As people get older, they start to worry about their health. I’ve seen the terrible toll that Alzheimer’s disease can have on those who are afflicted and on their loved ones. As populations age, we will have to grapple with this disease more and more.
Tens of millions of people suffer from Alzheimer’s disease. Billions of dollars have been spent trying to create drugs that treat it.
Yet despite the intense focus, none of the drugs that have been tested actually work to relieve the clinical symptoms that make this such a debilitating disease.
Last year, the first disease modifying therapy for Alzheimer’s disease (aducanumab) was approved by the U.S. Food and Drug Administration (FDA) despite protests of the FDA’s own advisors. Three advisors resigned because they weren’t convinced the drug even worked.
Even the U.S. National Institutes of Health admits that the drug might not provide any benefit.
The medication helps to reduce amyloid deposits in the brain and may help slow the progression of Alzheimer’s, although it has not yet been shown to affect clinical outcomes such as progression of cognitive decline or dementia. ..
Aducanumab was approved through the FDA’s Accelerated Approval Program. This process requires an additional study after approval to confirm the anticipated clinical benefit. If the follow-up trial fails to verify clinical benefit, the FDA may withdraw approval of the drug. Results of the phase 4 clinical trial for aducanumab are expected to be available by early 2030.
Or in other words, the treatment was approved before it was shown to have any clinical benefit because it reduces amyloid deposits. I’ll get to why that is such a controversial statement in a little bit. But suffice it to say that we may not know if this costly treatment works before 2030. And based on what we now know about Alzheimer’s disease, reducing amyloid deposits is not going to be a silver bullet.
So we have a drug that is prohibitively costly that is available in one country, but we don’t know if it actually works.
How did we get here?
In this newsletter, I’ll cover one topic instead of many, for a change - Alzheimer’s disease. I’ll talk about how we got the disease wrong from the start and how that has hampered a hundred years of progress. And why we need changes on how we study diseases. This was the subject of my column last week for Hindustan Times, but there were details that I left out in the interest of brevity.
We may have gone down the wrong path from the start.
Alzheimer’s disease is an irreversible and debilitating disease which causes mental decline, short-term memory loss, problems with speech, and difficulty in performing routine activities. It is primarily a disease of the elderly, and it affects millions of people worldwide. Alzheimer’s disease is a type of dementia but there are others as well.
Now there’s a point worth making. Your brain is your brain. It doesn’t change or care what kind of specialist you talk to. But your neurological or psychiatric condition will get defined and pigeonholed based on whether it was first described in the medical literature by neurology, psychiatry, or pathology. The clinical characteristics determine what disease or disorder you are diagnosed as having.
How you define a disease determines how it is diagnosed and treated.
Since its discovery over a century ago, Alzheimer’s disease has been characterised by the presence of plaques in the brain made of a protein called amyloid-beta (or amyloid, for short). The prevailing wisdom has been that the accumulation of amyloid in plaques is what leads to the progression of Alzheimer’s disease.
In addition to plaques made of amyloid, researchers have shown that there are tangles of a protein called tau.
In other words, the pathological presence of amyloid is what has characterized Alzheimer’s disease, and the neurological symptoms of the disease are thought to be secondary. But what if pathology is not the main indicator? That is precisely the problem that we have here.
Drug discovery has focused entirely on trying to reverse the symptoms of Alzheimer’s by getting rid of amyloid plaques.
And so now we are in this ridiculous situation where we have an FDA. approved drug that reduces the pathological sign (amyloid plaque) without anyone actually knowing if it makes patients better (which should be the real job of treatment shouldn’t it?).
The single-minded focus on one theory to the exclusion of others has stymied the development of Alzheimer’s disease drugs. Over the past three decades, hundreds of candidate drugs that target the accumulation of amyloid have failed to prevent the memory loss and cognitive decline that harm Alzheimer’s patients. Their brains have gotten clearer but their symptoms have not gone away.
How did researchers get focused on one theory of how Alzheimer’s disease develops to the exclusion of others?
In his brilliant book, How Not to Study a Disease, neurobiologist Karl Herrup exposes how the problems of the field can be traced back to the first case which was described based on its pathological features (plaques and tangles).
But Herrup also found after asking different physicians that there’s no single definition that covers the entire range of clinical cases. Each physician focuses on a different aspect of the disease.
As Herrup notes, “Alzheimer’s disease was to be defined by the presence of plaques. Yet plaques are a feature that is not present in 15 per cent of the people with a clinical diagnosis of Alzheimer’s, and a feature that is present in people of all ages including 30 per cent of elderly people without any cognitive impairment. If this doesn’t make sense to you, it’s because it doesn’t make sense.”
Or in other words, a significant number of people who have been diagnosed with Alzheimer’s don’t have the plaques (that were supposed to be the characteristic feature) and around a third of elderly adults have plaques without having Alzheimer’s.
This loose association did not deter those researchers who declared that anyone with plaques had “preclinical” Alzheimer’s disease even though they had no symptoms.
But there is another problem with trying to explain plaques as the sole cause of Alzheimer’s disease. There is only a weak link between plaque burden and the severity of disease symptoms.
Having more amyloid buildup doesn’t mean you will have more severe Alzheimer’s. And likewise reducing it hasn’t led to improving symptoms.
The research continues to mount that amyloid deposit buildup might not be the cause of Alzheimer’s disease.
A research article published in Nature Neuroscience on June 2 adds to the evidence. In the new research article, mice that had been given a form of Alzheimer’s disease showed damage inside neurons of the brain which occurred prior to the formation of amyloid-containing plaques. It was thought that damage in Alzheimer’s disease is due to amyloid plaque buildup outside of neurons, but this study shows that damage within neurons happens even before those signs show up.
Though the research was conducted in mice (which does not capture all the aspects of human Alzheimer’s disease), it lends support to the need for studying other mechanisms of Alzheimer’s disease progression.
In short, researchers have taken for granted that amyloid plaques are a cause of Alzheimer’s disease because the two are linked, but it's possible that they are a consequence of disease progression in certain cases or even coincidental.
Despite these criticisms and some spectacular drug failures, the amyloid hypothesis isn’t dead. Some researchers believe that drugs that target amyloid are being administered too late when irreversible damage has already been done. We need to treat people with preclinical Alzheimer’s disease.
Right now, other drugs that target the pathway for the accumulation of amyloid are in the pipeline. And for the sake of those who suffer from Alzheimer’s disease, let’s home that one of these will fare better for at least a subset of patients.
But we cannot afford to continue to put all of our eggs in one basket. It’s clear that other research avenues need to be investigated. What we need is accelerated research on other disease targets.
Then there’s also an alternate theory that infections might play a part in Alzheimer’s disease.
How Long-COVID symptoms might be like Alzheimer’s disease
Last year, I mentioned a long COVID condition in elderly patients that had been dubbed “Alzheimer’s-like syndrome” by researchers. For decades there has been mounting evidence that some pathogens might be involved in at least some cases of Alzheimer’s disease. But this theory was considered fringe. Now, it is finally being seriously considered by the wider Alzheimer’s disease field
What else I’ve read
This is a very good summary of what we know about the latest Omicron lineages.
Human brains are hotter than previously thought.
Don’t wait to get your kids vaccinated.
Could we live without plastic?
Endnotes:
Friends, I’m really looking forward to being in India again next month through August.
Up until the pandemic, I had been visiting two or three times a year, but this will be the longest gap since I left the country two decades ago.
Here’s a photo from near my hometime the last time I was visiting in 2019.
I can’t wait to be back!
Thank you Sir for explaining things in simple words.
Welcome home, have a safe trip and make most of it. One thing covid has taught us is to make best use of the time as life is precarious. Your newsletter enriches us as reader and helped us through these tough times.
Godspeed
My father was diagnosed with Alzheimers and he is no more. The times were trying but thanks to a wonderful doctor who counseled us throughout, it was much easier for us and for father too. The regimen was more of test, observe, and treat but it was the doctor's enormous patience, devotion of time to listen and talk that did wonders.