Promising evidence has suggested potential links between mind-wandering and Alzheimer’s disease (AD). Yet, older adults with diagnosable neurocognitive disorders show reduced meta-awareness, thus questioning the validity of probe-assessed mind-wandering in older adults. In prior work, we employed response time variability as an objective, albeit indirect, marker of mind-wandering to identify patterns of functional connectivity that predicted mind-wandering. In the current study, we evaluated the association of this connectome-based, mind-wandering model with cerebral spinal fluid (CSF) p-tau/A β 42 ratio in 289 older adults from the Alzheimer’s Disease NeuroImaging Initiative (ADNI). Moreover, we examined if this model was similarly associated with individual differences in composite measures of global cognition, episodic memory, and executive functioning. Edges from the high response time variability model were significantly associated with CSF p-tau/A β ratio. Furthermore, connectivity strength within edges associated with high response time variability was negatively associated with global cognition and episodic memory functioning. This study provides the first empirical support for a link between an objective neuromarker of mind-wandering and AD pathophysiology. Given the observed association between mind-wandering and cognitive functioning in older adults, interventions targeted at reducing mind-wandering, particularly before the onset of AD pathogenesis, may make a significant contribution to the prevention of AD-related cognitive decline. Author Summary Response time variability is considered an objective, albeit indirect, marker of mind-wandering. In this study, we applied a previously-derived connectome-based model of response time variability to resting-state data obtained from 289 older adults in the Alzheimer’s Disease NeuroImaging Initiative. The network strength of the high response time variability model was correlated with a cerebrospinal fluid (CSF)-based ratiometric measure of amyloid and tau pathology. Additionally, our results demonstrated that the network strength in the high response time variability model was also linked with global cognition and episodic memory. This study provides the first empirical support for the association between a neuromarker of response time variability—an indirect marker of mind-wandering—and AD pathophysiology.