Proposing Alzheimer's to be Several Distinct Conditions
The research linked below isn't the first time scientists have proposed that what we currently call Alzheimer's disease is in fact a collection of different and distinct ways to end up with a similar end result. You might lump this in with other portions of the theorizing and exploration of alternatives that is taking place at least partially in reaction to the slow pace of progress towards working therapies based on the dominant amyloid hypothesis. The development of immunotherapies to clear amyloid is the current leading edge of that work, but trials have been disappointing to date. It may well be that this is simply because building a robust platform for immunotherapies targeting the brain is inherently challenging, rather than issues with amyloid as a target, but that hasn't stopped a great many competing hypotheses from emerging in the meanwhile.
Deciphering the mechanism that underlies the development of Alzheimer's disease in certain families but not in others, researchers have proposed that the malady is actually a collection of diseases that probably should be treated with a variety of different approaches. The late onset feature typical to distinct neurodegenerative diseases, and the common temporal emergence patterns of these maladies, raise key questions: first, why do individuals who carry disease-linked mutation show no clinical signs until their fifth or sixth decade of life? In addition, why do apparently distinct disorders share a common temporal emergence pattern? One possible explanation is that as people age, the efficiency of the mechanisms that protect younger people from the toxic aggregation of proteins declines, thus exposing them to disease. Indeed, previous studies clearly indicate that the aging process plays key roles in enabling neurodegenerative disorders to onset late in life.Since neurodegenerative disorders stem from aberrant protein folding, an international research team postulated that an aging-associated decline in the activity of proteins that assist other proteins to fold properly may be one mechanism that exposes the elderly to neurodegeneration. To identify such mechanisms, they searched for similar mutational patterns in different proteins that are linked to the development of distinct neurodegenerative disorders. Their research showed that the development of Alzheimer's disease in certain families, and of a familial prion disorder in other families, originate from very similar mutational patterns. Based on this discovery, they identified that the malfunction of the protein cyclophilin B, which helps nascent proteins to attain their proper spatial structures, is responsible for the manifestation of both maladies. They also comprehensively characterized the mechanism that underlies the development of Alzheimer's disease in individuals who carry these mutations, and found that it has no relevance to the emergence of the disease in patients who carry other Alzheimer's-linked mutations. "This study provides important new insights: first, it shows that the development of distinct neurodegenerative disorders stems from a similar mechanism. More importantly, it indicates that Alzheimer's disease can emanate from more than one mechanism, suggesting that it is actually a collection of diseases that should be classified."
"The development of immunotherapies to clear amyloid is the current leading edge of that work, but trials have been disappointing to date. It may well be that this is simply because building a robust platform for immunotherapies targeting the brain is inherently challenging, rather than issues with amyloid as a target [...]"
But they have been effective in clearing amyloid, that is, the immunotherapies have been "robust" in doing what they were supposed to do, so it's hard to see how that could be the explanation.
If the amyloid pathology is primary, the intervention must come too late or there are secondary drivers of the degeneration (hyperphosphorylated tau?) that take over in the later stages.
Before all these trials, there were two main camps: an abeta camp (baptists) and a tau camp (tauists). It seems to me that the trial results favor the tauists, so I don't understand why there is this peculiar neglect of that theory. Couldn't they have been right after all?
Fist, the study under discussion is of mutations in the presenilin protein that relate to malformations of the protein itself: whether they really occur under physiological conditions and contribute to familial AD or not, they really can't relate to the "sporadic" AD of aging.
Posted by: José at November 4, 2015 1:09 PM: But they have been effective in clearing amyloid, that is, the immunotherapies have been "robust" in doing what they were supposed to do, so it's hard to see how that could be the explanation.
Ish ... a lot of them haven't been very effective at clearing amyloid, or have been very limted in the range of Abeta species they target, or have had too narrow a therapeutic window to really do a clinically meaningful job of clearing amyloid.
Posted by: José at November 4, 2015 1:09 PM: If the amyloid pathology is primary, the intervention must come too late or there are secondary drivers of the degeneration (hyperphosphorylated tau?) that take over in the later stages.
Indeed, and that's the bigger issue; see previous comments about "failures" of Abeta vaccines in clinical trials to date.
Posted by: José at November 4, 2015 1:09 PM: Before all these trials, there were two main camps: an abeta camp (baptists) and a tau camp (tauists). It seems to me that the trial results favor the tauists, so I don't understand why there is this peculiar neglect of that theory. Couldn't they have been right after all?
I still think the evidence leans closer to the BAPtists, but fortunately, it doesn't matter what the temporal and causal relationships amongst the different kinds of cellular and molecular damage involved in AD are, or the etiopathological chain linking them to disease. If we clear out all the damage, and do so before the original substrate of an identity is lost beyond repair, we can prevent, arrest, and to some extent even reverse the disease, whichever camp is "right" (or if indeed either is).
Take a look at this:
"Experiments by Heidelberg researchers provide insight into novel gene therapy approach to treat Alzheimer's."
http://www.medicalnewstoday.com/releases/302109.php
"Until now, scientists believed that the overproduction of beta amyloid peptides was the main cause of Alzheimer's. More recent investigations, however, have demonstrated that another APP cleavage product, the APPsα protein, also diminishes over the course of the disease,"
And here is the Heidleberg's press release:
https://www.uni-heidelberg.de/presse/news2015/pm20151104_protein-repairs-nerve-cell-damage.html
few highlights:
"These findings were used to investigate a new approach for a possible gene therapy for Alzheimer’s."
"“After introducing the APPsα, we saw that the nerve cell damage could be repaired. The number of synaptic junctions increased, and spatial memory began to function again,” reports Ulrike Müller. "
The possible neuroprotective effects of APPsα and other alternative cleavage products of APP have been the subject of research for some years, and this new report from the Müller lab appears from a first glimpse (I've not read beyond the abstract) to be a novel and straightforward way of testing the predictions of that research. However, there are inherent safety and side-effect problems and ultimate limits to even the potential durability and efficacy attempts to slow or delay the diseases and disabilities of aging by modulating the metabolic pathways involved in them (as discussed in more detail here, and extensively throughout Ending Aging).