by Buck Institute

Buck professor Julie Andersen weighs in on Aduhelm, the controversial Alzheimer’s drug

Neuroscientist Julie Andersen runs a Buck lab focused on understanding how aging drives Alzheimer’s and Parkinson’s diseases in order to identify new treatments that would slow or prevent them from happening.  She supports the recent preliminary decision by Medicare to cover the costs of the controversial Alzheimer’s drug Aduhelm only for certain patients enrolled in clinical trials. If this very narrow approval path is confirmed in a final policy decision later this spring, concerns have been raised in some quarters that this may mean that many patients would not be able to access the first Alzheimer’s treatment approved by the Food and Drug Administration (FDA) in the last ten years.

Here’s an edited version of Dr. Andersen’s conversation with Kris Rebillot, the Buck’s Senior Director of Communications.

How did you come to support Medicare’s proposal to limit coverage of Aduhelm only to those in clinical trials?

Given the concern over serious side effects and questions over the efficacy of Aduhelm, I think the decision by Medicare makes sense.  The first tenant of medicine is “first, do no harm,” and I don’t think we’ve passed that bar when it comes to Aduhelm. Many members of the FDA advisory panel that recommended against approving Aduhelm quit when the FDA approved the drug. That’s a really strong statement of concern.

I’m concerned about side effects related to Aduhelm. Having a headache is one thing, but dying from a brain bleed, which happened to a patient during the clinical trials of Aduhelm, is a very serious matter. My concern is also heightened by the fact that in the Biogen Phase 3 trial, 80% of the participants were white; minority populations were not really included. Hispanic and black populations not only experience higher incidents of Alzheimer’s disease, but they also have higher risk factors for things like vascular disease and hemorrhage which puts them at higher risk for side effects of the drug. I think erring on the side of caution and covering the cost of the drug in clinical trials that would hopefully include those populations is the right way to go.  

Aduhelm is designed to clear the amyloid plaques that are one of the hallmarks of Alzheimer’s disease.  Many drugs that target amyloid plaques have failed in clinical trials.  What’s going on here?

The idea behind these drugs is that you clear the amyloid, or A-beta, plaques with the hopes of improving cognition. But the jury is still out on whether these plaques are causative in terms of affecting cognition.   It may be that the presence of A-beta is just a hallmark, a tombstone – the plaques may have really nothing to do with loss of cognition. To be honest, there seems to be more of a correlation between loss of cognition and the formation of tau tangles in the brain. However, there are some ongoing clinical trials using tau antibodies that, as far as I know, haven’t really panned out. 

Timing of treatment is also an issue when it comes to the plaques. Maybe clearing amyloid plaques in someone who has just been diagnosed with Alzheimer’s disease would be efficacious. But if you’re looking at people at a later stage of the disease, it could be that the horse is already out of the barn and getting rid of those plaques doesn’t really impact pathology.  There have also been issues with immune response in patients. In earlier clinical trials when they gave A-beta antibody treatments, patients would have immune reactions and they had to be pulled off the treatment.

What’s happening in research?  Are scientists considering other approaches for studying the causes of Alzheimer’s and developing potential treatments?

As far as current clinical trials go the major emphasis is still on A-beta and tau. But in the research community I do think people have started to come around in the last few years by acknowledging that removing A-beta plaques may not be sufficient in order to stop the course of the disease. And I think there has been more of a recognition that there may be underlying processes, through environmental exposure or genetic stability, which could be making a person more susceptible to the formation of plaques and tangles. There’s more of an understanding that we need to be looking upstream of those aggregates in order to understand what’s really going on. For example, there’s been a lot of research in the last 10 years or so that’s demonstrated that deficits in mitochondrial function within neurons seems to proceed formation of these protein aggregates and maybe we want to be looking at that earlier process.

Some experts expect Alzheimer’s will end up being similar to cancer in that it’s not just one disease, but that there will be many “types” of Alzheimer’s. 

Yes, I agree with that completely, because I think Parkinson’s is like that, too. It’s a syndrome. There are so many differences in how people present with the disease. In Parkinson’s there’s a lot of variability with age of onset, how quickly patients progress, and the fact that symptoms can vary widely. Some people have tremor, some people have more rigidity. I think Alzheimer’s is going to be like that, because the disease impacts people so differently.  Plus there’s the fact that historically it’s been, ‘Oh, an autopsy of this person showed a lot of plaques and tangles, so that means Alzheimer’s.’ Well, that doesn’t even really hold, because we have people that have a lot of plaques and tangles that don’t have Alzheimer’s. There’s a whole piece about protective factors that are likely at play which we don’t yet understand.

Are you doing work in your lab that goes beyond the traditional focus on a-beta plaques?

One project in my lab is focused on cellular senescence and its resulting chronic inflammation.  We’re looking at whether exposure to A-beta elicits cellular senescence in neurons and whether that exposure kicks off a pathway whereby the spread of senescence becomes independent of A-beta – which would make chronic inflammation the real driver of pathology.

I talked earlier about deficits in mitochondrial function as being a potential contributor to Alzheimer’s.  We’re very interested in that process and processes that allow cells to get rid of damaged mitochondria. We’re studying autophagy, which is a mechanism that cells use to recycle damaged mitochondria and synthesize new ones. We think robust autophagy could allow energy production to be maintained in neurons.  And given that autophagy tends to decline with age, we think boosting that process could be a key factor in preventing or treating Alzheimer’s.

It sounds like it may take combination therapies in order to treat both Alzheimer’s and Parkinson’s diseases. 

It’s completely possible that these diseases are due to a combination of events. With aging we see an increase in cellular senescence and a reduction in the ability of cells to undergo autophagy. And maybe we need to impact both of those processes in order to elicit an effective therapy. We’re spending a lot of time currently, particularly with the Lithgow lab, screening for compounds that enhance mitochondrial function or promote the turnover of damaged mitochondria as well as developing novel therapeutics for cellular senescence. 

Interested in knowing more?  The full news release about the Aduhelm policy recommendation can be read here at the Centers for Medicare and Medicaid Services (CMS). There are instructions for those wanting to comment on the policy.  CMS is expected to announce a final policy decision by April 11.   

Science is showing that while chronological aging is inevitable, biological aging is malleable. There's a part of it that you can fight, and we are getting closer and closer to winning that fight.

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