Non-linear associations of amyloid-$\beta$ with resting-state functional networks and their cognitive relevance in a large community-based cohort of cognitively normal older adults

A large community-based study of 968 cognitively normal older adults reveals that early amyloid-beta pathology alters brain network connectivity in a non-linear, network-specific manner. Researchers from Emory University used resting-state functional MRI and cerebrospinal fluid biomarkers to map 14 large-scale functional networks. They discovered inverted U-shaped associations between amyloid-beta 1-42 levels and connectivity in the precuneus network and ventral default mode network (DMN), meaning connectivity initially increases with amyloid burden before declining. This pattern was absent in the dorsal DMN, indicating selective vulnerability of certain networks to early Alzheimer's pathology.

Crucially, higher connectivity in amyloid-beta-related networks—including the dorsal and ventral DMN, precuneus, and posterior salience network—was linked to better performance on tests of visual memory, visuospatial skills, and executive function. No significant relationships were found between tau proteins and functional connectivity. These findings, published in Alzheimer's Research & Therapy, highlight that functional brain changes occur well before cognitive symptoms appear, and that preserving connectivity in these specific networks might be key to maintaining cognitive function. The study's community-based design enhances its generalizability compared to previous clinic-based research.