ALS manifests very differently among people who develop the disease. It can occur anytime in adulthood. People usually only live two to five years after diagnosis, but it can range from six months to more than 20 years. Some people living with ALS, about 30 to 50 percent, experience cognitive or behavioural difficulties. Why does the disease affect people so differently?

Dr. Ekaterina Rogaeva, a geneticist at the Tanz Centre for Research in Neurodegenerative Diseases at the University of Toronto, believes the answer may lie in how environmental factors modify DNA as people age. Her research has focused on gene mutations that are associated with movement disorders and dementia, including ALS, Alzheimer’s disease, Parkinson’s disease and frontotemporal dementia.

How environmental factors might modify genes

Aging is the biggest risk factor for developing ALS and other neurodegenerative disorders. We usually count age chronologically, using the number of years since birth, but emerging evidence shows that biological age differs from chronological age. The biological age of our cells may be based on how they have been modified by environmental factors, like exposure to smoking, for example. These environmental impacts can leave marks on DNA without changing its underlying structure in a process called DNA methylation. Using DNA extracted from blood samples, scientists can see the precise locations where age-related DNA methylation occurs and calculate DNA methylation age, which may be an estimate of biological age.

“Most healthy people have a DNA methylation age that is very close to their chronological age,” said Dr. Rogaeva. “But when we look at DNA samples from people recently diagnosed with ALS, we find differences between DNA methylation age and chronological age up to sixteen years.”

Previous insights from studies of identical twins and people with C9ORF72-ALS

Several years ago, Dr. Lorne Zinman observed identical twins with very different disease onset and progression at the Sunnybrook Health Science Centre ALS Clinic. His observation sparked Dr. Rogaeva curiosity to learn more about how this was possible, given that identical twins share almost identical DNA. Together, Dr. Rogaeva, her research associate Dr. Zhang, Dr. Zinman and Dr. Janice Robertson at the Tanz Centre for Neurodegenerative Diseases at the University of Toronto have conducted genetic studies on blood samples from identical twins. In their most recent twin study, one twin had no ALS symptoms but the other had been living with ALS for 17 years, and had a more prominent history of narcotics abuse than the unaffected twin. Overall, they found that the DNA methylation age of ALS-affected twin was five years older than the unaffected twin. Similar findings were observed for another pair of identical twins.

Next, Drs. Rogaeva, Zhang, Robertson and Zinman tested their theory using blood samples from a broader population — 46 unrelated people with the C9ORF72 gene mutation, the most common genetic form of ALS. Again, they found that an accelerated DNA methylation age was associated with an earlier age of onset and a shorter disease progression for ALS and published their findings.

Investigating the theory in sporadic ALS

With an ALS Canada Research Program project grant of $125,000, Dr. Rogaeva will build on these previous discoveries in identical twins and people with C9ORF72-ALS and investigate whether DNA methylation age can also explain differences in disease onset and progression in people with sporadic ALS. Most cases of ALS, about 90 per cent, are sporadic, meaning that they are not linked to an inherited single gene mutation.

Using blood samples and clinical data collected at diagnosis from 250 people with sporadic ALS, Drs. Rogaeva and Zhang will analyze the associations between the signs and symptoms of the disease at diagnosis and DNA methylation levels, including DNA methylation age. If they find accelerated biological age in these samples, they will validate their findings by conducting the same analysis using a large number of DNA methylation profiles collected for Project MinE, a multi-national initiative that aims to sequence and analyze entire DNA profiles collected from 15,000 people living with ALS. ALS Canada is a contributor and is spearheading Canada’s participation in the project.

“My prediction is that accelerated DNA methylation age, as calculated by marks on DNA, is associated with earlier disease onset and faster disease progression,” said Dr. Rogaeva. “From previous work, we know that there are 353 spots within the genome where we can observe DNA methylation age. We will explore whole genomes to see if we can find more spots to add more information for calculating DNA methylation age.”

“If someone were to discuss this concept with me five years ago, I would have said it’s science fiction,” shared Dr. Rogaeva. “But because I can see the link between DNA methylation and ALS in our own dataset and find an association of DNA methylation age with several other neurodegenerative diseases, it reinforces that genetic factors are secondary to age as a risk factor for these diseases.”

It’s important to note that any influence of biological age on ALS is only applicable in those who are susceptible to getting the disease in the first place, likely through a complex set of genetic factors. That said, if DNA methylation age does influence the timing of disease onset and severity of ALS in this broader population of people with sporadic ALS, it may prove to be a valuable tool for further understanding this susceptibility to developing ALS and enable earlier diagnosis, making it possible to treat people with ALS sooner.

This research project is one of 8 research projects funded in 2018 by the ALS Canada Research Program, which is the only dedicated source of funding for ALS research in Canada. The funding of the project followed a rigorous scientific assessment by panels of global ALS experts. The panelists evaluated a larger pool of applications to identify the projects that demonstrate scientific excellence and have the potential to most quickly advance the field of ALS research in order to develop effective treatments.

ALS Canada is a registered charity that receives no government funding. Everything we do – from funding research to providing community-based support for people living with ALS – is possible only because of donor generosity and partnerships with provincial ALS Societies who contribute to the ALS Canada Research Program.

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Posted in: Research