People have been trying to use an immunological strategy to treat Alzheimer’s disease for a long time and a recent authorised treatment has sparked controversy
A diagnosis of Alzheimer’s disease is one of the most frightening events in one’s life.
It is the only one of the 10 most prevalent fatal diseases in affluent countries that does not have a disease-modifying medication. African Americans have twice the prevalence of European Americans regarding Alzheimer’s disease.
According to a new study, late-life dementias, including Alzheimer’s disease, cost society more than heart disease and cancer combined. To better understand Alzheimer’s disease, researchers have found the features of crucial proteins that make up amyloid plaques [amyloid- (A) and neurofibrillary tangles (tau)].
There is a pattern of lesion creation in the brain networks that govern memory and cognition, supported by significant genetic research. Advances in developing antibodies that target these proteins are underway, and the recently authorised treatment for Alzheimer’s, Aducamumab, has sparked controversy.
People have been trying to use an immunological strategy to treat Alzheimer’s disease for a long time. It’s logical to wonder if the immune system could help clean up extra beta-amyloid in the brain since it has been a characteristic of the disease for decades.
Because the central nervous system is rarely the target of an immune response, it wasn’t regarded a very likely possibility for a long time. Antibodies can accomplish some things in there. Therefore, we’ve had to rethink the “immunoprivileged” idea.
As far as I know, Elan was the first company to take a serious stab at developing an anti-amyloid antibody in the 1990s, and since then, the notion has been pursued with billions of dollars.
Having been in the Alzheimer’s research field for some time, I can simply sum up the situation: none of these antibodies has ever been proven to treat patients. The fact that some of them have removed amyloid from the brain is not in question.
When amyloid plaques seemed like the most likely cause for Alzheimer’s disease for so long, and they kept failing, it made you rethink your assumptions. You start to wonder if amyloid is a cause of the disease when you consider the complete failures for every other attempt at the amyloid mechanism (secretase inhibitors, for example).
How to milk a rhino?
The current situation of Alzheimer’s clinical research should be examined once more. Biogen’s anti-amyloid antibody, Aduhelm (Aducanumab), was approved by the FDA even though, in my opinion (and I’m not alone), it had not demonstrated efficacy and had a greater risk for damage. The problem is that there is no evidence to the contrary.
Since the FDA approved Aducanumab, Biogen has received an adverse event report from one of the patients receiving the drug, which seems to be a death from cerebral oedema. Aside from bapineuzumab and solanezumab, this was a rare side effect observed in the clinical trials of the anti-amyloid antibody. These failed effectiveness trials make the evidence stronger that anti-amyloid antibody therapy in general causes cerebral oedema rather than having a favourable effect.
The history of Alzheimer’s clinical trials to the year 2021 would be shocking to anyone who travelled back in time to 1991 and saw it. No one would be surprised “It’s going well, keep going!” seems like an outlandish statement at this point.
They explain that the most plausible explanation is that beta-amyloid is not the cause of Alzheimer’s and that treating it is like trying to extinguish a fire by eliminating the smouldering embers. Non-amyloid alternatives?
Derek Lowe just reported the apparent failure of an infectious illness hypothesis trial, and it’s a bummer. Genentech, for example, has been attempting to demonstrate something against the Tau protein, another long-standing target. Anti-tau antibody (semorinemab) results have been “puzzling” to say the least.
Patients at the moderate stage of Alzheimer’s disease showed decreasing cognitive loss on the ADAS-Cog11 (Alzheimer’s Disease Assessment Scale). The drug had previously failed in a trial with patients in the early stages of the disease. In addition, there was no improvement in actual function or the outcomes of the other two measures.
Testing it on people
According to the findings, “This probably didn’t do anything, and if it did, it’s probably not going to be noticed in the actual world, anyhow.” sounds like the most likely conclusion. To their credit, the Genentech team is carrying out additional research to see how long the effect lasts and whether its significance increases over time.
The alternative is to seek FDA approval because, hey, these results are at least as convincing as those of Aducanumab, right? More than that? This means we’ll be hearing “Well, why not my drug?” for a long time.
The second piece of vaccine-related news is a little unusual. Despite indications from animal models that it clears amyloid, there is no amyloid-related antigen in this nasally given vaccination candidate. Protollin, the active substance, is generated from bacterial cell wall proteins and is the primary active ingredient.
As a vaccine adjuvant, it was developed because of decades of use of bacterial surface components as an adjuvant. Because of the immunostimulatory effects, it appeared that Protollin could impact amyloid deposition in mice, which led to the idea of testing it out in people.
It appears that no anti-amyloid antibodies are being produced; rather, the innate immune system is being stimulated by microglia and other cell types. As a result, there has been some optimism that the anti-amyloid-antibody world’s negative effects may be avoided as well.
This one gets the same reaction from me: give it a shot, and best of luck to all. Warnings apply: Even the most well-engineered rodents don’t represent Alzheimer’s disease pathophysiology as accurately as humans, so there is much room for errors.
In addition, there are the usual issues about safety and tolerability for any novel vaccination or immunomodulatory medication, which must be addressed in human trials. Even if they are long shots, these clinical trials are appropriate and represent the best shot we have at Alzheimer’s disease at this time. So you can be thrilled about something while also being sad about it and longing for things to be different.
Let us hope for the best
There is, however, a way out of this situation. When it comes to amyloid plaques, things aren’t as simple as they appear to be. Many phases of amyloidosis must occur before the insoluble plaques we observe with dying neurons twisted in them can be formed.
It’s a long process. “Well, they weren’t targeting the Right Amyloid” has been a constant justification whenever an anti-amyloid antibody has failed. Since we fully understand what the Right Amyloid is, we’ve been hoping that the next antibody study will clear it, and I’ve lost track of how many times I’ve been promised this was imminent.
For this candidate, the newfound optimism is that researchers found a pseudo-beta hairpin shape in one section of beta-amyloid protein and the production of a stabilised, shortened vaccination antigen. The results of immunotherapy in two mice models of Alzheimer’s disease are highly intriguing.
Amyloid toxicity may begin with N-terminal truncated versions, according to some research. As a result, this antibody is less likely to become stuck in the plaques itself, which has been a concern with other antibody/vaccine techniques (such as Biogen’s) that have had inflammatory toxicity issues.
This is something that, in my opinion, should be tried out. According to the study’s authors, there is still a lot of work to be done before a human trial is ready. A choice must be taken regarding whether to employ a vaccine or inject monoclonal antibodies directly.
Running the experiment is the only way to find out what causes Alzheimer’s disease, even though I’m suspicious of the amyloid hypothesis at this stage. We are still in the dark concerning Alzheimer’s aetiology, so I am not ready to play any trumpets or declare that triumph is at hand just yet.
You can argue the same about every other technique we have to the sickness, so let’s see if this one works. Nevertheless, if this doesn’t work, the amyloid hypothesis will be dealt a severe blow.
In closing, since these clinical studies represent our best hope for curing Alzheimer’s disease, I believe that despite their long odds, they are necessary. Because of this, you may both feel delighted with it and wish for a better future at the same time. — The Health
Dr Wael MY Mohamed is with the Department of Basic Medical Science, Kulliyyah of Medicine, International Islamic University Malaysia (IIUM).