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.
Jingxiang Wen, Guoyu Lan, Yuan Fu et al.· Alzheimer's Research & Thera...· 0 citations
OBJECTIVE
Recent studies suggest that combining plasma phosphorylated tau (p-tau) with β-amyloid (Aβ) may improve diagnosis accuracy for Alzheimer's disease (AD). However, the cross-sectional and longitudinal concordance of these markers with Aβ positron emission tomography (PET) positivity remains incompletely understood. This study aimed to evaluate the diagnostic performance of plasma p-tau, alone and in combination with plasma Aβ, in AD.
METHODS
We included 326 participants from the Alzheimer's Disease Neuroimaging Initiative and 357 Chinese older adults from the Greater-Bay-Area Healthy Aging Brain Study who underwent Aβ-PET imaging. Longitudinal data were available for 285 Alzheimer's Disease Neuroimaging Initiative participants. Plasma p-tau181, p-tau217, Aβ42, and Aβ40 were measured on different analytical platforms. Diagnostic performance for Aβ-PET positivity was assessed using a two-cutoff approach.
RESULTS
Combining plasma p-tau with Aβ42 or the Aβ42/40 ratio reduced the intermediate zone. Notably, p-tau217/Aβ42 showed stronger agreement with Aβ-PET positivity than p-tau217 alone. Among individuals classified as p-tau217/Aβ42 positive but p-tau217 intermediate, 57.1 to 83.3% were Aβ-PET positive. Longitudinally, most Stable Positive (88.0-96.1%) and Stable Negative (89.4-90.9%) cases defined by p-tau217 or p-tau217/Aβ42 were Aβ-PET positive and Aβ-PET negative, respectively. Critically, 69.7 to 75.8% of Non-positive to Positive cases defined by p-tau217/Aβ42 were Aβ-PET positive.
INTERPRETATION
These findings provide novel insights into the cross-sectional and longitudinal diagnostic performance of plasma p-tau217/Aβ42 in AD. To be specific, plasma p-tau217/Aβ42 can reduce the intermediate zone and improve agreement with Aβ-PET positivity, and longitudinal p-tau217/Aβ42 monitoring is particularly informative for identifying Aβ-PET-positive patients who were p-tau217/Aβ42 negative or intermediate at baseline and were misclassified as low risk of AD. ANN NEUROL 2026.
Mingxing Jiang, Guoyu Lan, Jiayi Zhu et al.· Annals of Neurology· 0 citations