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Background: Cognitive reserve (CR) explains interindividual differences in the impact of neurodegenerative burden on cognitive and daily functioning. A residual model was proposed to estimate CR more accurately compared to static measures (i.e., years of education). However, the functional brain correlates of residual CR markers (CRM) remain unexplored. Methods: Resting-state functional MRI, structural MRI, and cerebrospinal fluid (CSF) biomarkers of 112 amyloid-{beta} (A{beta}) negative healthy controls and 206 A{beta}+ individuals were included and stratified using CSF biomarkers according to the A(myloid)/T(au)/N(eurodegeneration) classification scheme. CRM was calculated utilizing residuals obtained from a multilinear regression model using global cognition as dependent variable and demographic and disease burden factors as predictors. Associations between the CRM and intrinsic network connectivity (INC) in resting-state networks associated with cognition were explored, including the default mode network (DMN), frontoparietal networks (FPN), salience network (SAL) and dorsal attention network (DAN). Moreover, we identified regional INC associated with memory performance and tested their association with CRM. Results: CRM was positively associated with INC in the DMN in the entire cohort. In a subgroup analysis, the A+T+N+ group revealed an anti-correlation between SAL and DMN. Furthermore, CRM was positively associated with anti-correlation between the memory-related regions in the FPN and the DMN in the A+ and A+T/N+ subgroups. Conclusions: CRM is associated with alterations of functional connectivity in resting-state networks of cognitive function, particularly the DMN and the FPN. Our results foster the understanding of the individual functional network differences associated with CRM in the AD continuum.

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