Cortical gray–white matter contrast alterations precede amyloid‐β positivity and macrostructural changes in older adults without dementia

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INTRODUCTION: Early Alzheimer's disease (AD) involves subtle cortical changes that may precede atrophy. Magnetic resonance imaging (MRI) microstructural markers may detect earlier pathology than classical morphometry. METHODS: We analyzed cross-sectional MRI and amyloid-β (Aβ) positron emission tomography (PET) data from 1323 non-demented AMYPAD participants. Cortical volume, thickness, gray-white matter contrast (GWC), and mean diffusivity (MD) were related to global Aβ burden and estimated time to Aβ-positivity using regression, correlation, and change-point analyses. RESULTS: Microstructural measures showed stronger age associations than macrostructural measures, whereas all measures were unaffected by apolipoprotein E (APOE) -ε4 carriership. GWC and MD showed minimal overlap with volume and thickness. Higher Aβ burden was most strongly associated with reduced GWC and cortical thinning. Change-point analyses showed GWC alterations preceded Aβ-positivity by several years. DISCUSSION: Cortical microstructural MRI, particularly GWC, changes earlier than atrophy and may serve as an early in vivo marker of AD pathology.

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