Blood Biomarkers of Presymptomatic Frontotemporal Dementia

Abstract

Frontotemporal dementia (FTD) is characterised by neuronal loss and pathological protein inclusions in the frontal and/or temporal lobes of the brain. The presymptomatic stage, marked by molecular changes years before symptom onset, offers a critical window for early detection, intervention, targeted monitoring, and tracking of disease progression. Currently, no validated fluid biomarker exists to distinguish this early phase of FTD. FTDGeNZ, a natural history study tracking a family with a mutation in the microtubule-associated protein tau (MAPT) gene, provides insights into presymptomatic FTD. Six family members carry the FTD-causing mutation, with the remaining members serving as non-carrier controls. In this research, we conducted case-control analyses to identify plasma-derived miRNAs and proteins as potential biomarkers of presymptomatic FTD. We utilised baseline data from six carriers and 17 controls, alongside longitudinal data from three timepoints with six carriers and 12 controls. Additionally, we optimised a pipeline to investigate plasma-derived extracellular vesicles as a source of potential molecular biomarkers. High-throughput sequencing at a depth of 24 million read pairs per sample, followed by statistical testing and qPCR validation, identified three miRNAs (let-7d-3p, miR-100-5p, miR-342-3p) as potential cross-sectional biomarkers, and two miRNAs (miR-10b-5p, miR-92b-3p) as longitudinal candidates. Statistical modelling of untargeted liquid chromatography-mass spectrometry data revealed 16 potential protein biomarkers in the cross-sectional analysis and 36 candidates in the longitudinal analysis. Notably, we observed reduced expression of three candidate miRNAs (miR-92b-3p, miR-100-5p, miR-10b-5p) in carriers, while four of their target proteins (FLNA, TLN1, TPM4, RAP1B) were upregulated. Furthermore, functional analysis revealed that FLNA, TLN1, TPM4, along with another 16 identified candidate proteins (ACTB, ACTN1, FBLN1, GAPDH, ITGA2B, ITGB3, KRT2, MSN, MYH9, PDLIM1, PFN1, PPIA, THSB1, TNXB, TPM3, VCL), were associated with actin-cytoskeletal dynamics, suggesting that these processes may become dysregulated early in FTD disease progression. This work represents the first longitudinal quantification of plasma-derived miRNA and protein expression changes in presymptomatic genetic FTD. With further follow up these findings may enable early identification of at-risk individuals and provide insights into the underlying aetiology of the disease