On Alzheimer's Disease Research, Both Appropriate and Inappropriate Pessimism

On Alzheimer's Disease Research, Both Appropriate and Inappropriate Pessimism

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This is a pessimistic popular science article on the state of Alzheimer’s disease research. I think the tone appropriately pessimistic where it examines the present dominant approach to building therapies, which is to say clearing amyloid-β from the brain via immunotherapy. I think it inappropriately pessimistic for the near future, however, given the various projects currently under development. Take, for example, the brace of approaches based on restored drainage of molecular wastes in cerebrospinal fluid, or filtration of cerebrospinal fluid to achieve much the same outcome. Further, and closer to widespread availability in the clinic, senolytic therapies to clear senescent cells have been used to demonstrate that senescent immune cells in the brain, and the neuroinflammation that they cause, are a significant contribution to both Alzheimer’s disease and other neurodegenerative conditions. Removing these cells may well do more for Alzheimer’s patients in the near term than any other approach attempted to date.

Not only have there been more than 200 failed trials for Alzheimer’s, it’s been clear for some time that researchers are likely decades away from being able to treat this dreaded disease. Which leads me to a prediction: There will be no effective therapy for Alzheimer’s disease in my lifetime. Alzheimer’s sits right at the confluence of a number unfortunate circumstances. If you understand why there won’t be much headway on Alzheimer’s, you’ll also understand a bit more why modern medicine has been having fewer breakthroughs on major diseases.

For decades it was widely believed that the cause of Alzheimer’s was the build-up of abnormal proteins called amyloid and tau. These theories dominated the field and led some to believe we were on the verge of effective treatments – through preventing or removing these abnormal proteins. But had the theories been correct we would likely have had at least one or two positive clinical trials. In retrospect, the multi-decade amyloid fixation looks like a mistake that could have been avoided. It was always possible that the classic plaques and tangles were epiphenomena of aging and not the cause of the disease. Epiphenomena are characteristics that are associated with the disease but are not its cause.

But even more convincing that researchers are closer to the beginning than the end in 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 numerous environmental toxins. And the past few years have seen more evidence for viral, bacterial, and fungal infections. These viral and bacterial hypotheses were portrayed as eureka moments. But this begs the question: How did powerful tools of epidemiology miss associations with things like cold sores and gum disease?

Here’s the thing – regardless of type, Alzheimer’s has a powerful age-related association. This is true even for patients with early-onset inherited form of Alzheimer’s. Give someone the worst possible genome for Alzheimer’s – including the dreaded APOE e4 gene that may be associated with a 10-fold increase in risk – and that person still needs to age a bit before developing the disease. If correct, this conception of the disease means we’re even further away from an effective treatment. Aging is not disease. It is the normal arc of life and an ineluctable part of being human (“dust unto dust”). As such, the biology of aging didn’t get the attention that was bestowed on organ systems and diseases during the golden years of research funding. In retrospect, I think this may have been a grave mistake. If you list the 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 an understanding of the basic science of Alzheimer’s most important risk factor.

Link: https://theconversation.com/no-cure-for-alzheimers-disease-in-my-lifetime-114114

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