Two biotech CEOs are cautiously optimistic about the controversial amyloid hypothesis, which suggests a sticky brain plaque causes Alzheimer’s — a departure from most of the rest of the industry, which has largely abandoned the theory, once dogma, after a long string of clinical trial failures.
But Susan Catalano, the co-founder and CSO of Cognition Therapeutics, said her company is still indirectly targeting it for drug development, in part because she thinks other researchers didn’t appreciate the different forms the plaque-forming substance can take.
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An error in my previous posting was in saying the amyloid processing enzymes turn amyloid precursor protein into amyloid oligomers. Actually, they cut the APP into chains of various lengths, two of which are believed to be particularly toxic and are known as amyloid beta. Amyloid beta then seems to form oligomers (small clusters) spontaneously, being as sticky as it is. I have not found any discussion of free amyloid beta (i.e. monomers) in my reading on the subject, and they might not exist at a significant level.
There you go again with the mischaracterization of plaques as the current view of the Amyloid Hypothesis. That was the original view back in the 1990’s. Plaques are late stage in the disease, do not correlate well with degree of impairment, and many cognitively normal seniors die with plaque accumulation comparable to that seen in Alzheimer’s — these were always problems with the original form of the hypothesis. The current view is that late-onset Alzheimer’s Disease is the result of toxic effects of accumulation of amyloid oligomers, which occurs early in the disease. Because amyloid production is not increased in LOAD, and the amyloid level in CSF is actually lower in LOAD patients than in normals, it appears to be caused by impaired amyloid clearance. Another variant of the current view is that amyloid is a protective reaction against some agent, possibly a toxin or an infection. Amyloid oligomers are sticky indeed, and this could be a way to sequester such agents. Amyloid accumulation begins early in the disease, and it can be imaged using a PET scan with florbetapir. The hope is that early treatment before symptoms occur or at least the stage of mild cognitive impairment can allow an effective treatment before the damage is too severe. Treatment at later stages might only arrest or slow down progression of the disease. Florbetapir may allow identification of patients that can be rescued before their quality of life is too badly degraded and allowing them to live independently at home without the high cost of moving to an assisted living facility.
What that treatment that will be will remain a question for some time to come. Many of the failed attempts at treatment have been to attack the enzymes which process amyloid precursor protein into amyloid oligomers. This was not a misguided approach. About 10% of all Alzheimer’s cases are early-onset AD, and about half of that is the genetic (familial) form. The genetic defects which cause EOAD affect either the APP itself or the APP-processing enzymes. In these cases, overproduction of the amyloid oligomers does appear to be part of the causal mechanism of familial AD. However, familial and non-familial forms of AD really should be considered two separate diseases with different causes but similar symptoms. Research seems to have been led astray by assuming these two forms shared a causal mechanism. It may be that non-familial AD, which is about 95% of all AD, presents a completely different set of targets which will require drugs or other treatments that have yet to be developed — or which have been developed for other purposes but yet to have been tested against AD, such as antibiotics and antiviral drugs.