Biomarkers

Alzheimers Dement. 2025 Dec;21 Suppl 2:e105504. doi: 10.1002/alz70856_105504.

ABSTRACT

BACKGROUND: Although research has been prolific identifying proteomic changes in frontotemporal dementia (FTD), there are not strong evidence for the identification of biomarkers to help the understanding of the underlying pathologies. We explored proteomic profiles in genetic FTD associated to underlying pathologies.

METHOD: This is a follow up study from a proteomic database in the GENetic FTD cohort (GENFI) in which a total of 238 cerebrospinal fluid (CSF) samples were measured by untargeted mass spectrometry. We performed ANCOVA analyses to identify the best predictors to differentiate among pathologies and then studied the pathways where these proteins are indicated.

RESULT: Previous results from the study revealed individual proteomic changes in each genetic form of FTD. For the present work, we combined C9orf72 and GRN mutation carriers to conform the TDP-43 group and compared them against MAPT mutation carriers and controls. Among the proteins significantly altered in the disease groups compared to controls (155 in the TDP-43 group and 52 in the tau group), 14 proteins were specific of MAPT mutation carriers but not on the others and 43 were only significantly changed in the TDP-43 group. We identified DNASE2 and PLBD2 as potential predictors differentiating the underlying pathologies. Both proteins are significantly decreased in tau pathology, when compared to TDP-43 pathology (DNASE2 p-value<0.0001, PLBD2 p-value=0.006). These two proteins are also the ones driving the significant changes in the cluster identified as "Lysosomal proteins" in our network analysis.

CONCLUSION: Our results suggest a proteomic difference related to the underlying pathologies of FTD that, combined with the proteomic signatures linked to the genetic mutations, could provide key insights in the search for potential biomarkers for this disorder.

PMID:41518228 | DOI:10.1002/alz70856_105504