Healthcare (Commonwealth Union) – A new study recommends that individuals at risk for rare inherited forms of frontotemporal dementia consider genetic testing for a common variant that may offer protection against the condition.
Frontotemporal dementia, a major cause of dementia that often emerges in midlife, can result from rare genetic mutations or arise without a clear hereditary link.
Dr. Mario Masellis, neurologist at Sunnybrook Health Sciences Centre and professor at the University of Toronto’s Temerty Faculty of Medicine pointed out that they know that mutations in three specific genes are linked to genetic frontotemporal dementia. He indicated however that when these mutations are paired with a common protective variant in the TMEM106B gene, the disease may never develop—or it may be delayed or present with milder symptoms.
Dr. Masellis is the principal investigator of the Canadian arm of the international Genetic Frontotemporal Dementia Initiative.
“It is important to take into consideration this protective variant when an individual is involved in a clinical trial or when someone is considering finding out their genetic mutation status for frontotemporal dementia. This is particularly important if they come from a family with a known genetic cause, since the presence of two copies of this protective variant will alter risk and can modify outcomes of research investigations.”
In a study appearing in the journal Brain, scientists recommend that future clinical trials for neurocognitive disorders take into account a specific protective genetic variant. This is because the variant can influence key outcomes typically measured in such research, including brain atrophy, blood-based biomarkers of neurodegeneration, and cognitive function.
This protective variant had been previously identified through large genome-wide association studies, which found it offered protection against a particular form of the disease marked by a distinct abnormal brain protein known as TDP. The variant appeared to be especially beneficial in individuals with mutations in the GRN gene. However, the biological mechanism behind its protective role had remained unclear.
In the latest research, scientists analyzed this variant in 518 participants who either had or were at risk for developing genetic frontotemporal dementia.
Dr. Masellis, who is also a researcher with the Hurvitz Brain Sciences Research Program at Sunnybrook Research Institute stated that their findings reveal that people who inherited two copies of the protective variant—one from each parent—and, to a lesser extent, those with just one copy, experienced slower brain shrinkage, reduced neurodegeneration, and better preservation of cognitive abilities. This effect was particularly noticeable in individuals carrying a GRN mutation.
The research was jointly led by Saira Mirza, a research associate at the Dr. Sandra Black Centre for Brain Resilience and Recovery at Sunnybrook, and Maurice Pasternak, a PhD student at the Institute of Medical Sciences within Temerty Medicine.
Researchers of the study pointed out that around one in three individuals with frontotemporal dementia (FTD) inherit the condition from a parent. Although these inherited forms are relatively uncommon, they tend to lead to earlier onset and cause severe disruptions in behaviour and language, deeply affecting individuals and their families during the most active years of life.
At present, there are no approved treatments that can alter the course of genetic frontotemporal dementia. However, a number of potential drugs are currently undergoing testing in clinical trials.
The authors explained that understanding how both genetic and sporadic frontotemporal dementia progresses—and identifying factors that influence its course—is essential for developing new treatments, especially in the early stages before significant brain damage occurs.
They further indicated that a common protective variant must be considered, as it can distort research outcomes and lead to misleading results in clinical trials. The authors further indicated that their findings are a step toward precision medicine, where therapies could be designed to harness the brain’s own protective genetic mechanisms.
