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Monday, February 6, 2023

A New Dementia Test Raises More Questions Than Answers

A dementia diagnosis usually starts with a family member noticing that something isn’t quite right: a partner becoming forgetful, a normally placid parent losing their temper more often. From there, there are doctor’s appointments—memory and behavior tests that haven’t changed in years, brain scans if the money is there, or one of the battery of new blood tests looking for the biomarkers of brain damage. And then: nothing.

Neurodegenerative diseases like dementia and Alzheimer’s are more feared than cancer and heart disease combined, according to a 2016 survey, and one of the most frightening things about them is how little we still know. There are no cures, and few effective treatments.

So you might question the benefits of a 5-minute test that can assess your risk of getting dementia before you show any symptoms. The Integrated Cognitive Assessment (ICA) test, developed by the British startup Cognetivity Neurosciences, has been granted Food and Drug Administration clearance to be marketed in the United States and is being trialled at several NHS trusts in the UK. But is there any point in taking a test for a disease you can’t do anything about?

The ICA is designed as a “semi-supervised” screening test, says Cognetivity CEO Sina Habibi. It could form part of an annual health check-up for the over-50s, looking for the earliest signs of neurodegenerative disease before they become apparent in behavior. “In the same way you look at blood pressure, you could look at the brain with a cognitive test to see if there’s something malfunctioning,” he says.

An early diagnosis could help people plan ahead and put their affairs in order—but arguably that’s something they should probably be doing anyway. Lifestyle tweaks such as eating less fat, exercising more, or drinking less can also reduce risk, particularly in vascular dementia, which is caused by poor blood supply to the brain and is therefore closely linked to heart health.

The procedure runs on an iPad. A zebra appears onscreen and then disappears, replaced by a railway bridge. There are flashes of beach scenes in black and white, and then a glimpse of an exotic bird, all interspersed with monochrome grids and fuzzy static—a captcha at warp speed. The user’s task is simple: They tap on the right side of the screen whenever they see an animal in one of the pictures, and on the left side when they don’t.

The test, which was spun out of research at the University of Cambridge, is billed as a quick and easy replacement for the pen and paper memory tests often used early in a dementia diagnosis. (In the widely-employed Montreal Cognitive Assessment, for instance, subjects have to name animals from line drawings, read a list of words and repeat them, or copy a drawing of a cube.) The ICA instead uses an AI, trained on patients with early-onset dementia, which combines the subject’s speed and accuracy on the iPad task with information on lifestyle, age, ethnicity, and other factors to calculate a risk score.

Rather than measuring memory or executive function, it aims to assess the raw information processing speed of the visual system, with a test that should work the same regardless of someone’s language skills, cultural background, or education level, according to Habibi. “We’re focussing on the CPU of the brain rather than the hard drive,” he says. It leans on the fact that our visual processing system, when healthy, has apparently evolved to quickly detect animals—hence the zebra—so any slowdown in this process could hint at an underlying problem.

At the end of the test, participants hand the iPad back to their doctor or nurse, who taps in a passcode to gain access to the patient’s risk score from 1 to 100, with anything over 50 indicating an elevated risk of dementia. It’s up to the medical professional how they choose to present that information.

There are concerns that, given the lack of treatment options, widespread use of screening tests may only serve to overwhelm the health system with anxious people who have been told they are at risk of dementia but aren’t yet showing symptoms. “I worry that this will have huge implications for people. There isn’t the infrastructure to fully support families affected by dementia,” says Karen Harrison Dening, head of research and publications at the charity Dementia UK. Already, she says, the NHS often doesn’t have enough money to pay for brain scans for everyone who needs one in the UK. “Where are they going to go for that post-test counseling?” she asks. “We just don’t have the infrastructure—and there is a moral obligation to support them.”

Habibi admits that the question of why someone should take the test comes up in almost every meeting he has with potential investors. “If you ask me, with any problem, the earlier you know the better—at the very high philosophical level,” he says. He and others also argue that recent advances in medical science are changing the equation.

“There have been a lot of developments that make it more likely there will be a benefit of advance diagnosis than there would have been 15 years ago,” says Ivan Koychev, a clinical psychiatrist and researcher at the University of Oxford, who has used the ICA test in research for Dementias Platform, a UK project aimed at speeding up detection.

We know a lot more about the risk factors, for instance, and how to slow down the course of the disease through changes to diet, or by increased socialization. In 2019, research by David Llewellyn at the University of Exeter found that people with a genetic risk of Alzheimer’s disease can suppress it by adhering to a strict lifestyle.

Our understanding of the mechanism of the disease is shifting, too, in a way that could make early diagnosis more valuable. Dementia has a very long preclinical phase—as long as 20 years, in some cases—during which scans and blood tests can detect subtle changes but symptoms have not yet appeared.

Two proteins start to show up in the brains of patients with dementia during this window: tau and amyloid. Researchers have struggled for years to untangle exactly what role they play, but now some think they have an answer. In dementia and Alzheimer’s patients, amyloid forms tangles and plaques in the spaces between brain cells. The theory is that once it builds up to a certain level, it triggers tau protein—which is normally part of the scaffolding of neurons—to convert from a normal to a toxic state. That’s what causes the bulk of the symptoms, by killing cells and interfering with neurons’ ability to send clear signals.

In June 2021, the FDA granted accelerated approval to aducanumab, the first new drug for Alzheimer’s disease in 18 years. It’s designed to stick to amyloid molecules and make it easier for the immune system to clear them out. But it’s a controversial approach, because in the past drug treatments aimed at clearing amyloid have failed to make much of a difference.

In the emerging theory of dementia, however, the timing of the intervention may be critically important. With better early detection, drugs like aducanumab could be given when they still have time to make a difference. “If you remove the amyloid at a very early stage, maybe that’s when the real benefit happens,” says Koychev. If amyloid could be cleared from the brain before it triggers tau to turn toxic, perhaps the worst effects could be delayed or avoided altogether.

Easy-to-use digital tests could be combined with brain scans and blood tests to help researchers build a map of exactly how amyloid and tau proteins correlate with cognitive impairments—and whether clearing them makes a difference. Rather than a blanket approach of screening everyone, Koychev suggests targeting those in the most at-risk groups with regular assessments.

He notes, however, that there is still a lot of disagreement in the field, and there are serious doubts over whether the new drug for Alzheimer’s will work as hoped. But it has reinvigorated research after what Habibi calls a “long period of drought” in a field that has lagged behind cancer in terms of investment and interest from pharmaceutical companies. Dening thinks that is due to a combination of factors—the stigma of the disease, the advanced age of the people who usually get it, and a fatalist “well, that’s just what happens when you get old” attitude.

Things are finally changing as a large and affluent demographic cohort moves into the age bracket where the risk is the highest. Tests like the ICA are targeted at them, but Koychev hopes they will also “democratize access to brain health.”

Because they’re digital and only semi-supervised, they can be taken anywhere you can take an iPad. That means they can reach people who have been left out of traditional studies into the condition, which are often populated by groups of volunteers that don’t accurately reflect the underlying population. They can also be taken more often, to build a picture of an individual’s cognitive performance over time—Cognetivity has a separate iPhone app called OptiMind designed for home-tests that aims to do just that.

We may still lack good treatments for dementia and Alzheimer’s disease, but the ability to detect them earlier could change our attitude toward them, which in itself may improve our understanding and spark investment in the solutions we need. “Brain health will become something people monitor and look after, just as you look after your physical health,” says Koychev.

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