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

Background: Non-linear alterations in brain network connectivity may represent early neural signatures of Alzheimer's disease (AD) pathology in cognitively normal older adults. Understanding these changes and their cognitive relevance could provide sensitive biomarkers for early detection. Most prior studies recruited participants from memory clinics, often with subjective memory concerns, limiting generalizability. Methods: We examined 14 large-scale functional brain networks in 968 cognitively normal older adults recruited from the community using resting-state functional MRI, cerebrospinal fluid (CSF) biomarkers (amyloid-β 1-42 [Aβ], total tau, phosphorylated tau 181), and neuropsychological assessments. Functional networks were identified using group independent component analysis. Results: Inverted U-shaped associations between CSF Aβ and functional connectivity were observed in the precuneus network and ventral default mode network (DMN), but not in the dorsal DMN, indicating network-specific vulnerability to early amyloid pathology. Higher connectivity in Aβ-related networks, including dorsal and ventral DMN, precuneus, and posterior salience networks, was associated with better visual memory, visuospatial, and executive performance. No significant relationships were observed between CSF tau and functional connectivity. Conclusions: Using a large, community-based cohort, we demonstrate that non-linear alterations in functional connectivity occur in specific networks even during the asymptomatic phase of AD. Moreover, Aβ-related network connectivity is cognitively relevant, highlighting functional brain networks as promising imaging markers for early detection and prognosis of AD.