The prestigious journal Trends in Neurosciences recently published a scientific commentary authored by Dr. Oriol Dols-Icardo, a researcher with the Neurobiology of Dementias group at the Sant Pau Research Institute (IR Sant Pau) and the Memory Unit at Hospital de Sant Pau. The article provides a critical and contextualized analysis of recent advances in the genetics of frontotemporal lobar degeneration with TDP-43 inclusions (FTLD-TDP), a neurodegenerative disease that ranks among the most common causes of dementia after Alzheimer’s disease.
The commentary focuses on a study by Pottier and colleagues published in Nature Communications, which represents the most extensive whole-genome sequencing analysis conducted to date in patients with FTLD-TDP. The study included nearly 1,000 patients diagnosed with FTLD-TDP and its pathological subtypes A, B, and C, as well as more than 3,000 control individuals, and identified multiple genetic variants—both common and rare—specifically associated with each subtype. Some of these risk factors have also been linked to other diseases such as amyotrophic lateral sclerosis (ALS), Alzheimer’s disease, and hippocampal sclerosis, all of which are associated to varying degrees with the presence of TDP-43 inclusions.
As corresponding author, Dr. Dols-Icardo led the writing of the commentary and invited two prominent international researchers to contribute: Dr. Lianne M. Reus from Vrije Universiteit Amsterdam in the Netherlands, and Dr. Alfredo Ramírez from the University of Cologne and the German Center for Neurodegenerative Diseases – DZNE. All three experts emphasize the importance of these findings for advancing the understanding of the biological and clinical heterogeneity of FTLD-TDP.
“Our commentary highlights that the different subtypes of FTLD-TDP may be driven by distinct genetic mechanisms, which supports the notion that they represent separate biological entities,” explains Dr. Oriol Dols-Icardo. Furthermore, TDP-43 is the primary aggregated protein in FTLD-TDP, ALS, and hippocampal sclerosis, but it is also present in 60% of individuals with Alzheimer’s disease. Dr. Dols-Icardo points out that “some of the identified genetic factors also play a key role in these diseases. This approach brings us closer to earlier and more accurate diagnosis and more personalized risk stratification, with clear implications for the development of targeted therapies.”
The article also underscores the need to replicate the findings in independent cohorts, as well as the importance of having in vivo biomarkers capable of distinguishing between the pathological subtypes of FTLD-TDP. In addition, it highlights how next-generation sequencing technologies—particularly long-read techniques—can reveal structural variants, alternative isoforms, and complex splicing variations associated with TDP-43 dysfunction, a key protein not only in FTLD but also in other neurodegenerative disorders.
This commentary is a significant contribution to the current scientific discussion on neurodegenerative diseases associated with TDP-43 protein inclusions and reinforces Sant Pau’s leadership—and that of its research team—in the field of neurodegenerative diseases.
Dols-Icardo O, Reus LM, Ramirez A. Genetic architecture of FTLD-TDP pathological subtypes. Trends Neurosci 2025. https://doi.org/10.1016/j.tins.2025.06.005
