Genetic Discovery May Improve Diagnosis of Rare Dementia Subtype

Early symptoms can mimic personality changes or stress, delaying diagnosis and complicating care. A rarer subtype, atypical frontotemporal lobar degeneration with ubiquitin-positive inclusions, is typically confirmed only at autopsy. Researchers now report a major genetic risk factor that may enable clearer biological stratification of this hard-to-study condition.

VIB and Antwerp University have identified a repeat expansion within an intron of the GOLGA8A gene that is strongly associated with atypical frontotemporal lobar degeneration with ubiquitin-positive inclusions (aFTLD-U). The discovery provides a biological entry point for a sporadic disease subtype that has resisted genetic characterization and could aid diagnosis and patient stratification. The work assembled rare, pathologically confirmed cases through international collaboration.

The team first conducted a genome-wide association study (GWAS) in 59 pathologically confirmed aFTLD-U cases compared with thousands of controls. Long-read sequencing then resolved a complex, highly duplicated genomic region and pinpointed a dinucleotide repeat expansion in GOLGA8A. The repeat varies in length and sequence composition, with certain longer expansions showing a strong association with disease and representing, according to the researchers, an unusually robust genetic signal.

The repeat expansion was present in nearly 60% of aFTLD-U cases analyzed, highlighting a potentially fundamental role in disease biology. Although the functional consequences are still under investigation, the authors indicate that distinguishing aFTLD-U genetically is increasingly important because different frontotemporal dementia (FTD) subtypes may respond differently to therapies. They also note the broader implication that substantial genetic contributions can underlie conditions currently considered sporadic.

The study was published on March 12, 2026, in Nature Genetics and was led from the VIB-UAntwerp Center for Molecular Neurology with contributions from international partners. The researchers are now examining how the repeat might influence gene regulation and cellular processes in vulnerable brain regions.

“We see this risk factor as a kind of prerequisite for disease in a large fraction of patients. 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,” said Rosa Rademakers, professor at the VIB-UAntwerp Center for Molecular Neurology.

“Long read sequencing proved crucial to uncover and characterize the repeat. 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,” said Wouter De Coster, postdoctoral researcher in Rademakers’ lab.

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VIB-UAntwerp Center for Molecular Neurology