THE HEALTH | JANUARY-FEBRUARY , 2022

BRAIN BITES

BY DR WAEL MY MOHAMED

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 amyloidrelated 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

Dr Wael MY Mohamed is with the Department of Basic Medical Science , Kulliyyah of Medicine , International Islamic University Malaysia ( IIUM ). stimulated by microglia and other cell types . As a result , there has been some optimism that the anti-amyloidantibody 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