Researchers at the VIB and University of Antwerp have identified a major genetic risk factor for a rare form of frontotemporal dementia, marking an important advance in understanding this complex condition. The discovery, reported in Nature Genetics, provides a crucial biological entry point into a disease subtype that has long been difficult to investigate. This insight has the potential to improve diagnostic precision and patient stratification while opening new directions for the development of targeted treatments tailored to specific disease mechanisms.
Frontotemporal dementia is less common and less widely recognised than Alzheimer’s disease, yet it is one of the leading causes of dementia in younger adults. The condition primarily affects brain regions responsible for behaviour, personality, decision-making, and language, meaning that early symptoms often manifest as changes in social conduct, reduced empathy, impulsivity, or language difficulties. These symptoms can appear long before memory problems become evident, often complicating early diagnosis and contributing to delays that may affect careers, relationships, and overall quality of life.
One specific subtype, known as aFTLD-U, is characterised by atypical frontotemporal lobar degeneration and the presence of ubiquitin-positive inclusions, which distinguish it from other forms of frontotemporal dementia. Individuals with this subtype may begin to exhibit behavioural symptoms as early as their thirties or forties, yet a definitive diagnosis has historically been possible only through post-mortem examination. Its rarity has made large-scale study challenging, even as the need to distinguish between different subtypes has become increasingly important, given that they may respond differently to emerging therapies.
The research team undertook a global effort to assemble a sufficiently large dataset of confirmed aFTLD-U cases. Using a genome-wide association approach across dozens of cases and thousands of controls, combined with advances in long-read sequencing technology, they identified a repeat expansion located within an intron of the GOLGA8A gene. This repeat varies in both length and sequence composition, with longer expansions showing a particularly strong association with the disease. Notably, this represents the first instance of a disease-linked repeat involving only two nucleotides, highlighting a previously underappreciated form of genetic variation.
The strength of the genetic signal observed in this study is striking, especially when compared with findings from larger studies of more common conditions. Long-read sequencing proved essential for detecting and characterising this complex repeat region, as traditional short-read methods are often unable to resolve such intricate genomic structures, particularly in areas like GOLGA8A that exist in multiple copies across the genome. This technological advantage enabled researchers to uncover a level of detail that would otherwise have remained hidden.
Although the functional impact of this repeat expansion is not yet fully understood, its presence in a substantial proportion of cases suggests a fundamental role in disease biology. Ongoing work is focused on determining how this genetic feature influences gene regulation and cellular processes in vulnerable brain regions. The findings also reinforce a broader perspective that even conditions considered sporadic may have significant genetic contributions. Identifying such factors offers a pathway towards earlier diagnosis and more precise classification, and ultimately supports the development of therapies that target the underlying biological mechanisms of disease.
More information: Wouter De Coster et al, A repeat expansion in GOLGA8A is a major risk factor for atypical frontotemporal lobar degeneration with ubiquitin-positive inclusions, Nature Genetics. DOI: 10.1038/s41588-026-02537-7
Journal information: Nature Genetics Provided by Vlaams Instituut voor Biotechnologie
