Sequential associations of myelin dysfunction with Aβ and Tau pathology in Alzheimer's disease: a dynamic myelin perturbation.

Background

Myelin dysfunction has emerged as a potentially pivotal factor in Alzheimer's disease (AD); however, its temporal dynamics and relationship with hallmark pathological processes remain incompletely understood. This study aimed to investigate dynamic demyelination and its association with the progression of Aβ and Tau pathology in AD.

Methods

A total of 1,237 participants from the Alzheimer's Disease Neuroimaging Initiative (ADNI) with 18F-florbetapir (FBP) PET imaging were included. White matter SUVR (WM SUVR), defined as the adjusted FBP signal in white matter, was used as a proxy measure of myelin integrity. Cross-sectional and longitudinal analyses were conducted to examine associations between WM SUVR and AD progression, as well as AD-related biomarkers. Using cortical Aβ accumulation as a temporal reference, we further evaluated two-year changes in cortical Aβ and cumulative Tau PET signals in individuals with and without reduced myelin integrity (WM - vs. WM + uptake).

Results

WM SUVR demonstrated a gradual decline with advancing AD severity. Lower WM SUVR was associated with changes in Aβ42/40 and pTau181 levels in both cerebrospinal fluid (CSF) and plasma. In early-stage AD, the WM - group exhibited a higher two-year rate of cortical Aβ accumulation compared with the WM + uptake group. At comparable levels of cortical amyloid, the WM - group showed significantly higher Tau PET signals in temporal meta-regions of interest and more extensive cortical spread in later stages.

Conclusions

Progressive myelin dysfunction is observed across the course of AD as a notable perturbation within neurodegenerative processes. Early alterations in myelin integrity are associated with subsequent Aβ accumulation, whereas later changes coincide with increased Tau aggregation. These findings support a conceptual framework in which myelin degeneration shows temporally structured associations with AD pathology and may serve as a sensitive marker of vulnerability, particularly in early disease stages.