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Conflicting Results from Anti-Alzheimer’s Treatments: Brain Shrinkage?

The FDA approved 2 new anti-Alzheimer’s treatments. Leqembi is left. Will it approve donanemab? MABS may shrink the brain. Isn't that Bad?

The Alzheimer’s Association estimates that nearly 7 million Americans have Alzheimer’s disease (AD)…”About 1 in 9 people age 65 and older (10.7%) has Alzheimer’s.” It is a crisis! That’s why effective anti-Alzheimer’s treatments are so critical. Even with all the headlines about new drugs, though, we have no meaningful medications to reverse the inevitable downward descent of this disease. And there is one side effect of the new monoclonal antibody (MAB) treatments that has us alarmed. It is brain shrinkage. Neuroscientists call it brain atrophy. Whatever you call it, it’s not good news.

The Brits Are Poised to Approve New Anti-Alzheimer’s Treatments…but Fear Brain Atrophy:

British drug regulators are considering the approval of two new anti-Alzheimer’s drugs: lecanemab and donanemab. Lecanemab has already received FDA approval in the United States and is being sold under the name Leqembi. Although some advocates are calling lecanemab and donanemab “miracles” against AD, we are concerned about both effectiveness (or the lack thereof) and safety. You can read what we think about such anti-Alzheimer’s treatments at this link.

Instead of a “Food and Drug Administration” (FDA), the United Kingdom has the Medicines and Healthcare Products Regulatory Agency (MHRA). It will be making a decision on lecanemab as early as next week.

Some experts there are concerned about a few potentially serious side effects. They include both brain swelling and brain shrinkage. They are also worried about brain bleeding. In the clinical trial for lecanemab, roughly one fifth of the volunteers on the drug experienced ARIA (amyloid-related imaging abnormalities). That could include bleeding or swelling. Such adverse reactions might make dementia worse even if the drugs reduce the amount of amyloid in the brain.

Some experts are more concerned about the long-term effects of brain shrinkage. They worry that this effect may accelerate cognitive decline over years of treatment.

Dr. Robert Howard was a researcher of Psychopathology at King’s College London until he became a Professor of Old Age Psychiatry at University College London. He has served as Dean of the Royal College of Psychiatrists. He is a heavy hitter in the UK when it comes to potential treatments for dementia.

Dr. Howard told the DailyMail.com (Feb. 19, 2024):

“…the benefits of taking the ‘miracle’ drugs are ‘literally too small to be noticeable’ by a patient or doctor.

“‘Patients who’ve had these drugs, their brains seem to shrink faster than people who get placebo,’ he said.

“Obviously, losing brain volume is something we’ve always regarded as being a very bad thing. If you look at the studies, the imaging data does seem to suggest that people are actually losing probably slightly more than a teaspoon of brain.

“My anxiety in the longest term is people may be showing these tiny benefits over 18 months. But if their brains have actually shrunk, what’s going to happen to them in three years and five years, eight years?

“Will they actually show an accelerated decline? I’m extremely worried about the risks of people being misdiagnosed and being given a treatment that can’t help them and can only hurt them.”

Other UK experts have also expressed concerns about brain atrophy associated with anti-amyloid Alzheimer’s drugs. That’s largely because these drugs do not reverse symptoms of AD.

Why Do Drug Companies Love Anti-Amyloid Drugs?

Pharmaceutical manufacturers have spent billions trying to develop effective anti-Alzheimer’s treatments. The dominant theory has been that a sticky peptide called amyloid-beta causes the destruction of neurons and inevitably leads to dementia.

Despite the theory, most of the experimental drugs have flamed out. A study published in the New England Journal of Medicine, September 21, 2023 threw shade on the anti-amyloid approach to treating Alzheimer’s disease (AD). The results of the A4 clinical trial of solanezumab were not only disappointing; they sent up a huge warning flare about such medications.

The Anti-Amyloid Juggernaut:

A whole generation of neuroscientists has been trained to believe that amyloid-beta is the bad guy behind AD. Drug companies believed that if they just developed monoclonal antibodies (MABs or mAbs) that bind to this protein, they could prevent cognitive decline.

Researchers were very successful at creating lots of MABs. And these medications were very good at reducing amyloid plaque in the brains of AD patients.

The trouble was that most of the drugs did not produce a detectable clinical benefit. Patients did not regain lost memories. They were not able to go back to work or recognize forgotten family members. Most important, treated AD patients were not kept out of nursing homes. Professor Rob Howard said it succinctly:

“…the benefits of taking the ‘miracle’ drugs are ‘literally too small to be noticeable’ by a patient or doctor.”

One of the excuses that drug companies used to explain many of these failures was the too late to work hypothesis. Their theory was that the damage from amyloid-beta started long before patients and families could detect cognitive decline. If only anti-amyloid drugs could be started early enough, they hypothesized, the benefits would become obvious.

Starting Anti-Alzheimer’s Treatments Early:

Probably the idea that early treatment might produce clear benefits explains why Eli Lilly invested so heavily in a clinical trial (A4) of solanezumab.

Here is how the company described its study:

“Launched in 2013, the A4 Study was a first-of-its-kind secondary prevention trial, enrolling more than 1,100 individuals between 65 and 85 years of age who had PET-imaging evidence of amyloid plaque accumulation in the brain and who did not have clinical impairment. Participants were randomized to either solanezumab or placebo and then treated for approximately 4.5 years.”

What makes this clinical trial so important is that it was started so early in the process. The New England Journal of Medicine article describes the concept carefully.

Here is what it said:

“Approximately 20 to 40% of cognitively unimpaired older persons show evidence of elevated amyloid accumulation. Some evidence suggests that these ‘amyloid-positive’ but cognitively unimpaired older persons represent a preclinical, or asymptomatic, stage of Alzheimer’s disease and may be at high risk for cognitive decline.”

The A4 clinical trial of solanezumab was characterized as an:

“…early-intervention trial aiming to slow cognitive decline at the stage of preclinical Alzheimer’s disease in older persons who were not cognitively impaired at baseline but had elevated amyloid levels on screening positron-emission tomography (PET).”

If early anti-Alzheimer’s treatments with monoclonal antibodies work, this clinical trial should have proved highly beneficial.

There is another reason the A4 clinical trial is extremely valuable. It lasted roughly 4.5 years! That is a very long time for such a study. Many anti-Alzheimer’s studies only run for 18 months. That may not be enough time to accurately assess the benefits and risks of such treatments.

Again we quote Professor Rob Howard on anti-Alzheimer’s treatments:

“My anxiety in the longest term is people may be showing these tiny benefits over 18 months. But if their brains have actually shrunk, what’s going to happen to them in three years and five years, eight years?”

The Results of the A4 Clinical Trial:

The study published in the New England Journal of Medicine on September 21, 2023 was titled:

“Trial of Solanezumab in Preclinical Alzheimer’s Disease”

In other words, these patients did not have symptoms of cognitive decline! The results of the solanezumab clinical trial were disheartening. One might go further. The authors downplayed one aspect of the study, but it caught our attention.

Cognitive performance was worse rather than better:

“Numerical worsening with respect to the primary and secondary end points in the solanezumab group as compared with the placebo group, although not significantly different between groups, was unexpected…”

“One conjecture is that the increase in the dose by a factor of four (to 1600 mg every 4 weeks) during our trial may have severely depleted monomeric Aβ and yielded cognitive worsening, similar to that seen with inhibition of γ- or β-secretase. Further analyses will explore the effect of the dose increase on cognitive and clinical outcomes.”

OK, that’s deep in the weeds of neuroscience. The bottom line is that volunteers getting this anti-amyloid drug were worse off than those taking placebo.

Let me describe the study this way. Amyloid levels were lowered by the drug. That’s what it was supposed to do. But the PACC (Preclinical Alzheimer Cognitive Composite) score was actually worse after 240 weeks in the drug group compared to the placebo group:

-1.43 in the solanezumab group
and
-1.13 in the placebo group

Although the difference (-0.30) was not statistically significant, it was disappointing that the folks on the anti-amyloid treatment did worse than the patients on placebo.

The authors of the study describe the PACC score as:

“…the sum of the four resulting z scores, with negative scores indicating worsening of cognitive performance.”

Why Was Cognitive Performance Worse for People Taking Solanezumab?

A meta-analysis of anti-amyloid drug treatments was published in the journal Neurology (May 16, 2023). The authors analyzed 31 clinical trials and concluded that anti-amyloid drugs caused “accelerated brain volume loss.” That’s doctorspeak for brain shrinkage or “atrophy.”

The investigators conclude:

“These findings reveal the potential for anti-Aβ [amyloid beta] therapies to compromise long-term brain health by accelerating brain atrophy and provide new insight into the adverse impact of ARIA [Amyloid-related imaging abnormalities].”

A Worrisome Outcome!

We could not discover whether there was brain shrinkage in the participants of the A4 clinical trial who were taking solanezemab. That would be very interesting information indeed.

Many of the other clinical trials of anti-Alzheimer’s drugs have not lasted as long as the A4 study. We suspect that it takes at least a couple of years to see “accelerated brain volume loss.” If companies stop their trials after 18 or 24 months, they might see a bit of benefit before the negative effects of shrinkage become detectable.

Is There Any Good News About Anti-Alzheimer’s Treatments?

There has been tremendous interest in other anti-Alzheimer’s treatments. That’s because the FDA granted “accelerated” approval for two monoclonal antibodies. First came aducanumab (Aduhelm). Lecanemab (Leqembi) followed and was recently given “traditional” FDA approval. Read about this latest development at this link.

A Different Anti-Alzheimer’s Treatment:

Donanemab:

On July 17, 2023, JAMA published the TRAILBLAZER-ALZ 2 clinical trial of donanemab for “early symptomatic Alzheimer Disease.”

The authors concluded:

“Among participants with early symptomatic Alzheimer disease and amyloid and tau pathology, donanemab significantly slowed clinical progression at 76 weeks in those with low/medium tau and in the combined low/medium and high tau pathology population.”

How Good Was Donanemab As One of the Anti-Alzheimer’s Treatments?

One of the ways to measure Alzheimer’s disease is with the “integrated Alzheimer’s disease rating scale” (iADRS) score. This measurement system goes from 0 to 144. People who score high, say around 140-144 have virtually no cognitive impairment. They would be considered normal.

People who score low have greater impairment. A zero would be the worst possible score on the iADRS scale. At the end of 76 weeks, people with low and medium amounts of tau in their brains who received placebo averaged 9.27 points worse than when they started. People on donanemab averaged 6.02 points worse than their baseline score. So, both groups got worse. But those on the drug scored 3.25 points better than those on placebo. Remember, though, the score goes 144 to 0. We leave it to you to decide how good that is.

People with low, medium and high amounts of tau in their brains did slightly less well on donanemab. Those on placebo experienced a decline of 13.11 points, whereas the people getting drug declined 10.19 points. The difference was 2.92 points on a 144 point scale.

Making Sense of Contradictory Anti-Alzheimer’s Treatments:

Neuroscientists have been testing anti-amyloid drug treatments against Alzheimer’s disease for a really long time. One analysis in Nature Reviews Drug Discovery (April 5, 2019) was titled “Anti-amyloid failures stack up as Alzheimer antibody flops.” The author listed a number of “mabs” that “failed phase III trials” because of “lack of efficacy.”

Everyone wants good news about truly effective drugs against Alzheimer’s disease. I absolutely want to see medications that keep people out of nursing homes and fully functional. I suspect that the FDA is poised to approve donanemab for AD.

If true, that will make three drugs that the FDA will have green-lighted. The approval of aducanumab, lecanemab and potentially donanemab will make the drug companies very happy. These are very pricey medications. By the way, the maker of aducanumab (Aduhelm) recently announced that it was going to “realign resources for Alzheimer’s Disease Franchise.” In other words, it was giving up on this drug and pulling the plug. Read more about this retreat at this link.

Will any of these anti-amyloid medications make a difference in clinical outcomes that people care about? Only time will tell. Is it possible that with time, there will be brain shrinkage and ultimately worse outcomes? We may never know if drug companies stop their clinical trials after 18 months or two years.

Final Words:

We keep asking these questions about all the anti-Alzheimer’s treatments:

1) Will these drugs restore memories?
2) Will these drugs help people recognize family members?
3) Will these drugs enable people to drive safely or resume any normal activities?
4) Will these drugs help people balance their checkbooks or pay bills?
5) Will these drugs help people resume work or complete chores around the house?

And most important to families:

6) Will these drugs delay or keep people out of nursing homes?

We would also like to know if there is brain atrophy after several years of treatment. If that happens, it might mean some anti-amyloid treatments are counterproductive. We have asked executives at the FDA about this and have been met with silence.

We have received no good answers regarding the clinical benefits of anti-amyloid medications. If all these anti-Alzheimer’s medications can do is marginally slow the deterioration on a test score, we are not sure they are worth tens of thousands of dollars annually.

What do you think? Please share your thoughts in the comment section below.

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About the Author
Joe Graedon is a pharmacologist who has dedicated his career to making drug information understandable to consumers. His best-selling book, The People’s Pharmacy, was published in 1976 and led to a syndicated newspaper column, syndicated public radio show and web site. In 2006, Long Island University awarded him an honorary doctorate as “one of the country's leading drug experts for the consumer.”.
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