Network Localization of Anxiety as an Early Manifestation of Alzheimer's Disease-related Neurodegeneration

Objective Anxiety is a prominent neuropsychiatric symptom in preclinical Alzheimer's disease (AD), but the neural circuitry linking anxiety and AD remains uncharacterized. We assessed whether anxiety in preclinical AD is independently associated with AD-related neurodegeneration and localizes to a common anxiety network. Methods In cognitively unimpaired (CU) older adults with 3T MRI and amyloid-beta PET (N=1,775), we examined whether an established AD-related atrophy network is associated with anxiety (STAI-6). Then, using Atrophy Network Mapping (ANM), which maps individual cortical atrophy patterns onto a normative functional connectome (N=1000), we derived an anxiety network. We tested its 1) spatial convergence with the AD network and with a causal anxiety network derived from lesion and neuromodulation data, 2) specificity relative to depression, 3) generalizability in samples from independent cohorts with AD and Parkinson's disease (total n=878), and 4) association with longitudinal outcomes. Results In CU older adults, greater AD-network atrophy was associated with higher anxiety, independent of depression, cognition, cortical atrophy, and amyloid burden. Anxiety localized to a network closely resembling the AD network (r=0.74, p=0.04) and the causal anxiety network (r=0.72, p=0.02). This convergence extended across the AD continuum and to the Parkinson's disease cohort and was specific to anxiety relative to depression. Greater anxiety-network atrophy was associated with cognitive decline over 4.6 years. Conclusion Anxiety localizes to a brain circuit resembling the AD-related atrophy network, is consistent across the AD continuum and may extend beyond AD. These findings support anxiety as an independent marker of early AD-related neurodegeneration.