Major genetic risk factor for rare form of dementia identified

Researchers at VIB and Antwerp University have identified a major genetic risk factor for a rare form of frontotemporal dementia. The discovery, published today in Nature Genetics, provides a biological entry point for a disease subtype that has been difficult to study. It could not only help to improve diagnosis and patient stratification, but also opens up new avenues toward targeted treatments.

Frontotemporal dementia or FTD is less common and less widely known than Alzheimer’s disease, yet it is a leading cause of dementia at younger ages. It affects the brain regions involved in behavior, personality, decision-making, and language. As a result, early symptoms often include changes in social conduct, loss of empathy, impulsivity, or language difficulties, sometimes long before memory problems become obvious. Prof. Rosa Rademakers (VIB-UAntwerp Center for Molecular Neurology) has built her career on mapping the genetic underpinnings of different forms of frontotemporal dementia.

“Frontotemporal dementia often strikes when people are still professionally active. Because early symptoms can look like ‘personality changes’ or stress, the road to diagnosis can be long, and along the way careers and relationships can be damaged,” says Rademakers.

One specific form of the disease, known to specialists as aFTLD-U, is characterized by atypical frontotemporal lobar degeneration and the presence of ubiquitin-positive inclusions, a pathological signature that distinguishes it from other FTD subtypes. Patients present with behavioral issues as early as in their thirties or forties, but a definite diagnosis is only possible at autopsy.

“Because this subtype is so rare, it has historically been difficult to study at scale. Yet, distinguishing it is increasingly important, since different FTD subtypes may respond differently to therapies,” says Rademakers.

Her plan to look for genetic drivers of aFTLD-U was met with skepticism by some, because this particular form of the disease is sporadic, meaning that there is no family history of the disease. She persisted, and in 2022, was awarded the one-million euro Generet Prize for Rare Disease Research (managed by the King Baudouin Foundation) to uncover the genetic cause and disease mechanisms of aFTLD-U.

A global gene hunt

It took years of international teamwork to collect samples from enough patients with this rare subtype to build a dataset strong enough to reveal clear genetic signals. Thanks to Rademakers’ growing collection, combined with advances in sequencing technology, the team has now been able to identify a new major risk factor.

“First, we ran a genome-wide association study in 59 pathologically confirmed aFTLD-U cases and thousands of controls. Next, long-read sequencing data enabled us to identify a repeat expansion in an intron of GOLGA8A,” says Dr. Wouter De Coster, postdoctoral researcher in Rademakers’ lab.

In their study, the research team found that the repeat shows variation in repeat length and in the composition of the repeating sequence. Importantly, certain longer expansions were strongly associated with aFTLD-U.

More and more repeat expansions have been linked to different diseases over the past few years, but this one is the first to involve a repeat of only two nucleotides.

“Long read sequencing proved crucial to uncover and characterize the repeat,” De Coster says. “With short-read sequencing, you often can’t resolve what’s going on in complex genetic regions like GOLGA8A, of which we all have dozens of copies, not even if you already know what you’re looking for. Our strong expertise in long-read sequencing really made the difference here.”

De Coster also emphasizes just how striking the genetic signal was: “We rarely see an association of this strength. Even in much larger studies of common disorders, signals typically aren’t this pronounced. Here, the data point to an unusually strong risk contribution.”

New questions and new hope

While the functional consequences of this novel repeat are not yet fully understood, its presence in nearly 60% of aFTLD-U cases points to a fundamental role in disease biology. The lab is now investigating what this repeat does at the molecular level, and how it might affect gene regulation and cellular processes in vulnerable brain regions.

The researchers realize the newly identified repeat does not tell the whole story.

“We see this risk factor as a kind of prerequisite for disease in a large fraction of patients,” explains Rademakers. “We suspect other aFTLD-U patients may have a similar underlying genetic risk we simply haven’t found yet, perhaps in other difficult-to-analyze parts of the genome. We also do not know why some carriers get sick while others do not. Despite the many open questions, it is important to realize that, for the first time, we now have a strong foothold on the underlying biology, which is essential for moving toward targeted therapies.”

The finding also carries a broader message for any disease today labeled as sporadic. Even without a clear family history, there can still be a substantial genetic contribution. We should see this as good news, says Rademakers, because identifying a concrete genetic factor can enable earlier and more precise diagnosis and may ultimately support therapies that target the underlying mechanism.