White matter diffusion alterations precede symptom onset in autosomal dominant Alzheimer's disease

Abstract

White matter alterations are present in the majority of patients with Alzheimer's disease type dementia. However, the spatiotemporal pattern of white matter changes preceding dementia symptoms in Alzheimer's disease remains unclear, largely due to the inherent diagnostic uncertainty in the preclinical phase and increased risk of confounding age-related vascular disease and stroke in late-onset Alzheimer's disease. In early-onset autosomal-dominantly inherited Alzheimer's disease, participants are destined to develop dementia, which provides the opportunity to assess brain changes years before the onset of symptoms, and in the absence of ageing-related vascular disease. Here, we assessed mean diffusivity alterations in the white matter in 64 mutation carriers compared to 45 non-carrier family non-carriers. Using tract-based spatial statistics, we mapped the interaction of mutation status by estimated years from symptom onset on mean diffusivity. For major atlas-derived fibre tracts, we determined the earliest time point at which abnormal mean diffusivity changes in the mutation carriers were detectable. Lastly, we assessed the association between mean diffusivity and cerebrospinal fluid biomarkers of amyloid, tau, phosphorylated-tau, and soluble TREM2, i.e. a marker of microglia activity. Results showed a significant interaction of mutations status by estimated years from symptom onset, i.e. a stronger increase of mean diffusivity, within the posterior parietal and medial frontal white matter in mutation carriers compared with non-carriers. The earliest increase of mean diffusivity was observed in the forceps major, forceps minor and long projecting fibres-many connecting default mode network regions-between 5 to 10 years before estimated symptom onset. Higher mean diffusivity in fibre tracts was associated with lower grey matter volume in the tracts' projection zones. Global mean diffusivity was correlated with lower cerebrospinal fluid levels of amyloid-β1-42 but higher levels of tau, phosphorylated-tau and soluble TREM2. Together, these results suggest that regionally selective white matter degeneration occurs years before the estimated symptom onset. Such white matter alterations are associated with primary Alzheimer's disease pathology and microglia activity in the brain.

Figure 1

Abnormal mean diffusivity changes as a function of EYO. P-value map of the statistically significant voxel-wise interactions of EYO × mutation status on mean diffusivity (red-yellow) superimposed on the white matter skeleton (blue, axial view), FWE-corrected at P = 0.05.

Figure 2

Tract-specific mean diffusivity changes as a function of EYO. Regression plots for the interaction EYO × mutation status on mean diffusivity are shown for each fibre tract and the PSMD value. The regression lines including the 95% CIs (shaded bands) for mutation carriers (red) and non-carriers (blue) as a function of EYO are displayed.

Figure 3

Time of first detectable changes in mean diffusivity. Ninety-five per cent confidence intervals of the estimated mean diffusivity and PSMD differences between mutation carriers and non-carriers at each EYO are shown. Red indicates the earliest time point of abnormal mean diffusivity values for a particular tract.

Figure 4

Trajectories of white matter alterations and biomarkers across EYO. Trajectories of alterations in mean diffusivity in the forceps major, and PSMD (green) along with those of core Alzheimer’s disease biomarkers and CSF soluble TREM2.

Figure 5

Global white matter alteration associated with Alzheimer’s disease biomarkers and CSF soluble TREM2. Regression plots for PSMD versus CSF amyloid-β_1-42 (A), precuneus PIB-PET (B), CSF total tau (C) and CSF-soluble TREM2 (D) in the carrier group. The shaded areas correspond to the 95% CIs of the regression lines. BP = binding potential; IS = internal standard.

Figure 6

Association between CSF markers and regional mean diffusivity in the carriers. Top: Map of P-values for the association between higher CSF soluble TREM2 and higher mean diffusivity (red–yellow) superimposed on the white matter skeleton (blue), FWE-corrected at P = 0.05. Bottom: Map of P-values for the interaction effect of CSF amyloid-β_1-42 by total tau on mean diffusivity. MD = mean diffusivity.