Photo by Naeblys
Long before she became a neurogeneticist at Cardiff University, Dr Rebecca Sims was acutely aware of the pain Alzheimer’s disease can wreak on families.
“My grandfather had Alzheimer’s, so I’ve seen the devastation of somebody living with the disease,” she says. “I’ve got friends as well whose family members have had other dementias.”
Sims herself has completed the largest ever genetic study of Alzheimer’s, an international collaboration which reported in April 2022. The Cardiff research mined the genomes of more than 100,000 people around the globe – who either have the disease or had a parent who suffered from it – for tell-tale clues which point to why they were susceptible.
All of which makes Sims perfectly placed to answer a particularly thought-provoking question – if there was a test which could tell you whether you were going to develop Alzheimer’s or not, would you take it?
Her own answer is a resounding no. This is largely because the disease remains incurable, despite many decades and billions of pounds of research investment. “It’s been in my family, but I don’t think I’d want to know,” she says. “At the moment, I wouldn’t see the benefit, if I’m honest. There’s nothing in place which would help me with that, so I think it’s better to just live your life and not worry about that too much.”
But as the population ages, the question is becoming more pressing. Our growing understanding of the genetic and environmental risk factors for Alzheimer’s is making it increasingly viable to predict whether someone will develop the disease.
Alzheimer’s experts say that research has more than doubled the number of gene variants known to be associated with the disease, improving the accuracy of so-called polygenic risk scores which can be used to inform people about their potential of developing Alzheimer’s.
There are currently no predictive tests for Alzheimer’s available on the NHS. But private tests are available, including saliva tests offered by the genetic testing company 23andMe. These attempt to provide a percentage likelihood by looking at whether individuals possess certain variants of gene called APOE, which has been heavily linked with the disease.
However, the new information discovered in research such as Sims’s could make such forecasts far more accurate in years to come, though scientists are wary about giving a timeframe.
“We now have a total of 94 validated Alzheimer’s disease genes,” says Rudolph Tanzi, professor of neurology at Harvard Medical School. “We and others are trying to use all the Alzheimer’s disease genes as well as whole genome sequencing data from Alzheimer’s patients and family, with the goal of developing a reliable polygenic risk score for Alzheimer’s, beyond just APOE.”
Some people, who have had to care for close family members with the disease, feel that knowing such information could be beneficial as it would make it far easier to make certain life decisions at an earlier stage.
“I had to spend the best years of my life with both parents suffering from dementia, which was hell,” says Cheryl Gearhart, a 56-year-old designer. “They had no plan for retirement, care or wills. If such a test was available for everyone, it would help them plan their future.”
Medical ethicists draw some parallels between knowing you are at high risk of Alzheimer’s and Huntingdon’s disease, an incurable neurological disorder caused by a single gene defect which can be diagnosed even before birth. Individuals with Huntingdon’s begin to develop symptoms between the ages of 30 and 50.
“If somebody has the gene for Huntington’s disease, they have a similar or worse prognosis than for Alzheimer’s,” says Dominic Wilkinson, professor of medical ethics at the University of Oxford. “What we know from that is that there are some people who do want to know that information for planning their life. Do they save up for a pension or spend their savings on travelling the world? But it’s important that people are aware of what they’re letting themselves in for before taking a test that might reveal such information. Some might want to live their life without having a Sword of Damocles hanging over them.”
One of the additional complexities of Alzheimer’s is that genetic factors only represent 60-80 per cent of the risk for the disease. This means that no genetic test could ever be 100 per cent accurate. Environmental components such as whether someone remains sufficiently cognitively stimulated into old age, as well as diet, smoking, exercise and even loneliness, represent significant contributing factors towards the disease.
“It’s a complicated picture,” says Sims. “If you’ve got a high genetic risk of the disease, does that mean you’re going to get Alzheimer’s? The answer is no, because if you’ve got environmental factors that protect you, they can alleviate the cumulative effect of the genes. And vice versa: you can be at low risk genetically, but have some really high environmental risk factors in your life.”
At the moment, our understanding of the genetic landscape of the disease is predominantly based on white Caucasians, meaning that such tests could be less accurate in people of different ethnicities. However, scientists like Sims and Tanzi are working on developing gender-specific and ethnicity-specific tests which also incorporate environmental data, for example whether a person is a lifelong smoker or not.
Sims believes that this additional information, combined with the levels of certain protein biomarkers in the cerebrospinal fluid – the colourless liquid in your brain and spinal cord – could one day lead to a test which can predict Alzheimer’s risk with an accuracy of more than 90 per cent.
“If we get to the point where we’re combining those different datasets, we might well be able to be more certain in our accuracy with regards to predicting who’s going to get the disease,” she says.
But whether such a test became available on the NHS would depend on whether it could provide clinical benefit, enabling doctors to begin treatment to prevent or slow the progression of the disease.
Many Alzheimer’s experts argue that one of the reasons scientists have struggled to find medicines for the disease is because it is typically treated too late, once neurodegeneration has already set in. If tests can enable us to identify at-risk patients many decades earlier, treatments which attempt to prevent the accumulation of toxic proteins in the brain may well be far more effective.
“I believe that viable treatments are coming and then widespread testing will take off,” says Colin Masters, an Alzheimer’s researcher at the University of Melbourne. “We are looking to use an antibody therapy called aducanumab in patients with preclinical Alzheimer’s to try to prevent the onset of symptoms.”
The new genetic variants identified in Sims’s study have also provided a number of new potential treatment targets for the disease which may have been overlooked in the past. Immune cells called microglia, which are involved in the structuring and wiring of the brain, as well as how the brain handles inflammation, appear to be more heavily implicated in Alzheimer’s than previously thought.
“What the study showed us is that Alzheimer’s is not just about problems with toxic proteins accumulating in the brain, it is also a lot to do with how the brain fights inflammation and attack,” she says.
If some of these discoveries can be used to develop treatments for the disease, Sims says she might reconsider taking an Alzheimer’s test herself.
“If things changed and we got to a point where there were treatment options, I would take the test and I’d potentially take preventative medicines before getting symptoms,” she says. “But we’re not there yet.”