Dementia Drugs: Is the Tragedy Finally Over?  

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Over 30 years of research, hundreds of failed drugs and billions of dollars spent, there is almost nothing to show for it. Not that you’d know this, if you read the press or visited dementia support websites. I update the tragedy that isn’t just dementia; it’s the drugs that don’t treat it.  

Main Points

  • There are two main camps in dementia research, drug-industry-sponsored and independent;
  • The drug-industry-sponsored camp is well-funded, well-publicised, and promoted by dementia support groups;
  • The independent camp is poorly funded, poorly-publicised, and not promoted by dementia support groups;
  • Drug trial data show positive numbers but no noticeable improvement in patients’ cognition;
  • Selective use of trial subjects and data cast doubts over meagre results;
  • Independent trials show that lifestyle changes can improve cognition & even reverse dementia at early stage.

If you’d like the full state of play of dementia treatments and how to actively reduce your dementia risk, you can skip the blog and find out what’s in Dementia: Keep Your Marbles.

Dementia Rates Triple

Over those 30 years of research, dementia rates have tripled and, in 2016, dementia became the number 1 cause of death for Australian women. That’s the same year the amyloid cascade hypothesis (that amyloid plaque causes dementia) turned 25. Looking forward, today’s global dementia rates are expected to nearly double by 2030 and triple by 2050. Clearly, the next 25 years won’t be any rosier.   

Someone in the world develops dementia every 3 seconds.

Alzheimer’s Disease International

Any dementia information site will tell you we can’t stop dementia and there’s no cure. In other words, there’s a killer in our midst, but there’s no point in calling the cops. As we’ll see, there are good reasons.

Dementia research is generally split into two worlds:

  1. Industry-funded research looking for a blockbuster drug to treat it; and
  2. Independent research looking for non-drug ways to avoid, prevent or reverse it. 

1. The Drug Industry Solution

The most common form of dementia is Alzheimer’s Disease (AD), which accounts for roughly two out of three cases worldwide. The first AD drug approved by the US FDA was back in 1993, now 30 years ago and 100 years after AD was first discovered. It was called Cognex (or Tacrine) and was withdrawn 10 years later because it didn’t improve cognition but did cause serious side effects like confusion, hallucinations, extreme changes in behavior and convulsions.

Most of the hundreds of drug candidates since Cognex have focused on reducing the amyloid plaques said to cause AD. Yet, like Cognex, they made no impact on progress of the disease, which is why none was approved in those two decades.   

…neurodegeneration in AD is caused by abnormal accumulation of amyloid beta plaques in various areas of the brain.

Amyloid Cascade Hypothesis; National Library of Medicine

A Big Deal?

That changed in 2021. The FDA approved the drug Aduhelm from Biogen but it was withdrawn in 2022, just a year later for the same reasons as Tacrine: no impact but serious side effects (in this case, brain swelling and bleeding). The final nail in its coffin came recently when Biogen abandoned all ownership rights of Aduhelm in early 2024 .  (The article contains the full, colourful history of Aduhelm.)

A year after Aduhelm was withdrawn, Biogen gained accelerated approval for another AD drug called Leqembi (generic name Lecanemab). Like Aduhelm and the others, Leqembi targets amyloid plaques found in the brains of some AD sufferers. Yet, despite the fanfare, Leqembi only slows cognitive decline by 2.5% and that’s in a carefully-selected group of trialists (more below). In other words, if you called the cops, they might shout at the killer to slow his escape. For over US$2,000 a month, you might expect a bit more than that.    

Non-industry researchers say the ‘effect (after 18 months of fortnightly infusion treatment) was so small it probably wouldn’t be noticeable to a doctor.’ After all these years, that’s a cruel tragedy, yet the drug industry keeps going down the amyloid plaque hole hoping to find a new rabbit. Isn’t ‘doing the same thing but expecting a different result’ the definition of insanity?

Professor Robert Howard at University College London argues that ‘The amyloid treatment is a dead end. It means that the money and energy in drug development and trials isn’t being put into something that might work. The argument that maybe the drugs need to be given earlier to make a difference is really just a wish or a hope.’ He adds: ‘I worry that the “treat earlier” argument has become a way of saying “don’t blame the drugs for not working, blame the patients.” ‘

The amyloid treatment is a dead end. It means that the money and energy in drug development and trials isn’t being put into something that might work.

Prof Robert Howard, University College London.

2. The Independent Solution

Meanwhile, in mainly university clinics from Sydney to Chicago to Berlin, independent researchers are running trials using lifestyle changes to avoid, prevent or even reverse the early stages of dementia called MCI (Mild Cognitive Impairment). These include diet, exercise and vitamin supplements, which don’t sound nearly as sexy as a new drug, but their impact has been exceptional.

These researchers don’t believe a drug will ever cure AD because it’s a metabolic disorder, one they call Type 3 Diabetes or diabetes of the brain. Experts say that ‘…metabolic disorders are associated with external factors, such as an unhealthy lifestyle along with little physical activity and excessive caloric intake’ so you can see how a drug would struggle to affect these.   

A metabolic disorder is when something is wrong with the body’s metabolism — the ability to turn food into energy and get rid of waste.

Metabolic Disorder Definition

Dementia and Metabolism

There is a strong association between AD and Metabolic Syndrome. This is not a generic term but a condition defined by high blood sugar, high blood pressure, high triglycerides, Insulin Resistance, excess fat around the waist and poor fitness, which is a precursor to Type 2 Diabetes.

Can you see a picture forming? Poor lifestyle can lead to Metabolic Syndrome which can lead to dementia. With 30% of Australians and 35% of Americans, with Met Syndrome, this may help to explain the skyrocketing dementia rates.

The converse applies, too. Trials published by neurologist Dale Bredeson in 2018 showed that dementia could be reversed or stopped in the early stages with lifestyle interventions; some subjects even returned to work. Other researchers agree, saying that 90% of dementia cases could be avoided and that having a healthy dementia-free brain is a choice. In other words, dementia isn’t coming ‘ready or not.’

So, instead of calling cops to shout at the killer, we could be empowering patients to defend themselves.   

What Support Groups Say

You certainly won’t hear about research like this from Alzheimer’s support groups like Dementia Australia. Sure, it refers to healthy lifestyles reducing dementia risk but these are feel-good generalisations; there are no links to specific studies.  

In the meantime, other neurologists say that such trials aren’t big enough or rigorous enough to provide credible outcomes. It’s interesting that a 2.5% slow-down of cognitive decline in a trial of 1,795 people (the Leqembi trial) is credible, yet improvement in 100% of trial patients (the Bredeson trial) is not. 

Meanwhile, the US-based Alzheimer’s Association (AA) is actively recruiting for its POINTER clinical trial (Protect Brain Health Through Lifestyle Intervention to Reduce Risk): ‘The Alzheimer’s Association is launching a two-year clinical trial researching lifestyle intervention on protecting brain health and potentially reducing the risk of dementia’. An encouraging development. On the same page, though, AA, pours cold water on dietary factors with these words: ‘…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.’

True. There isn’t one magical ‘brain-restoring potion’, but combined lifestyle changes have made far more impact than any drug. Maybe, the AA clinical trial will show this once and for all. However, as we’ll see below, the selection of trial subject and data can be used to serve a desired outcome.

The Alzheimer’s Association is launching a two-year clinical trial researching lifestyle intervention on protecting brain health and potentially reducing the risk of dementia’.

Alzheimer’s Association

False Hope?

It’s hardly surprising that drug makers have zero interest in lifestyle-based treatments; they can’t patent them. That’s a given but, wouldn’t you think AD associations would support any research that helps patients – rather than suggesting researchers are giving them false hope?

That exactly what some independent researchers say in reverse, in an article called  The false hope of the new Alzheimer’s drugs. A decade ago, UK Prime Minister, David Cameron made dementia a focus of his time in office, launching the Prime Minister’s Dementia Challenge to find a treatment by 2025. It’s now 2024 and that treatment is as far away as ever.    

‘Too Big To Fail’

Back in 2011, the late pathologist Mark Smith and colleague, Rudy Castellani, said the amyloid hypothesis was too big to fail, adding that ‘such a degree of faith [on the part of researchers] would be the envy of any religion.’ Nothing has changed.

This tragedy will continue to play on the dementia stage, with drug-company-sponsored research going nowhere, yet being heralded as the only credible solution.  

Meanwhile, facing opposition from drug companies, AD support groups and industry-sponsored medical experts, researchers in university clinics around the world continue to change the lives of people lucky enough to volunteer for their trials. And the media will continue to ignore the good news.

Only with a paradigm shift and investment in alternative promising constructs will we avoid the unsavory outcome that a flawed, fundamentally misinterpreted set of data was too big to fail.

Castellani & Smith, Journal of Pathology

Drugs Update

Approvals

Aduhelm is still listed by many dementia groups as an approved AD treatment, despite its market withdrawal in 2022 and abandonment in 2024.

Leqembi gained traditional (that’s full) FDA approval in 2023 to treat people with early Alzheimer’s disease (Mild Cognitive Impairment) who also have high beta-amyloid levels in their brains.

Donanemab is another drug in the same class as Leqembi (generic name lecanemab). It’s made by competitor Eli Lilly and works in the same way. Despite independent reservations about Leqembi’s efficacy and risk, conditional approval of Donanemab is expected in 2024.

Benefits & Side Effects

Sebastian Walsh, NIHR doctoral fellow in Public Health at the University of Cambridge, provided an analysis of the benefits of both drugs in an article called ‘New Alzheimer’s drugs don’t deserve the hype – here’s why.’ These are the key points:

Tiny benefit: In the Donanemab trial, against a cognitive scale of 144 points, the drug group’s rte of decline was 10 compared to placebo at 13 points. That’s a three-point difference over 144. Walsh says this: ‘…would probably not be noticeable to the doctors looking after these patients.’

Yet in a note to investors, Lilly claimed that Donanemab slowed clinical decline by 35% which is impressive, but it’s the old trick of using ‘relative’ instead of ‘absolute’ data: the absolute reduction in cognitive decline was 2% (tiny and hence not noticeable) compared to the relative rate of 35% (the reported figure) which is huge. Understand how the numbers can be used here.

Adverse Events: 1 in 6 people taking Lecanemab was found to have evidence of brain bleeding, and 1 in 8 had brain swelling. These are the side effects which undid Aduhelm in 2022.

Highly selective trials: For every 10 patients whom doctors might deem eligible for the trials, seven or eight were rejected. That is, people with brain pathologies other than amyloid plaque were excluded, so the results were less representative of real-world populations and more favourable for the drug. As Walsh put it: ‘If the drug eligibility is restricted to match the trial eligibility, then very few people will be eligible… (the) already small effects are likely to be even smaller…’

Non-representative subjects: Trialists were less representative in other ways, too. They were 5 to 10 years younger than most people suffering AD in the US and UK. Younger patients are more robust and less likely to be affected by adverse drug effects.

‘If the drug eligibility is restricted to match the trial eligibility, then very few people will be eligible… (the) already small effects are likely to be even smaller…’

Sebastian Walsh, University Of Cambridge

Summing Up

In a nutshell, according to Walsh, the drugs were tested on non-typical patients, and yielded numerical results but no visible patient improvement. They did, however, cause serious side effects.

Walsh adds: ‘Sadly, I don’t think these drugs can make a big difference for people currently, or soon to be, living with Alzheimer’s disease. Also, the shortcomings are so profound, despite decades of expensive trials and patient sacrifice, I think it’s time to take the amyloid blinkers off and prioritise exploring other, neglected, options for treating dementia.’

Walsh’s final words say it all: ‘This isn’t the beginning of the end of Alzheimer’s, but perhaps it should be the end of the anti-amyloid drug pathway.’ We can only hope.

I don’t think these drugs can make a big difference for people currently, or soon to be, living with Alzheimer’s disease.

Sebastian Walsh, University Of Cambridge

For more on the dementia conundrum, including opinions from over 500 expert sources and an 11-step Dementia Prevention Plan, check what’s inside 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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