Structural and functional connectivity in tau mutation carriers: from presymptomatic to symptomatic frontotemporal dementia

INTRODUCTION: Microtubule-associated protein tau (MAPT) mutations cause frontotemporal dementia (FTD), characterised by behavioural, language, and motor impairments due to brain connectivity disruptions. We investigated structural and functional connectivity in 86 mutation carriers and 272 controls to map connectivity changes at different disease stages. METHODS: The CDR Dementia Staging Instrument plus National Alzheimer's Coordinating Center (NACC) Behaviour and Language domains (CDR plus NACC FTLD) stratified carriers into three groups: asymptomatic, prodromal, and symptomatic. We extracted measures of cortical thickness, white matter integrity, and functional connectivity, which were compared between each carrier group and controls using linear mixed models. RESULTS: Early isolated functional disruptions in salience/visual networks were present in asymptomatic carriers, along with anterior cingulate gray matter reductions. In prodromal carriers, functional changes extended to other networks, with additional structural damage in temporal poles/cingulate. DISCUSSION: This study shows that functional networks likely drive lifelong compensation for a genetically determined disease, manifesting clinically when structural damage reaches a critical threshold. This supports connectivity measures as potential biomarkers for MAPT-related neurodegeneration. HIGHLIGHTS: Our findings reveal the progressive and staged nature of structural and functional connectivity alterations in MAPT mutation carriers, with distinct patterns at each disease stage. In asymptomatic carriers, we identified early functional connectivity alterations in salience and visual networks, despite preserved white matter and only subtle gray matter atrophy. These appear to represent both response to pathology and possible compensatory mechanisms. In prodromal carriers, functional connectivity alterations were accompanied by structural damage, including cortical atrophy and white matter tract disruptions, in regions directly connected to early-affected networks. The sequential progression, from functional connectivity changes to structural degeneration, aligns with the hypothesis that tau propagates along axonal connections, disrupting neural network integrity before measurable atrophy occurs. We propose a theoretical data-driven model of biomarker evolution in MAPT mutation carriers, highlighting functional disruptions as early indicators and structural damage as a later-stage hallmark. These connectivity biomarkers have the potential to inform therapeutic strategies and clinical trial design.