Have We Been Barking Up the Wrong Tree?

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.

What's the Risk?

Nearly six months into the pandemic, we ought to know the important risk factors for serious illness or death from Covid-19. Whether because of poor record-keeping, lack of international cooperation, or sloppy statistical analysis, the information until now has been limited. 

Not just limited; the claims about risk factors to date have been quite misleading. I complained in my blog post in early May that the rates of certain conditions in patients dying of Covid-19 were actually no different from the rates of those same conditions in older people in general. For example, I noted that one study reported that the rate of high blood pressure in patients with severe cases of Covid-19 was 56.6 percent—but failed to comment that the rate of high blood pressure in the elderly population is 60 percent. Far from indicating that high blood pressure increases the likelihood of severe Covid-19 in older adults, this finding suggests that high blood pressure confers no extra risk or maybe is even protective. 

The only consistently observed risk factor for both severe illness and death has been older age, with age greater than 80 representing very high risk. Now, thanks to the existence of widespread, compatible electronic medical records in the British National Health Service (NHS), we have some useful data.

The study, published early on line in Nature Reviews, compares British patients who died of Covid-19 with all other British patients who are cared for in a group practice that used the necessary software (approximately one-third of the population). By using “a secure analytics platform inside the data centre of major electronic health records vendors, running across the full live linked pseudonymised electronic health records,” and after excluding people under age 18 and those with less than a year's worth of data, the investigators were able to collect health information on over 17 million individuals, including just under 11,000 with Covid-19 related deaths. The results confirm age as the single most potent risk factor, with a small number of other major risks.

To capture the most striking findings, I extracted data from the chart listing the hazard ratios (HRs) and 95% confidence intervals (CI) for Covid-19 death (Table 2) and present 3 separate tables: one highlighting very high-risk characteristics, one highlighting high-risk characteristics, and one showing characteristics associated with no or minimally increased risk. For added emphasis, I highlighted hazard ratios of greater than 3 in red and hazard ratios between 2 and 3 in blue.

Characteristics Associated with Covid-19 Deaths

The important difference between these charts and previous attempts at quantifying risk is that the hazard ratios reported have been age and sex-adjusted and have been further adjusted for other potential confounders along with age and sex.  

The conclusion from this analysis is that when we consider the age- and sex-adjusted hazard ratios, there are only four very high-risk conditions: old age, a hematologic malignancy diagnosed within the previous year, severe kidney impairment, and organ transplantation. Within the old age categorization, the hazard ratio goes from 8.62 to 38.29 as the age increases from 70-79 to 80 and older (the reference group is people aged 50-60). The only medical condition that comes close to this magnitude is organ transplantation, with a hazard ratio of 6. 

Another handful of conditions are in what I have classified as high-risk: obesity with a BMI of 40 or greater, poorly controlled diabetes, stroke or dementia, a hematologic malignancy diagnosed between 1 and 5 years earlier, liver disease, and other forms of immunosuppression. Incidentally, four out of six of these conditions drop out if we look at the “fully adjusted” column.

It’s worth noting some of the chronic conditions that were not associated with increased risk. High blood pressure, as I had previously suggested by comparing the rate in the very ill Covid-19 patients with the rate in the general older population, does not appear to be a risk factor. Mild to moderate asthma, defined in this study as someone with asthma who did not use oral steroids within the previous year, is also not a risk factor.

It’s also worth noting that the CDC has issued its own guidance about risk factors for Covid-19. Their conclusions, while overlapping with the NHS data, differ in important ways. Most important, their methodology differs. The CDC, lacking a domestic large, comprehensive data base, is forced to draw on evidence from small case series, cohort studies, and some meta-analyses, as well as a much earlier preliminary report from the NHS. The new NHS data, rigorously obtained and meticulously analyzed, should be seen as the gold standard.

When Will We Ever Learn?

Residents of long-term care facilities in the US have been hit harder by the COVID-19 pandemic than have any other group. They have almost all the known risk factors for becoming seriously ill with the disease: they are unambiguously old, with fully 41 percent over age 85, and almost all have one or more chronic diseases, generally multiple conditions that result in their needing personal care. To top it all off, they live in close proximity to one another, typically eating together in a common dining room and often sharing a room with another resident. As a result, nursing home residents account for at least one-third of U.S. COVID-19 deaths. In some states, such as Massachusetts, estimates by early May were that nursing home residents accounted for 60 percent of COVID-19 deaths. 

We learned from the devastating early experience with COVID-19 how to keep the corona virus from causing havoc in nursing homes. In particular, we came to understand the importance of protecting nursing home residents from staff members who might bring it into the facility. By testing staff regularly and mandating head to toe personal protective equipment, together with other draconian measures such as banning family visitors and restricting resident-to-resident interaction, the rate of illness, hospitalization and death among nursing homes residents plummeted. Now that the virus is again surging in the Sunbelt, with Florida, Arizona, and Texas reporting skyrocketing infection rates, how are nursing home residents faring in those areas?

The answer, in a word, is not well. The Florida Department of Health reported 3072 active cases in nursing homes and assisted living facilities as of July 13, up from 1408 on June 23. The rate had nearly doubled in two weeks.  Houston saw an 800 percent increase in cumulative new cases among nursing home residents between the end of May and the end of June—and Texas has more nursing homes than any other American state. 

Why is this happening? Only in mid-July did Florida announce it would test nursing home staff regularly. The government defined regularly as every other week—not likely to be often enough—but many facilities report no testing has taken place as yet. Phoenix nursing homes report a shortage of personal protective equipment, with 25 percent of facilities acknowledging they have only one week’s worth of masks, gowns, and gloves on hand for nursing assistants and other direct care personnel. 

So far, death rates have not soared the way they did in New York during the height of its outbreak, but they are beginning to rise. As epidemiologists point out, death is a “lagging indicator:” people first get sick, then some of them become sick enough to require hospitalization; next, some are admitted to the ICU, and then, over a period of weeks, the deaths start coming. The outbreaks began with younger people who ignored public health recommendations to wear masks, limit group gatherings (especially indoors), and maintain physical distance from others. Florida, Texas, Arizona, and other hot spots did not engage in a vigorous campaign to test people with symptoms, to isolate anyone with an infection, and to quarantine exposed individuals. The result was community spread. At that point, the outcome for nursing home residents is entirely predictable. Once COVID-19 is widespread in the community, it is going to make its way into nursing homes, carried by asymptomatic or minimally symptomatic staff members who do not wear adequate protective gear. And vulnerable older people who are dependent on staff members to go to the bathroom, to eat, to dress, and to bathe will themselves become ill. More and more of them will become very sick and many will die. 

States that experienced a major outbreak early in the course of the pandemic—in late March and much of April—learned through experience that in the absence of a vaccine or effective treatment, old-fashioned public health methods are the only scientifically sound and morally defensible way to act. The invasion of nursing homes has no doubt already begun in the states with soaring case rates; every hour of delay in instituting the only measures that we have just demonstrated can succeed will result in more viral transmission, more suffering, and more death.