent than this: not a condition only seen in the oldest old, but rather also the cause of a small but sizable fraction of some varieties of heart failure across the entire elderly population. It has been misdiagnosed due to lack of adequate testing for the condition, and thus the development of treatments has not been prioritized highly enough.

Numerous types of amyloid appear in tissues with aging, each consisting of a specific misfolded protein that precipitates to form form clumps and fibrils. In the case of transthyretin amyloid, these deposits clog blood vessels and lead to hypertrophy of the heart, ending with something that looks a lot like congestive heart failure.

The obvious path to dealing with amyloids and their contribution to aging and age-related disease is to periodically remove them. This is the approach taken by much of the Alzheimer's research community, but in that case has proven unexpectedly challenging to date even though a large amount of funding is devoted to, for example, the development of immune therapies to achieve this goal. In the case of TTR amyloidosis there is very little work under way, but the SENS Research Foundation has funded a so far successful program into the use of catabodies to degrade transthyretin amyloid. As this paper notes, the need for therapies is there, even if under-appreciated by the medical community at present:

Transthyretin (TTR) amyloidosis is a disease caused by systemic deposition of wild-type (WT) or mutant TTR fibrils, resulting in heart failure when deposition occurs in the heart. Mutant TTR deposition leads to familial TTR amyloid. Accumulation of the normal TTR protein causes WT cardiac amyloidosis (also known as senile amyloidosis).

In recent years, heart failure with preserved ejection fraction (HFpEF) has become increasingly prevalent among individuals hospitalized for acute decompensated heart failure. A recent autopsy series provided pivotal evidence that TTR amyloidosis is more prevalent among HFpEF population. Of the 109 Caucasian patients seen at Mayo Clinic hospitals between 1986 and 2001 with subsequent autopsy, 5% were found to have moderate or severe WT TTR deposits in the left ventricle, consistent with WT systemic amyloidosis as the primary etiology of heart failure. In addition, mild interstitial and/or variable severity of intramural coronary vascular WT TTR deposition occurred in 12% of this cohort. None of these patients carried an antemortem diagnosis of cardiac amyloid.

How TTR amyloidosis contributes to the development of HFpEF is not known. We can only hypothesize that the accumulation of dense TTR amyloid likely worsens diastolic function. Slow accumulation of pathologic TTR amyloid deposits in the heart may initially cause asymptomatic left ventricular (LV) hypertrophy, with relatively late diagnosis because of its gradual progression. The diagnosis of TTR cardiac amyloidosis is often missed until very late in the disease course, as it is an indolent illness affecting the same elderly population with HFpEF. Unlike light chain (AL) amyloidosis, there is no readily available blood test for misfolded TTR protein. Diagnostic algorithms, including non-invasive imaging modalities and endomyocardial biopsy, have been published elsewhere. Yet these algorithms can only be applied if cardiac amyloid is suspected.



The following links may be of interest -
"What’s killing supercentenarians? Amyloidosis, suggest two gerontologists"
"Supercentenarians and transthyretin amyloidosis: The next frontier of human
life extension"

- And, a possible (formerly) low cost treatment -
"Doxycycline disrupts transthyretin amyloid: evidence from studies in a FAP transgenic mice model"
"Doxycycline plus tauroursodeoxycholic acid for transthyretin
amyloidosis: a phase II study"

- But, the cost of generic doxycycline suddenly skyrocketed --
"When a drug costs 30 times what it once did"

Posted by: Lou Pagnucco at July 28th, 2015 11:40 AM

Lou, as for your first link, Dr. de Grey will never get that data from Dr. Coles, as Dr. Coles is dead. (I asked.) Seems like SENS has picked up the ball here.

(Dr. Coles may or may not stay dead; he's in a cryonic state and might be gotten back up several decades from now.)

Posted by: Slicer at July 28th, 2015 12:32 PM

"Unlike light chain (AL) amyloidosis, there is no readily available blood test for misfolded TTR protein."

Mmm, it isn't this a blood test?

Posted by: Antonio at July 29th, 2015 6:37 AM

@Antonio: it's the beginnings of a blood test, if it proves itself in followon research. The lack of a good diagnostic assay, and the ensuing gross (and always-too-late) underdiagnosis of senile cardiac amyloidosis and other emerging disorders of wild-type TTR aggregates, is why SENS Research Foundation funded that research ;) . If it pans out, we would have a diagnostic assay that can readily determine the presence of TTR amyloidosis, without requiring the patient to undergo — and doctors to prescribe, and insurers to agree to fund — an invasive, expensive, and highly technical cardiac biopsy, followed by a workup for molecular identification of cardiac amyloid that few centers can even perform. Having such a diagnostic assay is an important enabling technology for the clinical use of catalytic antibodies targeting senile cardiac (TTR) amyloid, which we are also funding.

Posted by: Michael at July 29th, 2015 11:07 AM

Thanks, Michael. I hope it reach the market soon.

Posted by: Antonio at July 30th, 2015 2:30 AM
Comment Submission

Post a comment; thoughtful, considered opinions are valued. New comments can be edited for a few minutes following submission. Comments incorporating ad hominem attacks, advertising, and other forms of inappropriate behavior are likely to be deleted.

Note that there is a comment feed for those who like to keep up with conversations.