Anxiety adds the risk of cognitive progression and is associated with axon/synapse degeneration among cognitively unimpaired older adults

Lin Sun; Wei Li; Qi Qiu; Yang Hu; Zhi Yang; Shifu Xiao; Alzheimer's Disease Neuroimaging Initiative

doi:10.1016/j.ebiom.2023.104703

Anxiety adds the risk of cognitive progression and is associated with axon/synapse degeneration among cognitively unimpaired older adults

EBioMedicine. 2023 Aug:94:104703. doi: 10.1016/j.ebiom.2023.104703. Epub 2023 Jul 8.

Authors

Lin Sun¹, Wei Li², Qi Qiu², Yang Hu³, Zhi Yang⁴, Shifu Xiao⁵; Alzheimer's Disease Neuroimaging Initiative

Affiliations

¹ Department of Psychiatry, Alzheimer's Disease and Related Disorders Center, Shanghai Mental Health Center, Shanghai Jiao Tong University School of Medicine, Shanghai, PR China. Electronic address: xiaosuan2004@126.com.
² Department of Psychiatry, Alzheimer's Disease and Related Disorders Center, Shanghai Mental Health Center, Shanghai Jiao Tong University School of Medicine, Shanghai, PR China.
³ Shanghai Key Laboratory of Psychotic Disorders, Shanghai Mental Health Center, Institute of Psychological and Behavioural Science, Shanghai Jiao Tong University School of Medicine, Shanghai, PR China.
⁴ Beijing Key Laboratory of Mental Disorders, National Clinical Research Center for Mental Disorders & National Center for Mental Disorders, Beijing Anding Hospital, Capital Medical University, Beijing, PR China; Advanced Innovation Center for Human Brain Protection, Capital Medical University, Beijing, PR China. Electronic address: yangz@mail.ccmu.edu.cn.
⁵ Department of Psychiatry, Alzheimer's Disease and Related Disorders Center, Shanghai Mental Health Center, Shanghai Jiao Tong University School of Medicine, Shanghai, PR China. Electronic address: xiaoshifu@msn.com.

Abstract

Background: Mental symptoms have been shown to be associated with dementia. As the most common neuropsychiatric disorder, it is unclear whether and why anxiety increases the risk of cognitive progression in elderly.

Methods: The aim of this study was to investigate the longitudinal effects of anxiety on cognitive impairment in non-dementia elderly and to explore the underlying biological processes using multi-omics including microarray-based transcriptomics, mass spectrometry-based proteomics and metabolomics, cerebrospinal fluid (CSF) biochemical markers, and brain diffusion tensor imaging (DTI). The Alzheimer's Disease Neuroimaging Initiative (ADNI), Chinese Longitudinal Healthy Longevity Survey (CLHLS) and Shanghai Mental Health Centre (SMHC) cohorts were included.

Findings: Anxiety was found to increase the risk of subsequent cognitive progression in the ADNI, and a similar result was observed in the CLHLS cohort. Enrichment analysis indicated activated axon/synapse pathways and suppressed mitochondrial pathways in anxiety, the former confirmed by deviations in frontolimbic tract morphology and altered levels of axon/synapse markers, and the latter supported by decreased levels of carnitine metabolites. Mediation analysis revealed that anxiety's effect on the longitudinal cognition was mediated by brain tau burden. Correlations of mitochondria-related expressed genes with axon/synapse proteins, carnitine metabolites, and cognitive changes were found.

Interpretation: This study provides cross-validated epidemiological and biological evidence that anxiety is a risk factor for cognitive progression in non-dementia elderly, and that axon/synapse damage in the context of energy metabolism imbalance may contribute to this phenomenon.

Funding: The National Natural Science Foundation of China (82271607, 81971682, and 81830059) for data analysis and data collection.

Keywords: Anxiety; Axon/synapse damage; Cognitive progression; Energy metabolism; Mitochondrial function.

MeSH terms

Aged
Alzheimer Disease* / diagnosis
Alzheimer Disease* / genetics
Amyloid beta-Peptides
Anxiety
Biomarkers / cerebrospinal fluid
China
Cognition
Cognitive Dysfunction* / cerebrospinal fluid
Diffusion Tensor Imaging
Disease Progression
Humans
tau Proteins / cerebrospinal fluid

Substances

tau Proteins
Biomarkers
Amyloid beta-Peptides

Grants and funding

U01 AG024904/AG/NIA NIH HHS/United States