Network Localization of Anxiety as an Early Manifestation of Alzheimer's Disease-related Neurodegeneration
- 1Brigham and Women's Hospital
Abstract
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.
Related
- TMEM55B downregulation promotes neurodegeneration in Alzheimer disease models.
- Plasma Proteomic Profiles of Alzheimer's Disease and Neurodegeneration in African Cohorts
- Bile acids in Alzheimer’s disease: a double-edged sword in gut–liver–brain signaling and neurodegeneration
- PARP1 deficiency mitigates amyloid pathology, neurodegeneration, and cognitive decline in a familial Alzheimer’s disease model
- Large-Scale Cerebellar-Cerebral Network Alterations Underlying Impaired Social Predictive Processing in Cerebellar Neurodegeneration.
BibTeX
@misc{lee2026network,
title = {{Network Localization of Anxiety as an Early Manifestation of Alzheimer's Disease-related Neurodegeneration}},
author = {S. Lee and J. Ha and A. H. Garimella and S. R. Baratono and G. T. Burt and H. T. Karim and C. Andreescu and R. A. Sperling and N. J. Donovan and M. D. Fox and S. H. Siddiqi},
howpublished = {bioRxiv},
year = {2026},
month = oct,
doi = {10.64898/2026.10.24.761536},
url = {https://www.biorxiv.org/content/10.64898/2026.10.24.761536v1},
note = {CC0},
}
RIS
TY - UNPB
TI - Network Localization of Anxiety as an Early Manifestation of Alzheimer's Disease-related Neurodegeneration
AU - S. Lee
AU - J. Ha
AU - A. H. Garimella
AU - S. R. Baratono
AU - G. T. Burt
AU - H. T. Karim
AU - C. Andreescu
AU - R. A. Sperling
AU - N. J. Donovan
AU - M. D. Fox
AU - S. H. Siddiqi
PY - 2026
DA - 2026/10/24
PB - bioRxiv
DO - 10.64898/2026.10.24.761536
UR - https://www.biorxiv.org/content/10.64898/2026.10.24.761536v1
AB - 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.
SN - 2692-8205
ER -