A redefinition of Alzheimer’s disease could be a boon for clinical trials, but some warn that it could put patients at risk.
The current guidelines for diagnosing Alzheimer’s disease were established in 2011 by the National Institute on Aging and the Alzheimer’s Association. The guidelines, originally published in the journal Alzheimer’s and Dementia, focus on observable symptoms such as memory impairments, language problems, and personality changes.
However, the same group recently proposed a new set of guidelines based on biomarkers rather than symptoms. Biomarkers are physiological changes that can be easily measured and may be associated with a disease. For Alzheimer’s disease, the most widely-recognized biomarkers are amyloid-beta and tau, two toxic proteins that accumulate in the brains of people with this disease. The new guidelines propose that Alzheimer’s disease should be defined based on the presence of amyloid-beta and tau in the brain, without regard to cognitive symptoms.
This new way of defining Alzheimer’s disease brings with it both advantages and potential risks. In a recent Perspectives article published in Neural Regeneration Research, my colleagues and I discussed what the new guidelines could mean for the future of Alzheimer’s disease research and brought up some of the ethical dilemmas that it could pose.
Positive Aspects of the New Definition
The new way of defining Alzheimer’s disease offers several advantages, particularly for pharmaceutical companies. Most drug candidates for Alzheimer’s disease work by trying to get rid of amyloid-beta from the brain. Unfortunately, Alzheimer’s clinical trials have been a resounding failure for the past 30 years (see Where’s our cure to Alzheimer’s disease?). As a result, several pharma companies including Pfizer have shut down their Alzheimer’s research programs entirely.
Many pharma researchers believe that the reason these drugs failed is because they were administered too late in the disease’s progression. By the time Alzheimer’s disease is diagnosed, the patient’s brain is already full of large amyloid-beta deposits. But perhaps if we could administer the drugs to people in their 30s or 40s, when amyloid-beta has started to accumulate but cognitive symptoms are not yet apparent, they might be more effective.
Clumps of amyloid-beta (shown in this illustration) can appear in the brain decades before the appearance of Alzheimer’s disease symptoms. Image Source
Under the current guidelines, these younger people who have amyloid-beta in their brains but no memory problems would not be considered to have Alzheimer’s disease. As a result, pharma companies would have to overcome steep legal issues in order to administer an experimental drug to people without a diagnosed disease. However, the new guidelines would allow these people to be diagnosed with Alzheimer’s, and thus they could be included in clinical trials.
This change would be great news for pharma companies, and possibly for the rest of us too. If they discover new drugs that can stop Alzheimer’s disease when administered at an earlier stage, it would be a huge breakthrough in preventing people from getting the disease. However, despite these advantages, there are some risks that we need to consider as well.
Ethical Issues with the New Guidelines
One of the biggest problems with this new definition is that many people who have amyloid-beta in their brains do not go on to develop the symptoms of Alzheimer’s disease. In fact, some studies suggest that as many as 1 in 3 seniors have enough amyloid-beta in their brains to meet the diagnostic criteria, yet they show no cognitive issues.
This discrepancy means that if we start diagnosing Alzheimer’s disease based on amyloid-beta alone, some people who receive the diagnosis in their 30s or 40s will never go on to experience any symptoms. Being diagnosed with a disease (particularly one that is currently incurable) can cause a substantial degree of anxiety and depression. There are ethical issues to be considered when we start diagnosing people with a disease they may never actually experience, causing undue stress for the patients and their families.
Another problem is that these asymptomatic individuals could be subjected to unnecessary treatments. In addition to the financial costs of such treatments, many Alzheimer’s clinical trials report adverse side effects, including increased rates of re-emergent infections and certain kinds of cancer. Treatments targeting amyloid-beta also increase the risk of ARIA (amyloid-related imaging abnormalities) by five-fold. ARIA is caused by tiny micro-bleeds in the brain’s blood vessels, which can result in confusion, headaches, and difficulty walking.
Cerebral micro-bleeds from ARIA appear as abnormal white regions on this brain scan. Image Source
In redefining Alzheimer’s disease based on amyloid-beta, rather than the symptoms that actually affect patients’ lives, we will be subjecting many patients to unnecessary emotional hardship and potentially-harmful treatments. Whether the benefits to clinical trails are worth this sacrifice is a question worth careful consideration.
Does Amyloid-Beta Actually Cause Alzheimer’s?
In addition to the ethical problems that I’ve discussed, there’s a darker possibility that this new definition could severely derail Alzheimer’s disease research. For decades, the “amyloid cascade hypothesis” was widely accepted among neuroscientists. This hypothesis states that amyloid-beta is the initial cause of Alzheimer’s disease, and therefore we must get rid of it in order to cure the disease.
However, a growing body of evidence suggests that the amyloid cascade hypothesis could be wrong. For one thing, many people with amyloid-beta never develop this symptoms of Alzheimer’s disease, as I mentioned earlier. In addition, several studies suggest that amyloid-beta actually serves important roles in the brain and body (see The Villain of Alzheimer’s Disease Could Actually Be a Hero). For example, it may help the immune system to fight off infections by clumping around microbes and preventing them from spreading.
It’s possible that getting rid of amyloid-beta is the wrong strategy for fighting Alzheimer’s. And if that’s the case, then redefining Alzheimer’s in terms of amyloid-beta will only distract future research efforts away from the real path to a cure.
The advantages of the new definition for aiding future clinical trials are important, and they could help us discover treatments that are effective before the development of symptoms. However, we need to weigh this against the ethical risks of diagnosing asymptomatic people with Alzheimer’s, as well as the questionable validity of the hypothesis the guidelines are based on.
This debate should not be only left up to researchers and clinicians; I believe it is important that patients and their families also discuss this important issue and make their voices heard by the scientific community.
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