Functional network phenotypes of mild behavioural impairment: cognitive effects moderated by amyloid.

BACKGROUND: Mild behavioural impairment (MBI) is a neurobehavioural syndrome that represents an at-risk state for incident cognitive decline. No study to date has systematically investigated whole-brain within- and between- network functional connectivity (FC) disruptions in MBI and their effects on cognitive performance in dementia-free individuals. Hence, we sought to evaluate the whole-brain functional network phenotypes associated with MBI and its subdomains, and their relationships with amyloid and tau pathology in predicting future cognition and function in dementia-free older adults. METHODS: We studied 203 dementia-free individuals aged between 55 and 90 years (77 males) from the Translational Biomarkers in Aging and Dementia (TRIAD) cohort with baseline functional MRI, amyloid-β [18 F]AZD4694 and tau [18 F]MK6240 PET imaging, and longitudinal neuropsychological assessments up to 32 months. Multivariate associations between MBI-Checklist (MBI-C) subdomain scores and whole-brain FC matrices were examined using partial least squares correlation. We then assessed how these MBI-related network phenotypes were associated with baseline and longitudinal changes in global cognition (via Montreal Cognitive Assessment (MoCA) scores) and functional performance (via clinical dementia rating (CDR) sum of boxes), and whether they interacted with baseline Alzheimer’s disease pathology (global amyloid uptake and tau temporal meta-region-of-interest uptake via PET) to influence future outcomes using linear regression models. RESULTS: We identified an MBI-related functional network phenotype characterized by greater MBI severity and widespread dysfunctions particularly in higher-order networks. Greater expression of this phenotype was associated with poorer baseline global cognition, as well as greater functional impairment at baseline and over time. Further, baseline global amyloid uptake, but not temporal tau uptake, moderated the effects of baseline MBI-related FC disruptions on longitudinal global cognition changes in dementia-free older adults. Specifically, individuals with higher amyloid burden and greater MBI-related FC disruptions showed accelerated cognitive decline over time. In contrast, the MBI-C total score did not show independent or interactive effects with amyloid and tau burden on longitudinal cognitive and functional outcomes. CONCLUSIONS: Our findings demonstrated a global MBI-related functional network phenotype in dementia-free individuals that was associated with impaired cognition and function. Moreover, this phenotype interacts with amyloid burden to accelerate cognitive decline, underscoring its relevance in preclinical Alzheimer’s disease. SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at 10.1186/s13195-026-01980-2.