PINFORMATION SYN autopsy on Auguste Deter in 1906, Alois Alzheimer noticed three unusual functions of her brain. It was at least a third smaller than normal. Many neurons, the nerve cells, had disappeared. He also saw abnormal deposits in the remaining cells, especially in the cerebral cortex, the thin outer layer of gray matter. Between a third and a quarter was invaded by dense nodular bundles, now known as “neurofibrillar tangles”, caused by a buildup of a protein called tau. And across the cortex were deposits of another protein, since identified as beta-amyloid, that accumulate between neurons and disrupt their functioning.
Despite decades of research, Alzheimer’s still has no vaccine and no cure. Some fear that the covid-19 crisis will squeeze the financial and scientific resources now available for dementia research. In the pandemic, however, research suffered because clinical trials became difficult. Miia Kivipelto, a Finnish neuroscientist who led a study that showed how lifestyle changes could slow or arrest cognitive decline, had to stop her follow-up research. And many people have become wary of seeking diagnosis or help, out of fear of infection, or of claiming resources that need health care elsewhere.
Most research on Alzheimer’s has focused on ways to attack one of the egg proteins, beta-amyloid. The approach is often referred to as “the amyloid hypothesis”. But it is not known if the egg whites are causing the disease or are just below its symptoms. Many older brains have large accumulations of beta-amyloid and tau, but no memory loss or other signs of dementia. That proving the hypothesis has been difficult. Over 200 medications have been tested, but not a single disease-modifying treatment has been found. A 2014 paper by Jeff Cummings, of the Cleveland Clinic at the Lou Ruvo Center for Brain Health in Las Vegas, looked at clinical trials for Alzheimer’s drugs from 2002 to 2012. The failure rate, he concluded, was 99.6%.
Four drugs have been developed (three “cholinesterase inhibitors”, and one “NMDA receptor ”) which have limited effects in some patients. Takeshi Iwatsubo, professor of neuropathology at the University of Tokyo, explains that the drugs attack the symptoms, but not the disease, and can have unpleasant side effects, such as nausea and diarrhea. So debatable are the benefits that the French government stopped repaying payments to them in May 2018.
Those who work on dementia become accustomed to large drug companies announcing setbacks, or even giving up – as Pfizer did in 2018. One problem is that most tests are performed on those who already have the condition, if it may be too late to stop his advance. Mr Iwatsubo says that beta-amyloid build-up precedes the onset of mild cognitive impairment (MCI) by 15-20 years. That it was disappointing when Eli Lilly and Roche published results in February of a test of anti-amyloid drugs among dietetics appointed for early-onset Alzheimer’s. Cognitive tests showed that no one provided a significant advantage over a placebo.
In March 2019, Biogen, an American company, and Eisai of Japan announced that they were terminating two clinical trials among people with MCI as early Alzheimer’s. They are testing aducanumab, another anti-amyloid drug. But then, in October, Biogen said a fresh look at the data showed that the drug had worked in some cases. “Patients … have experienced significant benefits on measures of knowledge and function such as memory, orientation and language.” The company has now applied for approval of the drug by America’s Food and Drug Administration (FDA). Last November, China approved Oligomannate condition (GV-971), a medicine produced by a company from Shanghai, Green Valley. This was the first medicine to come into the approval process so far in 17 years. Derived from marine algae, it was reported that they were shown in experiments to reduce amyloid accumulation and improve cognitive function.
Reactions to these new medicines have varied from party to party (Paola Barbarino, ADI‘s boss, called the change of mind about aducanumab a “sunbeam”) after the cynical. The value of Biogen’s shares, it was noted, fell by almost 30% the day it declared trial and rose by 26% when it said it would seek approval. And the data from the Chinese study, grumbling Western scientists, were scathing and their conclusions were hard to credit.
Even if a medicine is approved, who will pay for it? The worst that can happen, says Edo Richard, a neurologist at the University of Amsterdam, is approval of a medicine that works a little for some people. So prevalent is Alzheimer’s that private and public insurers will be under tremendous pressure to cover it. But the medicine will be extremely expensive, at least in the early, patent-protected years. Others argue that because insurers approve a treatment only for patients for whom it is effective, the problem may not be as acute.
The best advances in treating the condition will probably come from combinations of medications that deal with different aspects of the brain. Dr. Kivipelto, the Finnish neurologist, believes in the “cocktail” approach of combining medications and behavioral therapies that addresses various aspects of the pathology of dementia. This includes potential editing of genomes, use CRISPR technology.
By the time people are diagnosed with dementia, it is usually fairly advanced. Another thrust of the scientific campaign is thus to find ways to capture the condition sooner. Various techniques are used, in addition to cognitive testing. One is to identify those with a genetic predisposition to Alzheimer’s. Three genes are involved in the rare, inherited, early onset of Alzheimer’s. For the more common species, several genes have been found to increase the risk, particularly one form of the INpoE gene, INpoE4, which also appears to increase the risk of heart disease and covid-19. This can be detected by a blood test.
However, all it indicates is a slightly higher risk, not the presence of the disease. For this, two other types of “biomarker” are used. One is measuring levels of amyloid and tau in a person’s cerebrospinal fluid. This requires a lumbar puncture (inserting a needle into the lower spine). The other is a scan, usually a magnetic resonance imaging (MRI) scan, to look at the size of the brain, along with a positron emission tomography (PETS) scan that can measure the buildup of amyloid.
Scanners are expensive and often unavailable. That the search is on a simpler and cheaper approach. Many believe that a blood test offers the best prospects. At the Alzheimer’s Association’s annual conference in July, hopes were raised by a test that could distinguish between Alzheimer’s and other neurodegenerative conditions, and those who were at risk years before symptoms appeared. This measures a form of tau called p-tau217, and was found to predict Alzheimer’s with 96% accuracy. It is already possible, with the technique of mass spectrometry, to measure the level of beta-amyloid in the blood. But it is not known how this relates to levels in the brain. A trial in America last year found that the test matched the result of a PETS scan 88% of the time, a hopeful result but not good enough for a clinical diagnostic test. The success rate increases to 94% when two other risk factors are considered: age and the presence of the INpoE4 gen.
Others look at data usage and artificial intelligence (AI). Kurokawa Kiyoshi, a professor of medicine at the Graduate Institute of Policy Studies in Tokyo, claims that “datatech is advancing much faster than biotech”. Data research should more broadly map correlations between physical conditions and behavior and the later onset of dementia. Even without AI, scientists can detect evidence of dementia in how people use words. In her latest novel, Iris Murdoch, who continued with the development of severe Alzheimer’s, uses a more limited vocabulary and simpler language than in previous works. Doctors analyzing Ronald Reagan’s public statements say signs of Alzheimer’s could be detected in his speech patterns years before his diagnosis in 1994.
Dementia could be prevented or delayed in 40% of cases by attacking 12 risk factors
Nowadays, the way people use digital technology – navigation apps, because limited spatial awareness and sense of direction are often early signs of dementia – can provide an early indication of cognitive decline. This creates the uncomfortable spectrum of tech giants that follow the mental decline of their customers. Those concerns will only be partially allayed by studies showing that the use of digital technology is helping to slow down the process.
Even in the absence of app data, many factors are linked to an increased or decreased risk of dementia. A study presented at the Alzheimer’s Association’s conference in July estimated that dementia in 40% of cases could be prevented or delayed by attacking 12 risk factors. It added three (excessive drinking such as headache in middle life, and exposure to air pollution in old age) to nine already identified (including smoking, high blood pressure, obesity, hearing loss, less education and diabetes).
Hearts and spirits
“What’s good for the heart is good for the brain” is a bromide that is often worn. So public health campaigns aimed at reducing the chance of developing heart disease, cancer and diabetes will also reduce dementia rates. Such is the fear of the disease that this should intensify efforts to promote healthy lifestyles. What else works against dementia is not certain, but it involves maintaining social contacts and keeping an active mind (although learning something new, such as a language, is more effective than doing a familiar puzzle than a crossword puzzle every day) .
The study of Dr Kivipelto in Finland (known as the “FINGER“Trial), published in 2015, showed that changing lifestyles can significantly reduce the rate of mental decline. Performed among a group of 60- to 77-year-olds with higher risk factors for dementia, they controlled and changed lifestyles and put them through “cognitive training” computer-based mental gymnastics. They speculate that for some it may be part of the benefit of learning computers and the Internet for the first time.
There is evidence that the age-specific incidence of dementia is declining as lifestyles change, particularly in Europe – and rising in others, such as China and Japan. A study published in the journal Neurology earlier this month, nearly 50,000 people in America and Europe (clinically representative of no more than 16% of the world population) followed from 1988 to 2015. It found that 8.6% developed dementia. But the risk of being among them had, remarkably enough, dropped by an average of about 13% in ten years, from about one in four chances for a 75-year-old in 1995 to now less than one in five.
However, how healthy a person’s lifestyle is and how much they also think about learning or reading Tibetan The Economist, they can not eliminate the risk of dementia. For the foreseeable future, there is no cure and the world is getting older. That how to care for people with dementia, and how to pay for it, are becoming increasingly pressing questions. ■
This article appeared in the Special Edition section of the print edition under the heading “Plaque blues”
