A new study suggests that individuals at risk for rare genetic forms of frontotemporal dementia (FTD) should consider being additionally tested for a common genetic variant in another gene – TMEM106B – known to be protective against disease onset.
FTD is a leading cause of dementia, typically developing in midlife, such as the recent case of famous American actor, Bruce Willis. It can be caused by rare genetic mutations or can occur in the absence of these mutations, that is, it is sporadic in nature.
“We know that rare mutations in mainly three genes can cause genetic FTD, but in combination with this common protective [TMEM106B] variant, the disease may never start, it may come on later, or be more mild,” says Dr. Mario Masellis, principal investigator of the Canadian arm of the international Genetic Frontotemporal Dementia Initiative (GENFI), and a neurologist at Sunnybrook Health Sciences Centre.
“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 FTD. 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.”
Published in the April 22, 2025 issue of the journal Brain, the researchers recommend that this protective variant should be accounted for in clinical trials targeting FTD due to its effect on common outcome measures of brain shrinkage (atrophy), biomarkers of neurodegeneration (such as blood tests and other measurements), and cognition (thinking, learning, memory and reasoning skills) that are assessed in these studies.
This protective variant in gene TMEM106B, rs1990622, was discovered in previous large-scale genome-wide studies, which showed that it significantly reduces risk for those with a particular type of FTD associated with a unique abnormal protein signature in the brain called TDP, and this protective effect was even stronger in individuals with mutations in a gene called GRN. However, researchers never fully understood how this variant worked to protect against disease onset. In this large seven-year study, the investigators examined the interactive effects of this variant in 518 individuals with/or at risk for genetic FTD.
“Our study shows that individuals with two copies of this protective variant (one from each parent), and also to a lesser degree in those with one copy, had less brain shrinkage, less neurodegeneration and less decline in cognition, especially if they carried a GRN mutation,” adds Dr. Masellis, also a scientist in the Hurvitz Brain Sciences Research Program at Sunnybrook Research Institute and a professor in the Division of Neurology, Department of Medicine with the Temerty Faculty of Medicine at University of Toronto. Other key team members who co-led this work include Dr. Saira Mirza, research associate within the Centre for Brain Resilience and Recovery at Sunnybrook Research Institute, and Maurice Pasternak, PhD candidate in the Institute of Medical Sciences at the University of Toronto.
“Knowledge of the natural progression of both genetic and sporadic FTD and the identification of factors that modify its course are crucial for the effective development of novel therapeutics, ideally during the stages between the appearance of initial symptoms and their full development or even earlier, before irrecoverable brain damage has occurred. This common protective variant should be accounted for as it can and will skew research results, leading to either false positive or false negative findings in clinical trials. This work is guiding us to precision medicine in action as therapeutic strategies may arise from exploiting protective genetic mechanisms.”
Approximately one-third of individuals with FTD inherit it from their parents. The genetically-inherited forms of FTDare a rare group of heterogeneous neurodegenerative disorders causing a younger onset of dementia that comes with profound changes in behaviour and language abilities, significantly impacting individuals and their families in the prime of their lives; often when they may have young children and are still working.
While there are currently no approved disease-modifying therapies for genetic FTD, several drug candidates are being evaluated in clinical trials.
Dr. Masellis’ research was supported by grants from the Canadian Institutes of Health Research (CIHR) project grants and the Weston Brain Institute.