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Intrinsic functional connectivity of large-scale brain networks has been shown to change with aging and Alzheimer’s disease (AD). These alterations are thought to reflect changes in synaptic function, but the underlying biological mechanisms are poorly understood. This study examined whether Neuronal Pentraxin 2 (NPTX2), a synaptic protein that mediates homeostatic strengthening of inhibitory circuits to control cortical excitability, is associated with functional connectivity as measured by resting-state functional magnetic resonance imaging (rsfMRI) in five large-scale cognitive brain networks. In this cross-sectional study, rsfMRI scans were obtained from 130 older individuals (mean age = 69 years) with normal cognition (N = 113) and Mild Cognitive Impairment (N = 17); NPTX2 was measured in the same individuals in cerebrospinal fluid (CSF). Higher levels of NPTX2 in CSF were associated with greater functional connectivity in the salience/ventral attention network, based on linear regression analysis. Moreover, this association was stronger among individuals with lower levels of cognitive reserve, as measured by a composite score (comprised of years of education, reading, and vocabulary measures). Additionally, higher connectivity in the salience/ventral attention network was related to better performance on a composite measure of executive function. Levels of NPTX2 were not associated with connectivity in other networks (executive control, limbic, dorsal attention, and default-mode). Findings also confirmed prior reports that individuals with MCI have lower levels of NPTX2 compared to those with normal cognition. Taken together, the results suggest that NPTX2 mechanisms may play a central role among older individuals in connectivity within the salience/ventral attention network and for cognitive tasks that require modulation of attention and response selection.