Cortical amyloid-beta burden is associated with changes in intracortical myelin in cognitively normal older adults

Amyloid-beta (Aβ) aggregates and myelin breakdown are among the earliest detrimental effects of Alzheimer's disease (AD), likely inducing abnormal patterns of neuronal communication within cortical networks. However, human in vivo evidence linking Aβ burden, intracortical myelin, and cortical synchronization is lacking in cognitively normal older individuals. Here, we addressed this question combining ¹⁸F-Florbetaben-PET imaging, cortical T1-weigthed/T2-weighted (T1w/T2w) ratio maps, and resting-state functional connectivity (rs-FC) in cognitively unimpaired older adults. Results showed that global Aβ burden was both positively and negatively associated with the T1w/T2w ratio in different cortical territories. Affected cortical regions were further associated with abnormal patterns of rs-FC and with subclinical cognitive deficits. Finally, causal mediation analysis revealed that the negative impact of T1w/T2w ratio in left posterior cingulate cortex on processing speed was driven by Aβ burden. Collectively, these findings provide novel insights into the relationship between initial Aβ plaques and intracortical myelin before the onset of cognitive decline, which may contribute to monitor the efficacy of novel disease-modifying strategies in normal elderly individuals at risk for cognitive impairment.