The New Alzheimer’s Drugs: Do They Work?

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In July last year year, Leqembi became the first drug ever to gain full approval to treat Alzheimer’s Disease. Two other drugs almost made it before Leqembi, and two more are in the pipeline – but how effective are they? Do they improve thinking or memory? The short answer? No.

Main Points

  • Leqembi is approved to treat early Alzheimer’s Disease in the USA, Australia & elsewhere;
  • Suitable patients must have Mild Cognitive Impairment and ‘amyloid plaque’ in their brains;
  • To check for plaque, a PET scan is needed initially & ongoing, to monitor brain changes;
  • Brain swelling, bleeding & shrinkage were reported in over 10% of Leqembi trialists;
  • Leqembi slows the rate of cognitive decline by so little that no one may notice.
  • There are safer, more direct ways to combat Alzheimer’s Disease.

(If you’re a boomer and concerned about the risk of Alzheimer’s, you can get all the facts about the causes and the 11 practical steps you can take to prevent it. We’ve put them altogether in our guide: Dementia: Keep Your Marbles. Click to find out what’s inside)

What is all the fuss about?

The fuss is because, after 25 years and billions of dollars spent on Alzheimer’s Diseases (AD), Leqembi (generic name lecanemab) is the first drug to clear all the hurdles by the US FDA (Food & Drug Administration) to gain full or ‘traditional’ approval. And dementia (of which Alzheimer’s is 70%) is a big deal: it’s become the #1 cause of death for Australian women.

Although it’s been 100 years since Alzheimer’s Disease was discovered, only three drugs got as far as ‘conditional’ approval and all of these were in the last 20 years. That’s probably why AD patient advocate sites are so excited about Leqembi: they haven’t had much good news for a long time.

They’ve had bad news, though: two of the three drugs to gain ‘conditional’ approval had to be withdrawn due to side effects.

  • For Tacrine (generic name Cognex), conditionally approved in 1993, these included confusion, hallucinations, extreme changes in behavior and convulsions.
  • For Aduhelm (generic name Aducanemab), conditionally approved in 2021, the side effects included brain swelling* and brain bleeding* in 40% of patients. (Get the full history here).

*These symptoms are now given the collective name of ‘ARIA’ (amyloid-related imaging abnormalities). I’m wondering if the term was coined to make the side effects seem more benign.

What about Leqembi?

Leqembi has about half the rate of ARIA (13-14% compared to 35% for Aduhelm) but has a similar mode of action, and that’s what is causing more concern. Both of these drugs, and two others in the pipeline – Eli Lilly’s donanemab and Roche’s gantenerumab – are focused on reducing what’s called ‘amyloid-beta’ in the brains of people with early Alzheimer’s Disease (AD).

That’s one reason all four of these drugs cause ARIA to some extent, but the problem is more basic than that. For decades, many have questioned if reducing amyloid has any impact on the disease at all (more on this below). In other words, if amyloid is reduced, do patients start to think or remember better?

(By the way, Tacrine, the first AD to be approved and the fifth in this group, had a different mode of action; it reduced acetylcholine in patients’ brains. That’s odd because current treatments for AD symptoms do the reverse.)

On a Road to Nowhere

How could the mode of action of four AD drugs be in doubt, you ask? Let me explain.

Since 1992, the FDA has allowed drug makers to use ‘biomarkers’ or surrogate markers to test if their drugs work. A biomarker is a measurement of a substance said to mimic a natural process. Using them is less invasive for patients and allows much faster drug assessment and approval under the FDA’s Accelerated Approval Program. For Alzheimer’s, the biomarker is ‘amyloid-beta’, that protein we mentioned before, which is found in plaques in the brains of some sufferers and in those of non-sufferers, too.

For 25 years, reducing this protein has been the mark of success for treating AD. That is, if amyloid-beta levels went down, the drug was a success. Yet, there were serious doubts about whether this link existed, as far back as the 1990s.

Ever since the 1990s, researchers and clinicians have been spending uncountable hours (and uncountable dollars) trying to turn the amyloid hypothesis into a treatment for Alzheimer’s’. Every single one of these interventions has failed in the clinic. Every last damn one.

Dr Eric Lowe, former AD researcher, in Science

Aduhelm was taken off the market in Europe just 12 months after launch because this link couldn’t be found.

That is, amyloid-beta went down but patients’ cognition didn’t improve. Fierce Biotech editor Ben Adams was more blunt: ‘The amyloid theory just won’t die…the FDA has just resurrected it for a long and healthy future.’ Bloomberg agreed; ‘For Alzheimer’s patients, their families, researchers, and the pharmaceutical industry, the bigger question is whether drugs targeting amyloid have been a multi-billion dollar dead end.’

That’s why Leqembi generated so much excitement; it was the first drug that actually slowed cognitive decline. That’s also why it was the first to gain full not conditional FDA approval, in July 2023.

How Is Leqembi Different?

In the clinical trial that convinced the FDA, Leqembi slowed the rate of cognitive decline of AD sufferers by 27% over 18 months, or a benefit of five months. This does look very impressive until you dig into the figures.

Matthew Schrag, Assistant Professor of neurology at Vanderbilt School of Medicine did, and says the 27% figure was relative only to the placebo result; the absolute result (per 100 trialists) was 2.5% over 18 months or almost nothing. Schrag says: ‘This (the 27%) is a really deceptive number… the change is so small that most patients probably would not be aware of the difference…’ (Read our post here to understand the difference between relative and absolute numbers.) Bear in mind, no one is talking about helping people’s brains to function better; they’re talking about slowing the rate at which they decline.

Others agree. Neuro-psychologist Karen Sullivan says much the same: ‘the real world impact of this may not be noticeable to families. What is effective statistically isn’t always effective clinically’. Jerry Avorn, professor of medicine at Harvard Medical School agrees: ‘It will just make Grandma forget a tiny bit less.’ In fact, she might start to forget less, slightly more slowly.

Meanwhile many patients will ‘wrongly expect the medication will improve their memory and thinking skills’.

You can understand why, when patient advocate groups make pronouncements like: ‘The Alzheimer’s Association celebrates today’s U.S. Food and Drug Administration action to grant traditional (full) approval of Leqembi.’ Yet, as this article states, the Alzheimer’s Association partly funded the development of Leqembi and Aduhelm, but the casual observer may not be aware of this.

...this is a really deceptive number… the treatment really only improved patients’ condition by about 2.5%… most patients probably would not be aware of the difference.

Neurologist Matthew Schrag

Another side effect of Leqembi is brain shrinkage, which is usually a measure of the progress of AD; that is, as the disease progresses, the brain usually shrinks.

As a Leqembi clinical trial side effect, brain shrinkage has been little reported. It fact, it’s been ignored, says Professor Scott Ayton, from the Howard Florey Institute of Neuroscience and Mental Health in Melbourne. We may hear more about this as more experts examine the trial data but, clearly, brain shrinkage is not a welcome side effect from an AD treatment.

We’re talking about the possibility of brain damage (from a treatment)… I find it very peculiar that these data, which are very important, have been completely ignored by the field.

Scott Ayton, Neuroscientist, Howard Florey Institute of Neuroscience and Mental Health

How To Make a Real Impact on AD?

Aside from not improving patients’ memories or thinking skills, the bigger tragedy is this: by believing that drugs are the only answer, any non-drug-based ways to prevent, avoid or reverse AD are being ignored. That’s especially so when groups like the Alzheimer’s Association sum up like this:

‘A growing body of evidence suggests that eating a healthy diet may lower the risk for cognitive decline and dementia. However, not a single food, beverage, ingredient, vitamin or supplement has been proven to prevent, treat or cure Alzheimer’s disease or to benefit cognitive function or brain health.’

Sure, there is no miracle ‘super food’ to reverse dementia, but there is a combination of factors that make far more impact than any drug. This borne out by evidence from independent trials across the globe, some going back decades. Below are four examples; there are hundreds more. (See them summarised in everyday English, along with the real causes of Dementia and what you can do to prevent it, in our guide: Dementia: Keep Your Marbles.)

DIET

Researchers from the Rush University Medical Centre in Chicago ran a couple of diet trials over 5 years, with almost 1,000 men and women aged 58 to 98. All were from retirement homes and none had dementia at the start of the trial.

They were put on the MIND diet, a combination of a Mediterranean Diet and the DASH diet (Dietary Approaches to Stop Hypertension). Their cognitive function was tested before, during and after the trial period, using 21 comprehensive measures.

At the end of the trials, the leaders concluded that ‘by eating the right foods, you could protect your brain from neuro-degeneration and slow age-related cognitive decline by up to 8 years’ That figure is eight years, not five months, the stated benefit from Leqembi.

By the way, this is not an insignificant trial. It’s 60% of the size of the confirmatory trial (1,800 people) for Leqembi that granted its final approval in July 2023.

..by eating the right foods, you could protect your brain from neuro-degeneration and slow age-related cognitive decline by up to 8 years’.

MIND Diet Study reported in Mental Health Daily

EXERCISE

In a smaller study over a much longer period, University of Gothenburg researchers tracked the fitness of 200 women from 1968 to 2012, in order to check the relationship between fitness and dementia.

Only 5% of the fittest women had developed dementia at the end of the 44-year study, compared with 32% of the women with a low fitness score. In the same study, researchers found that the onset of dementia in women with high fitness scores was 11 years later compared to those with a medium fitness score. Sure, the trial was small, but the result was clear.

Exercise reduces the risk of dementia in women ‘by almost 90 per cent.’

Title of the article reporting the Gothenburg study

SUPPLEMENTS

Brain shrinkage is widely accepted as an indicator of AD and is measured directly in patients, not via biomarkers. So it was big deal in 2013, when Emeritus Professor David Smith and colleagues at Oxford University showed that giving vitamin B supplements to seniors with high homocysteine levels resulted in a 700% reduction in brain shrinkage. High levels of this amino acid are ‘a known risk factor for Alzheimer’s disease’ and 40% of people over age 50 have them, so they’re very relevant to age and to AD.

As Malcolm Kendrick, doctor and author, put it: ‘Had any drug shown such a significant effect on brain shrinkage, I am 100% certain that the finding would have been shouted from the rooftops. We would be looking at a massive blockbuster. probably the biggest selling drug in the world – ever.’ 

Kendrick asks the obvious question: ‘Why, you might ask, is no-one doing anything about this?’ He gives the obvious answer, too: drug companies can’t make money out of vitamins. ‘..they cannot be patented; therefore any profit margin is far too puny to be of interest to them.’ It seems unlikely there will ever be drug industry funding into the efficacy of B vitamins for dementia or any other non-drug candidates.

Had any drug shown such a significant effect on brain shrinkage, I am 100% certain that the finding would have been shouted from the rooftops. We would be looking at a massive blockbuster. probably the biggest selling drug in the world – ever.

Dr Malcolm Kendrick

COMBINATION

It’s not surprising that a combination of all of these – diet, exercise and supplements – could make an even bigger impact than each separately.

In 2018, Dale Bredesen at the University of California published 100 case studies of patients with cognitive decline whom he’d treated with combination or, as he put it, ‘personalised’ regimes. His theory is that amyloid plaque isn’t the cause of AD but the result of it; it’s the result not the cause. His approach is to boost patients’ health and rebuild their neural networks, rather than trying to eliminate amyloid from their brains. He had success, too.

His regime included a low-carb, high-fat, high-plant, whole-food diet, regular exercise, improved sleep, reduced stress and specific supplements. Reduced stress was vital here but it wasn’t just the obvious kind; he removed what he called ‘insults’ to the system like toxins and infections, in addition to sources of obvious stress. The results? Each of the 100 participants in the study showed ‘documented improvement’ in memory and cognition, with many able to return to work. (The age group was age 55-75 so some were still of working age.)

This was a pretty stunning result, especially in contrast to ‘game changing’ drugs like Leqembi that make so little impact that no one may notice. Bredesen is confident enough to say: ‘Our generation will be the last generation to fear Alzheimer’s Disease’.

I think he’s probably right – but only if people believe that the fate of their marbles is in their own hands. Most still don’t.

AD Defence In Your Own Hands

There’s a pile of research into the causes of AD and non-drug-based ways to prevent it, albeit a smaller pile than for drug-based ways. This research is independently funded and it doesn’t get the industry-funded star treatment that drugs do, so you probably won’t see it in the news.

If you’d like to know all the good news about preventing dementia from many more independent researchers, check out what’s in our plain English guide: Dementia: Keep Your Marbles.

Dementia

DEMENTIA:
KEEP YOUR MARBLES

Discover how Aussie boomers can delay or prevent Alzheimer’s Disease

Kim Brebach

Kim Brebach

Hi, I’m Kim Brebach, boomer, information researcher, technical writer and Joiner of Dots at M&M. In my spare time, I review wines and love to cook.

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