Biomarkers.

Background: Identifying early pathological changes in Alzheimer's Disease (AD), and accounting for variability in progression between individuals, is crucial for timely and effective intervention. While Amyloid-b, tau, and neuronal loss are core pathological processes in AD with established biomarkers, myelin alterations have been shown to occur but remain under-investigated. The T1/T2w ratio represents an accessible MRI-based marker, providing a potential proxy measure of myelin integrity. Autosomal dominant AD (ADAD) provides a unique opportunity to investigate AD-related changes across its continuum, estimating time to/from symptom onset from family history. This study examines the T1/T2-weighted ratio as an indicator of extra-neuronal AD pathology in ADAD.

Method: Seventy-two ADAD family members were included: 28 presymptomatic mutation carriers, 20 symptomatic mutation carriers and 24 non-carrier controls (Table 1). Volumetric T1 and T2-weighted MRI sequences were acquired. Whole brain preprocessing and T1/T2w ratio were calculated for each participant using MRtool in SPM12 (bias correction, rigid registration, calibration, ratio), followed by tissue segmentation, DARTEL, normalisation and smoothing. Voxel-wise analysis compared T1/T2 across 1) presymptomatic mutation carriers vs. non-carriers and 2) symptomatic mutation carriers vs. non-carriers, adjusting for age and sex. In mutation carriers only, we assessed correlations between T1w/T2w ratio and 1) estimated years to/from onset (EYO), and 2) Mini-Mental State Examination (MMSE) scores.

Result: Symptomatic ADAD mutation carriers had lower T1w/T2w ratios than non-carriers in the medial parietal lobe (t = 7.06, p <0.001 family-wise error (FWE) corrected) (Figure 1), likely reflecting altered myelin integrity. After FWE correction, no significant differences were observed between presymptomatic mutation carriers and non-carriers. Across all mutation carriers, there was a positive correlation between T1w/T2w and EYO (i.e. lower T1/T2 was associated with less time to symptom onset), with significant clusters in the praecuneus (p < 0.05 FWE-corrected) (Figure 2). There was a positive correlation between T1w/T2w and MMSE (t= 5.82, p <0.05 FWE-corrected) (Figure 3).

Conclusion: T1w/T2w ratio is reduced in ADAD, suggesting reduced myelin integrity, and is associated with measures of disease stage (EYO) and severity (MMSE). T1w/T2w ratio could therefore provide a feasible biomarker of myelin integrity, potentially enhancing early AD prognostication, monitoring and treatment development.