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Balancing Hope and Realism

The Search for a Cure for Alzheimer's Disease
April 13, 2019 | Comments

“We may finally know what causes Alzheimer’s,” declared a recent headline in New Scientist’s daily news post. And so continued a deluge of articles heralding a paper claiming that a bacteria found in our mouths and the cause of gum disease (periodontitis), Porphyromonas gingivalis, might also be the cause of the most common form of dementia, Alzheimer’s disease.

        Nearly six million people in the U.S. are now living with Alzheimer’s disease, which is a leading cause of death, but only after imposing years of declining memory and function. Despite being first described in 1906 by Alois Alzheimer, the cause of the degenerative brain disease is still unknown.  Through the years, a myriad of things has cropped up that are risk factors for Alzheimer’s disease, including mutations in several genes, vascular disease, depression, and lack of exercise.  Each time one of these risk factors is reported, headlines blare that a “cause” has been discovered, usually blurring the distinction between what is a risk factor and an actual cause.

A case of gum disease (periodontitis). Is this the cause of Alzheimer’s disease? (source: Shutterstock).

Is the association of Alzheimer’s disease with the bacteria that causes gum disease another such association rather than an actual cause, or is this finally the real thing as many reports in the media imply? The excitement is based on a paper published in the journal Science Advances and the findings can be summarized as follows:

  •      The bacteria P. gingivalis was found in the brains of people who died with Alzheimer’s disease, confirming earlier reports.
  •      The bacteria’s DNA was also found in the cerebrospinal fluid (CSF) of living patients with Alzheimer’s disease.
  •      A toxic enzyme produced by the bacteria called gingipains was also found in the brains of deceased Alzheimer’s patients. The more gingipains these brains had, the higher were the levels of two proteins associated with Alzheimer’s disease, called tau and ubiquitin. The level of gingipains in brains from control subjects who did not have Alzheimer’s at the time of their deaths was lower.
  •      Swabbing the gums of mice with P. gingivalis resulted in the bacteria infecting the mouse brain, degeneration of brain cells, and increased levels of another key protein found in humans with Alzheimer’s disease called beta-amyloid. Giving a drug that blocks gingipains reduced the production of beta-amyloid and neurodegeneration in the mice.

There is no question that these findings are fascinating and need to be pursued. The pharmaceutical company that funded the study, Cortexyme, is now conducting clinical trials of a drug that blocks gingipains to see if it is effective in treating Alzheimer’s disease. Another group is working on developing a vaccine for P. gingivalis as a potential way of preventing Alzheimer’s in the first place.

A Disappointing Time

The possible link between gum disease bacteria and Alzheimer’s disease comes at a time of considerable disappointment among scientists studying the disease and continuing heartbreak among patients who have it and their loved ones. For many years, the prevailing hypothesis about Alzheimer’s disease causation focused on the beta-amyloid protein. First discovered in brains of people with the disease over a century ago, beta-amyloid accumulates in abnormally high amounts in the brains of affected patients, forming clumps outside of neurons called amyloid plaques. Scientists uncovered the molecular pathways by which another protein is abnormally processed to create beta-amyloid and showed that a genetically-modified mouse with high levels of beta-amyloid develops memory loss and brain degeneration similar to what is seen in patients with the Alzheimer’s disease. The “amyloid hypothesis” led scientists and pharmaceutical companies to vigorously pursue medications that block the production of beta-amyloid or destroy the beta-amyloid plaques that are already accumulated in brains of people with Alzheimer’s disease.

The abnormal protein beta-amyloid forms plaques in the brains of patients with Alzheimer’s disease (source: Shutterstock)

Some of these drugs do seem to clear both mouse and human brains of beta-amyloid protein, but unfortunately none of them so far work to relieve the symptoms of Alzheimer’s disease or stop its relentless course to dementia and death. The failure of anti-beta-amyloid medications has led to a major reappraisal of the amyloid hypothesis. Although not all proponents of the amyloid hypothesis have given up on the theory and there are still drugs in clinical trials that target beta-amyloid, scientists are now also eagerly trying to find completely different molecular targets to treat Alzheimer’s disease.

A New Hypothesis Emerges

One emerging hypothesis is that the plaques formed in the brain by beta-amyloid are not the cause of Alzheimer’s disease, but rather a reaction to infection and inflammation. Numerous different infectious agents have been proposed as the culprit for causing Alzheimer’s disease. The infectious disease hypothesis for Alzheimer’s is intuitively attractive because we do know many ways to treat infections, raising the hope that vaccines and anti-infective agents could represent actual cures for the disease.

But there are some very good reasons to be cautious in leaping onto the gum disease to Alzheimer’s disease link. These include the following:

  •      Some estimates show that about half of Americans have some form of gum disease, but most of them don’t get Alzheimer’s disease.
  •      The bacteria P. gingivalis is found in brains of people who died without having had Alzheimer’s disease. However, it could be that those people would have developed it if they had lived longer.
  •      Drugs that clear beta-amyloid and reduce neurodegeneration in mice so far have not been effective for people with Alzheimer’s disease.
  •      The first two authors of the Science Advances paper are also the co-founders of the drug company, Cortexyme, that stands to make considerable profit if its anti-gingipains drug, COR388, works.

These caveats raise the issue of whether we should be more careful instilling hope in caregivers and patients with Alzheimer’s disease. On the one hand, many people believe that hope is an important component in helping people deal with life-threatening illness. On the other hand, there is value in being realistic about Alzheimer’s disease so that plans can be made for the inevitable decline in memory, cognition, and function.  Instilling false hopes may lead some people to avoid making decisions that are often necessary to cope with someone who ultimately becomes unable to care for himself.

Kevin Lomangino, managing editor for the now sadly defunct HealthNewsReview, has been especially critical of what has been called the “Alzheimer’s industry complex”. Lomangino laments the fact that drug companies promote the hope that a “cure may be around the corner,” when, in fact, despite the investment of “decades and untold millions,” no such cure is yet available. “Meanwhile,” he adds, “advocates and caregivers in the community are becoming increasingly skeptical of the motives behind these claims and increasingly doubtful of the science that backs them.”

New ways of helping people with Alzheimer’s disease continue to proliferate. Often, however, close inspection blunts optimism. For example, a headline in a popular medical news service recently read “Californian ‘Holy Herb’ a Potential Treatment for Alzheimer’s?”. But before getting too excited that an extract of the herb yerba santa is going to help a loved one with dementia, read the paper upon which this headline is based and you will learn that the study is not a clinical trial of the herb but rather a laboratory screening test that predicts which compounds might work to treat dementia. No actual people with Alzheimer’s disease were given the “holy herb” in the study.

Or one might see the headline in the Washington Post that states “Changing ‘the tragedy narrative’: Why a growing camp is promoting a more joyful approach to Alzheimer’s” (February 21, 2019). The article described a 2016 “pilot study’ in a Canadian nursing home that found that dementia patients improved after 12 weeks of visits by “elder-clowns.” The article acknowledges that “large-scale studies on positive approaches to dementia have yet to be done,” leaving us to wonder why the Washington Post is reporting on this when there is no real evidence that having clowns visit people with dementia really works. Indeed, when the article was posted on Reddit, one person commented online “There is absolutely nothing joyful about this disease,” while another commentator expressed the opposite sentiment: “It gives me hope that the tides are changing”. Clearly, there are differences among people involved with Alzheimer’s disease about how much hope they can stand.

Will the findings regarding P. gingivalis really lead to a cure, as the co-founders of Cortexyme hope? Perhaps another infectious agent that is treatable with antibiotics will turn out to be the “magic bullet” we have been waiting for. Or maybe an herb or even clowns will work to make things better. It is important for science journalists to keep us up to date on progress in finding causes and treatments for Alzheimer’s disease. It is also important to instill hope in people living with life-shortening diseases and their caregivers so they have the resiliency to do everything possible to make the years left comfortable and as meaningful as possible.

But it is also important for journalists to temper their enthusiasm for supposed breakthroughs with realism. There are abundant hypotheses for what causes Alzheimer’s disease and many reasonable leads to follow. At this moment, the cause of the disease remains a mystery and there is no cure. Studies in test tubes, laboratory animals, and postmortem brains can point us toward causes and cures, but the results of them should never be promised as imminent cures. The responsible course is to carefully balance hope and realism, while always, of course, sticking to the science. We need to work together to find ways to help journalists, who are always facing deadlines and demanding editors and publishers, to navigate these difficult but essential distinctions.


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