Decreased amyloid-related structure–function coupling in preclinical Alzheimer’s disease

Résumé fourni par la source

Structural pathways of the brain facilitate functional communication, and their disruption in preclinical Alzheimer’s disease may reflect network vulnerability and compensatory brain maintenance. However, it remains unclear how early amyloid-β affects structure-function alignment, whether effects are explained by functional network organisation, how they relate to cognition, and which biological processes contribute to their development. We included 460 older adults without dementia from AMYPAD-PNHS with functional MRI, diffusion MRI, and amyloid-β PET. Structure-function coupling was quantified using the structural-decoupling index (SDI) at global, sub-network, and regional scales. Linear models investigated the effect of amyloid-β burden on SDI. Mediation analyses evaluated whether functional graph topology explained amyloid-associated SDI effects and whether SDI mediated the relationship between amyloid-β burden and cognition. Regional gene expression data were integrated to assess transcriptomic determinants of amyloid-related structure-function coupling. Amyloid-positive individuals exhibit higher global SDI, driven by visual cortices. Mediation analyses demonstrate that amyloid-related SDI alterations are explained by reductions in local clustering, indicating less segregated processing. Despite higher SDI in amyloid-positive individuals, elevated SDI in visual regions mitigates the negative effect of amyloid-β burden on cognition. Amyloid-related SDI changes correlate with genes associated with amyloid-β metabolism, microglial activation, and synaptic remodelling. Early amyloid-β pathology is associated with decoupling of brain structure and function, primarily in visual cortices, mediated by network reconfiguration and shaped by regional molecular architecture. These findings suggest that lower structure-function coupling may represent a compensatory mechanism in preclinical Alzheimer’s disease and highlight SDI as a biomarker for stratification and monitoring in prevention trials. Alzheimer’s disease (AD) affects how different parts of the brain communicate and results in changes in people’s behaviour and ability to remember and think. In its early stages, before symptoms appear, changes in brain connections may already be happening. In this study, we examined how a key protein known to be involved in AD called amyloid-β affects the relationship between brain structure and brain activity, known as structure–function coupling, in older adults without dementia. We analysed brain scans from 460 participants and used a measure called the structural-decoupling index to assess this relationship. We found that higher amyloid-β levels were linked to weaker alignment between brain structure and function, especially in brain regions involved in sight. Our findings suggest that early changes in structure–function coupling could be used to monitor disease progression and support future prevention strategies. Arunachalam et al. investigate how amyloid-β burden relates to brain structure–function coupling in cognitively unimpaired older adults. Higher amyloid-β is associated with reduced coupling in visual cortices, indicating early network reorganisation and potential compensatory mechanisms.

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