Summary: Frontotemporal dementia (FTD) is a devastating condition that often strikes during a person’s peak professional years, causing personality shifts and behavioral issues long before memory loss appears. A specific, rare subtype known as aFTLD-U has been notoriously difficult to study because it appears “sporadically” with no family history.
However, researchers have made a breakthrough by identifying a major genetic risk factor: a repeat expansion in the GOLGA8A gene. Found in nearly 60% of cases, this genetic signal is unusually strong for a sporadic disease, providing the first real “biological entry point” for developing targeted treatments for this rare form of dementia.
Key Facts
- The GOLGA8A Connection: Using advanced long-read sequencing, researchers identified a “repeat expansion” (a repeating sequence of DNA) in the GOLGA8A gene as a primary driver for the aFTLD-U subtype.
- Unusually Strong Signal: While most sporadic diseases have weak genetic associations, this repeat expansion was found in the majority of patients, making it a “prerequisite” for the disease in many cases.
- Early Onset: This specific form of FTD typically presents in a patient’s 30s or 40s, often leading to misdiagnosis as stress or psychiatric issues.
- Diagnostic Breakthrough: Because aFTLD-U could previously only be confirmed via autopsy, this genetic marker offers hope for earlier, more precise diagnosis in living patients.
source: VIB
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.”
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 scepticism 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 labelled 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.
Key Questions Answered:
A: This is the study’s big “revelation.” Even “sporadic” diseases—those that don’t seem to run in families—can have a massive genetic component. In this case, it’s a specific “stutter” in our DNA (a repeat expansion) that we all have, but in these patients, it’s much longer. It’s not necessarily “inherited” in the traditional sense, but it is built into the patient’s biology.
A: Unlike Alzheimer’s, which usually starts in the memory centers (hippocampus), FTD targets the frontal and temporal lobes. These are the areas responsible for social conduct, empathy, and decision-making. That’s why the first signs are often impulsivity or a loss of “social filters,” which can be devastating for careers and relationships.
A: Not quite yet for the general public, but this discovery makes a diagnostic test possible. Identifying this repeat expansion in nearly 60% of cases means doctors could eventually use a blood test to confirm this specific subtype while the patient is still alive, rather than waiting for an autopsy.
Editorial Notes:
- This article was edited by a Neuroscience News editor.
- Journal paper reviewed in full.
- Additional context added by our staff.
About this dementia and FTD research news
Author: Gunnar De Winter
Source: VIB
Contact: Gunnar De Winter – VIB
Image: The image is credited to Neuroscience News
Original Research: Open Access.
“A repeat expansion in GOLGA8A is a major risk factor for atypical frontotemporal lobar degeneration with ubiquitin positive inclusions” by Wouter De Coster, Marleen Van den Broeck, Matt Baker, Nikhil B. Ghayal, Sarah Wynants, Anthony Batzler, Cyril Pottier, Sara Alidadiani, Fahri Küçükali, Gregory D. Jenkins, Rafaela Policarpo, Marka van Blitterswijk, Mariely DeJesus-Hernandez, Alexandra I. Soto-Beasley, Júlia Faura, Elise Coopman, Saskia Hutten, Merel O. Mol, David Wallon, Anne Sieben, Elizabeth C. Finger, Melissa E. Murray, Shelley L. Forrest, Maria C. Tartaglia, Claire Troakes, Jeroen G. J. van Rooij, Aivi T. Nguyen, R. Ross Reichard, Natalie L. Woodman, Alissa L. Nana, Sandra Weintraub, Tamar Gefen, Bart De Vil, Istvan Bodi, Oscar L. Lopez, Susana Boluda, Serge Belliard, Florence Lebert, Florent Marguet, Qinwen Mao, Marsel M. Mesulam, Adam L. Boxer, Mathieu Vandenbulcke, EunRan Suh, Jolien Schaeverbeke, Jean-Charles Lambert, Sonja W. Scholz, Clifton L. Dalgard, Bryan J. Traynor, Raphael J. Gibbs, Gerard D. Schellenberg, Dorothee Dormann, Geert Joris, Tim De Pooter, Peter De Rijk, Svenn D’Hert, Jasper Van Dongen, Julie van der Zee, Mojca Strazisar, Marla Gearing, Thomas Kukar, Margaret Flanagan, Sebastiaan Engelborghs, Bernardino Ghetti, Kathy L. Newell, Andrew King, Sigrun Roeber, Howard J. Rosen, Salvatore Spina, Patrick Cras, Nilüfer Ertekin-Taner, Zbigniew K. Wszolek, Ryan J. Uitti, William P. Cheshire, Wolfgang Singer, Jochen Herms, Keith A. Josephs, Jennifer L. Whitwell, Ronald C. Petersen, Florence Pasquier, Gaël Nicolas, Rudolph Castellani, Jonathan Glass, Bruce L. Miller, Gabor G. Kovacs, Robert A. Rissman, Annie Hiniker, Vincent Deramecourt, Lee-Cyn Ang, Jin Lee-Way, Vivianna M. Van Deerlin, Brittany N. Dugger, Dietmar R. Thal, Lea T. Grinberg, Carlos Cruchaga, Thomas Arzberger, David G. Munoz, Julia Keith, Lorne Zinman, Ekaterina Rogaeva, Edward B. Lee, Stephen J. Haggarty, Olaf Ansorge, Masud Husain, Glenda M. Halliday, Safa Al-Sarraj, Owen A. Ross, Kristel Sleegers, Rik Vandenberghe, Bradley F. Boeve, Neill R. Graff-Radford, Julia Kofler, Charles L. White III, Tammaryn Lashley, Manuela Neumann, Joanna M. Biernacka, William W. Seeley, Harro Seelaar, John C. van Swieten, Jonathan D. Rohrer, Dennis W. Dickson, Ian R. A. Mackenzie & Rosa Rademakers. Nature Genetics
DOI:10.1038/s41588-026-02537-7
Abstract
A repeat expansion in GOLGA8A is a major risk factor for atypical frontotemporal lobar degeneration with ubiquitin positive inclusions
Atypical frontotemporal lobar degeneration with ubiquitin-positive inclusions (aFTLD-U) is neuropathologically characterized by aggregation of the FET family of proteins and clinically manifests as sporadic young-onset frontotemporal dementia.
Here we describe a major risk locus on chr15q14 identified through a genome-wide association study in 59 pathologically confirmed aFTLD-U cases and 3,153 controls (lead single nucleotide polymorphism rs549846383, P = 5.85 × 10−21, odds ratio 26.7).
When combined with data from 28 additional aFTLD-U cases, 3,712 controls and 3,215 individuals with other neurodegenerative diseases and by leveraging in-house and public long-read genome sequencing data from 1,715 individuals, we identified a tandem repeat expansion on the associated haplotypes in an intron of GOLGA8A.
We found variation in repeat length, motif length, and motif sequence, with long CT-dimer expansions strongly associated with aFTLD-U. Although the functional consequence of this repeat remains unknown, its presence in nearly 60% of aFTLD-U cases points to a fundamental role in disease pathogenesis.
