In vivo mapping of cortical amyloid beta‐myelin coupling in preclinical Alzheimer's disease

INTRODUCTION: Accumulating evidence suggests that amyloid-β (Aβ) preferentially deposits in poorly myelinated cortical regions and may interfere with remyelination. We hypothesized that this vulnerability would manifest as altered Aβ-myelin coupling in preclinical Alzheimer's disease (AD). METHODS: We assessed spatial coupling between amyloid positron emission tomography (PET) and myelin content estimated from T1w/T2w ratio maps in 151 cognitively unimpaired older adults. Associations with preclinical AD, blood-based biomarkers, resting-state functional connectivity (rs-FC), and subjective memory complaints (SMC) were examined. RESULTS: individuals exhibited increased positive and negative Aβ-myelin coupling in late- and early-myelinating regions, respectively, likely reflecting compensatory remyelination versus progressive myelin loss, along with disrupted rs-FC and greater SMC. Serum glial fibrillary acidic protein (GFAP) and plasma phosphorylated tau at threonine 181 (pTau-181) showed differential, region-specific associations with Aβ-myelin coupling, with GFAP partially mediating tau-related effects. Exploratory stratification suggested distinct biomarker profiles linked to the direction of coupling dominance, potentially reflecting different preclinical AD phases. DISCUSSION: Aβ-myelin coupling may represent a sensitive, stage-dependent marker of early AD-related cortical pathology.