Autonomic Dysfunction as a Preclinical Biomarker of Alzheimer’s Disease: From Heart Rate Variability to Neurodegeneration

Abstract

Early detection of Alzheimer’s disease (AD) remains constrained by the cost and invasiveness of established biomarkers such as cerebrospinal fluid assays and positron emission tomography. This diagnostic gap has intensified interest in low-cost, physiological markers that may signal neurodegenerative vulnerability during preclinical and prodromal stages. To synthesize human evidence supporting autonomic dysfunction, particularly heart rate variability (HRV), baroreflex sensitivity, and orthostatic hypotension – as a potential preclinical biomarker of AD and to explore its mechanistic and translational relevance. A narrative review of peer-reviewed human studies, systematic reviews, and longitudinal cohorts examining autonomic indices in cognitively normal adults, mild cognitive impairment (MCI), and AD was conducted. Evidence linking autonomic dysfunction to neurovascular regulation, sleep physiology, inflammatory control, and central autonomic network (CAN) integrity was integrated into a unified pathophysiological framework. Systematic reviews and cohort studies consistently demonstrate reduced vagally mediated HRV in individuals with MCI and AD. Longitudinal evidence indicates that autonomic cardiovascular instability, including orthostatic hypotension and impaired baroreflex sensitivity, predicts future dementia risk. Mechanistically, autonomic dysregulation intersects with neurovascular uncoupling, sleep-dependent amyloid clearance failure, inflammatory reflex dysfunction, and breakdown of CANs. Although autonomic biomarkers lack disease specificity, their noninvasive and scalable nature positions them as promising complementary tools for early risk stratification and multimodal dementia assessment. Future longitudinal studies with standardized autonomic testing are required to clarify their predictive and translational utility in AD.