Background Parasympathetic nervous system (PNS) is critical for adaptation to environment demands. PNS can reflect an individual's regulatory capacity of frontal brain regions and has been linked to cognitive capacity. Yet, the relationship of PNS function with cognitive decline and abnormal frontal function that characterize preclinical progression toward Alzheimer's disease (AD) is unclear. Here, we aimed to elucidate the relationship between PNS function and AD‐associated neurodegeneration by testing two competing hypotheses involving frontal regions’ activity (neurodegeneration vs. compensation). Methods In 38 older human adults with amnestic mild cognitive impairment (aMCI) or normative cognition, we measured AD‐associated neurodegeneration (AD signature cortical thickness; ADSCT), resting‐state fMRI of frontal regions’ spontaneous activation, and an electrocardiography measure of PNS (high frequency heart rate variability; HF‐HRV). HF‐HRV was assessed at rest and during a cognitive task protocol designed to capture HF‐HRV reactivity. Results Higher HF‐HRV at rest was significantly related to both more severe AD‐associated neurodegeneration (lower ADSCT scores) and worse cognitive ability. Cognitive impairments were also related to greater suppression of HF‐HRV reactivity. High activities of the anterior cingulate cortex significantly mediated relationships between ADSCT and both HF‐HRV at rest and HF‐HRV reactivity. Notably, these relationships were not affected by the clinical phenotype. Conclusions We show that AD‐associated neurodegeneration is associated with altered PNS regulation and that compensatory processes linked to frontal overactivation might be responsible for those alterations. This finding provides the first line of evidence in a new framework for understanding how early‐stage AD‐associated neurodegeneration affects autonomic regulation. This article is protected by copyright. All rights reserved