More of my blog posts deal with dementia than with any other subject and the news about Alzheimer’s disease over the years has been largely dispiriting, so who would have thought that I would leap at the opportunity to write about a new diagnostic test. But with so much of the medical literature relentlessly focused on COVID-19, it’s reassuring to realize that research on other subjects is continuing. The new study does not report a treatment, let alone a cure for Alzheimer’s disease. Furthermore, the prospect of screening healthy individuals to determine their future risk of developing progressive cognitive impairment is ethically fraught. Nonetheless, in the current climate, this report is good news.
It’s good news, and not just because it indicates that not all medical scientists have retooled as corona virus researchers, though it does that. It’s good news, and not just because it means it will be possible to target intervention studies to high risk individuals will permit studies to be carried out on smaller numbers of people and over a shorter period of time, though it means that. It’s good news because it shines a bright light on a long-neglected character in the Alzheimer’s story, the tau protein.
Back in 1906, when Alois Alzheimer peered into his microscope at tissue from the brain of a patient who had died of the disorder of cognition that would one day bear his name, he identified two unusual substances that he described as plaques and tangles. The plaques, which were located between neurons, would ultimately be found to be composed of a protein known as amyloid. The neurofibrillary tangles, which were located inside the nerve cell bodies, would eventually be identified as a protein called tau. These two substances have been recognized as the hallmarks of Alzheimer’s disease for over a century.
For years, the roles of amyloid and tau were hotly debated. Some researchers felt that amyloid was the result of Alzheimer’s; others were confident it was the cause. Some scientists were more interested in studying amyloid; others directed their efforts towards tau. But over the course of the last 25 years, amyloid has gained the upper hand. Study after study has sought to improve cognition in Alzheimer’s disease by ridding the brain of amyloid-laden plaques—and each time, the approach failed.
A great deal of excitement was engendered by immunotherapy back in 2001: the idea was to stimulate the body to create antibodies against amyloid with what was essentially a vaccine—but the study had to be stopped because a subset of patients developed meningitis. Then there was enthusiasm about the use of monoclonal antibodies. Several such antibodies have made it to phase 3 trials in which their efficacy was compared to placebo. In 2014, two studies of Bapineuzumab showed no benefit. In 2018, Solznezumab was tried for individuals with mild Alzheimer’s and it was unsuccessful. In the same year, additional negative results were reported for Verubecestat in people with mild to moderate Alzheimer’s.
All these negative studies don’t exonerate amyloid. Maybe the trials are initiated too late in the course of these disease’s development. Maybe the dose is too low. But with anti-amyloid strategies repeatedly striking out, I can’t help but wonder, as have others who know much more about the science than I do, that we’re looking at the wrong target.
Which is why the new study that focuses on tau is exciting. The authors found that their tau antibody test was able to diagnose Alzheimer’s disease as well as or better than more invasive existing tests—when they used the test in patients all of whom had some kind of neurodegenerative disease. That is, the test did well in answering the question: is this person being tested more likely to have Alzheimer’s or, say, Parkinson’s? That’s a very different question from: is this person normal or does he have Alzheimer’s? Not only was the population in which the test was studied composed exclusively of patients with some neurologic condition, not only did the population include a much larger proportion of people with Alzheimer’s than would be found in the general population, but the subjects were far from ethnically or racially diverse. So, it’s a long way from the article in JAMA to a widely useful diagnostic test.
Despite the test’s preliminary nature, it is a compelling piece of evidence that tau should get more attention. Two weeks before the on-line publication of the JAMA study, a small Swiss pharmaceutical company, AC Immune, announced that together with Johnson & Johnson, it was launching a trial of a vaccine designed to stimulate the body to produce antibodies against tau—leading its stock price to soar by 18.9 percent. Just a few weeks earlier, the giant Swiss pharmaceutical company, Roche, announced it, too, was investing in the development of an anti-tau vaccine.
It’s too early to say whether the attack on tau will fizzle, much like the previous attacks on amyloid. But maybe, just maybe, it will be a rousing success.