No treatment for Alzheimer's disease in my life

Biogen recently announced its intention to abandon aducanumab, its advanced-stage drug for the treatment of Alzheimer's disease, resulting in a loss of billions of dollars for investors.

They should not have been surprised.

Not only has there been more than 200 unsuccessful trials for Alzheimer's disease, but it's clear for some time that researchers will probably no longer be able to deal with this terrible disease in decades. Which leads me to a prediction: there will be no effective treatment for Alzheimer's disease in my life.

Clinically, I am an emergency physician. But my research focuses on diagnostic biomarkers, which are molecular indicators of the disease, and a diagnostic test for Alzheimer's disease is the Holy Grail.

Alzheimer's disease is at the confluence of a number of regrettable circumstances. Stay with me on this – it's mostly bad news for anyone of middle age or older, but there is some sort of reward in the end. If you understand why we are not making much progress on Alzheimer 's disease, you will also understand a little more why modern medicine has had less progress on major diseases.

We do not know what causes this disease

For decades, it was generally thought that the cause of Alzheimer's disease was the formation 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 removing these abnormal proteins. But if the theories had been correct, we would probably have had at least one or two positive clinical trials.

In retrospect, the fixation of amyloid over several decades looks like a mistake that could have been avoided. Although there is a correlation between amyloid and the risk of Alzheimer's disease, there are older people whose brain contains a significant amount of protein and yet is cognitively intact . The versions of this observation date back to at least the 1960s. This is one of the reasons why researchers have questioned the enthusiasm aroused by this hypothesis.

It was always possible that the clbadic plaques and tangles seen for the first time by Alois Alzheimer, and which are now known to consist of abnormal proteins, are epiphenomena of aging and not the cause of the disease. Epiphenomena are characteristics badociated with the disease but are not the cause.

But the long list of alternative theories is even more compelling as researchers are closer to the beginning than to the end to understand the cause of Alzheimer's disease. This now includes, but is not limited to, infection, disorderly inflammation, the abnormal metabolism of diabetes, and many environmental toxins.

And in recent years have seen more evidence of viral, bacterial and fungal infections. These viral and bacterial hypotheses have been portrayed as Eureka moments. But that begs the question: how powerful tools of epidemiology have they lacked badociations with things like cold sores and gum disease?

Not an illness with a cause

When Occam's razor – the principle that the simplest solution is often the best – is applied to this exhaustive list of possible causes, it has far-reaching implications. Alzheimer's disease is not a single disease, or many factors can help trigger it or promote it. Some authorities have been trying to argue such arguments for some time.

Either or both would be bad news because we would need to develop several effective treatments, possibly in combination.

Unfortunately, our biomedical system is designed for the development and testing of one drug at a time. Drug combinations dramatically increase the number of clinical trials needed to test for efficacy and toxicity.

We ignored the biology of aging

For 50 years after Alzheimer's description of the first patient, the disease was considered relatively rare. Called pre-senile dementia, it struck relatively early and was sometimes pbaded on to families. The much more common dementia in the elderly – senile dementia – was considered part of aging.

But here's the thing – no matter what type, Alzheimer's has a powerful age-related badociation. This is true even for patients with a hereditary form of Alzheimer's disease. Give someone the worst possible genome for Alzheimer's disease – including the dreaded APOE e4 gene that can be badociated with a 10-fold risk – and this person has to age a bit longer before developing the disease.

Combine the long list of risk factors with powerful age-specific badociation and Alzheimer's disease becomes a priority. Neurons may be the result of cell types and senescence of aging wears them inexorably. Any of the many cellular aggression can accelerate neurons to earlier cell death. The worst of them is perhaps a particularly bad gene that you have inherited from your parents, but all are additive to a greater or lesser degree.

If it is correct, this conception of the disease means that we are even further away from effective treatment.

Aging is not a disease. This is the normal bow of life and an ineluctable part of being human ("dust to dust"). The biology of aging has therefore not captured the attention to organ systems and diseases during the golden years of research funding.

In retrospect, I think that could be a big mistake. If you list the risk factors of the major diseases of modern life – heart disease, diabetes, dementia – the most powerful are almost always age.

Conclusion: We do not understand the scientific basis of the most important risk factor for Alzheimer's.

We can not even diagnose this disease accurately

Although it is generally known that it is impossible to accurately diagnose Alzheimer's disease in the course of life, one of the little secrets of research on this disease is that a significant fraction of patients can not be categorized, even in autopsy. The clbadic plaques and tangles that Alois Alzheimer has seen through his microscope may not be accurate biomarkers of this disease.

The single absolute requirement for the development of therapies is an accurate diagnosis. You can not start developing a medicine if you can not accurately identify who has the disease or not. Alzheimer's disease is the prime example because it is very difficult to diagnose. In living patients, diseases such as vascular dementia and Lewy body dementia may be indistinguishable from Alzheimer's disease. Some of the latest technologies are actually based on amyloid imaging, which according to some studies may not be a reliable diagnostic test.

Deadlines for new treatments are longer than expected

The Food and Drug Administration is taking a long time to approve a drug. From the moment a possible drug is designed, it often takes more than 10 years before it becomes available.

The brain has little or no repair mechanisms. So when we talk about treatments for Alzheimer's disease, we mean prevention and non-reversal.

The natural history of Alzheimer's disease is such that preventive treatment must be initiated early in the course of the disease. This will add years to the drug's development cycle. A decade between discovery and bed would be good news for a medicine against Alzheimer's disease.

But history teaches us that delays could be even worse. Shortly after the discovery of genetic engineering in the early 1980s, it was common to tell patients with diseases such as sickle cell disease that a genetic cure was needed in a few years. The abnormality of sickle cell disease and its location in the genome have been known for some time. The involved organ system is easy to access. Thirty years later, we still have not cured diseases such as sickle cell disease, and the pride of these early predictions is a painful memory for older doctors like me.

Alzheimer's disease seems much worse than that of sickle cell disease in the 1980s. We do not know the cause – which is probably multifactorial – and it is difficult to get an organ. And neurological diseases are a particular challenge because the brain is protected by something called the blood-brain barrier. Even if you have a potentially effective drug, it may not reach its target.

Add up all these considerations and the long road gets longer.

But no drug in the foreseeable future means that there is nothing to do. It seems that healthy lifestyle efforts could prevent Alzheimer's disease. And even if they do not, they are probably effective in preventing vascular dementia, which is almost as common.

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