Recently, Biogen announced that it was abandoning its late stage drug to Alzheimer's, aducanum, that caused investors to lose billions of dollars.
They shouldn't have been surprised.
Not only have there been more than 200 unsuccessful attempts for Alzheimer's, it has been clear for some time that researchers are likely decades away from treating this dreaded disease. Which leads me to a prediction: There will be no effective treatment for Alzheimer's disease in my life.
Clinically I am an emergency doctor. But my research interests include diagnostic biomarkers, which are molecular indicators of disease, and a diagnostic test for Alzheimer's is something of a holy grail.
Alzheimer sits right at the confluence of a number of adverse circumstances. Stick with me on this ̵
We do not know what causes this disease
For decades it was widely believed that the cause of Alzheimer's was the construction of abnormal proteins called amyloid and Tau. These theories dominated the field and led some to believe that we were on the verge of effective treatments – by preventing or eliminating these abnormal proteins. But if the theories were correct, we would probably have had at least one or two positive clinical trials.
Afterwards, the perennial amyloid fixation looks like a mistake that could have been avoided. Although there is a relationship between amyloid and risk for Alzheimer's, there are older people whose brains have significant amounts of the protein and yet are cognitively intact. Versions of this observation date back to at least the 1960s. This is one of the reasons scientists question the enthusiasm for this one hypothesis.
It was always possible that the classic plaques and tangles first seen by Alois Alzheimer and now known to be made of abnormal proteins were the epiphenomena of aging and not the cause of the disease. Epiphenomena are characteristics associated with the disease but are not the cause.
But even more convincingly that researchers are closer to the start than the end of understanding the cause of Alzheimer's is the long list of alternative theories. This now includes, but is not limited to: infection, disordered inflammation, abnormal diabetes-like metabolism, and many environmental toxins.
And in recent years there has been more evidence for viral, bacterial and fungal infections. These viral and bacterial hypotheses were portrayed as eureka moments. But this asks the question: How did powerful epidemiological tools coincide with things like cold sores and chewing diseases?
Not a disease with a cause
When Occam's shaver – the simplest solution principle is often the best – is applied to this laundry list of possible causes, it leads to some profound consequences. Whether Alzheimer's is not a disease, or many factors can help trigger or promote it. Some of the authorities have tried to make such arguments for some time.
Any of these would be bad news as we had to develop more effective treatments, possibly in combination.
Unfortunately, our biomedical system is designed for the development and testing of a substance at a time. Combinations of drugs dramatically increase the number of clinical trials needed to test for efficacy and toxicity.
We have ignored aging biology
For 50 years after Alzheimer's description of the first patient, the disease was considered relatively rare. Called pre-senile dementia, it hit relatively early and sometimes ran into families. The much more common dementia of old age – senile dementia – was considered part of aging.
But here's the case – regardless of type, Alzheimer's has a strong age-related association. This is true even for patients with hereditary genetic form of Alzheimer's onset. Give anyone the worst possible genome for Alzheimer's – including the dreaded APOE e4 gene, which may be associated with a 10-fold increase in risk – and that person should still age slightly before the disease develops.
Combine the long list of risk factors with the strong age association and Alzheimer's focus. Neurons can be the high thread action of cell types, and senescence of aging wears them unnoticed. Any of many cellular insults can accelerate neurons against previous cell death. The worst of these can be a particularly bad gene that you inherit from your parents, but everyone is additive to a greater or lesser extent.
If correct, this perception of the disease means that we are even further away from effective treatment.
Aging is not disease. It is the normal arc of life and an incurable part of being human ("dust to dust"). As such, the aging biology did not receive the attention given to organ systems and diseases during the golden years of research funding.
In my opinion, I think it could have been a serious mistake. If you list risk factors for the major diseases of modern life-heart disease, diabetes, dementia – the most powerful is almost always age.
Bottom line: We also lack understanding of basic research on Alzheimer's main risk factor
. We cannot even properly diagnose this disease
. Although it is widely known that it is not possible to diagnose Alzheimer's accurate throughout life, a dirty little secret of Alzheimer's research is that a significant portion of patients cannot be categorized even by autopsy. The classic plaques and tangles that Alois Alzheimer saw through his microscope cannot be exact biomarkers of this disease.
The only absolute requirement for the development of therapies is an accurate diagnosis. You cannot start developing a drug if you cannot accurately identify who has and does not have the disease. Alzheimer's is the hallmark of this because it is very difficult to diagnose. In living patients, diseases such as vascular dementia and Lewy body dementia cannot be distinguished from Alzheimer's. Some of the latest technologies are actually based on imaging amyloid, which some studies might not be a reliable diagnostic test.
Prolonged periods for new therapies are longer than predicted
It takes a long time for the Food and Drug Administration to approve a drug. From the moment a possible substance is first perceived, it is often more than 10 years until it is available.
The brain has few if there are any repair mechanisms. So when we talk about Alzheimer's treatments, we mean prevention, not the other way around.
Alzheimer's natural history is such that preventive therapy must be started early during the disease. This will add years to the drug development cycle. A decade from discovery to bedding would be good news for an Alzheimer's drug.
But history teaches us that the delays can be even worse. Shortly after the discovery of gene technology in the early 1980s, it was common to tell patients with diseases such as sickle cell that a genetic cure was only a few years away. The abnormality of the jug and its location in the genome had been known for some time. The organ system involved is easy to access. Thirty years later, we still do not have cured diseases like seal cell, and the hubris of these early predictions are painful memories for older doctors like myself.
The situation with Alzheimer's looks much worse than sickle cell disease seen back in the 1980s. We don't know the cause – which is probably multifactorial – and it's hard to get on the organ. And neurological diseases are a particular challenge because the brain is protected behind something called the blood-brain barrier. Although you have a potentially effective substance, it cannot reach its goal.
Add all these considerations, and the long way forward.
But no matter in the foreseeable future does not mean that there is nothing to do. There is some evidence that healthy lifestyle efforts can prevent Alzheimer's. And even if they do not, they are likely to be effective in preventing vascular dementia, which is almost as common.