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

Abstract

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.

Keywords: MAPT; functional connectivity; genetic frontotemporal dementia; graph analysis; gray matter; macroscale organization; mutation; neurodegeneration; tau; tau pathology; white matter.

FIGURE 1

Tracts segmented and extracted using the automated TractSeg tool. For tracts existing in the left and right hemispheres, only the right one is shown. Adjusted from Wasserthal et al. AF, arcuate fascicle; CC, corpus callosum (rostrum [CC 1], genu [CC 2], rostral body [CC 3], anterior midbody [CC 4], posterior midbody [CC 5], isthmus [CC 6], splenium [CC 7]); CG, cingulum; ILF, inferior longitudinal fascicle; SLF, superior longitudinal fascicle (I, II, III); UF, uncinate fascicle.

FIGURE 2

Cortical thickness effect sizes (Cohen's d) for each microtubule‐associated protein tau carrier group compared to controls. FTLD‐CDR score,A.  Clinical Dementia Rating plus National Alzheimer's Coordinating Center Behavioural and Language domains global score.

FIGURE 3

A. Summary of tracts showing significantly different diffusion metrics in each microtubule associated protein tau (MAPT) carrier group compared to controls, *p < 0.05, **p < 0.005. FA, fractional anisotropy; MD, mean diffusivity; RD, radial diffusivity; AD, axial diffusivity. B. Adjusted mean fractional anisotropy and radial diffusivity values from mixed model for each group, with shaded standard deviation, along tracts showing significant early changes in MAPT prodromal carriers compared to controls.

FIGURE 4

A. Summary of networks showing significant different graph metrics in each microtubule associated protein tau (MAPT) carrier group compared to controls, with the direction of change depicted by an arrow. B. Adjusted means and standard errors from mixed model for each group and for different graph metrics within salience and visual networks which showed early changes compared to controls.

FIGURE 5

Distribution of principal and secondary gradient embedding values for each network in controls and projected on cortical surface.

FIGURE 6

Principal and secondary gradient embedding values projected on cortical surface for each microtubule associated protein tau (MAPT) carrier group.

FIGURE 7

Theoretical model of gray matter, white matter, and functional connectivity neuroimaging biomarker evolution in microtubule‐associated protein tau‐mutation carriers.