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Association of Stress-Related Disorders With Subsequent Neurodegenerative Diseases

Educational Objective
To see whether severe psychiatric reactions induced by trauma or other life stressors increase the risk for neurodegenerative disease.
1 Credit CME
Key Points

Question  Do severe psychiatric reactions induced by trauma or other life stressors increase the risk for neurodegenerative diseases?

Findings  In a nationwide cohort study of individuals with stress-related disorders and those without such disorders, the exposed individuals were at a considerably higher risk of developing neurodegenerative diseases compared with their matched unexposed counterparts. This risk elevation was more pronounced for vascular neurodegenerative diseases (risk increase of 80%) than for primary neurodegenerative diseases (risk increase of 31%).

Meaning  These findings suggest that stress-related disorders may be associated with the subsequent risk of neurodegenerative diseases, possibly through a cerebrovascular pathway.


Importance  Posttraumatic stress disorder (PTSD) has been associated with increased risk for dementia. Less is known, however, about other stress-related disorders and their associations with neurodegenerative diseases.

Objective  To examine the association between stress-related disorders and risk for neurodegenerative diseases.

Design, Setting, and Participants  This population-matched and sibling cohort study was conducted in Sweden using data from nationwide health registers, including the Swedish National Patient Register. Individuals who received their first diagnosis of stress-related disorders between January 1, 1987, and December 31, 2008, were identified. Individuals who had a history of neurodegenerative diseases, had conflicting or missing information, had no data on family links, or were aged 40 years or younger at the end of the study were excluded. Individuals with stress-related disorders were compared with the general population in a matched cohort design; they were also compared with their siblings in a sibling cohort. Follow-up commenced from the age of 40 years or 5 years after the diagnosis of stress-related disorders, whichever came later, until the first diagnosis of a neurodegenerative disease, death, emigration, or the end of follow-up (December 31, 2013), whichever occurred first. Data analyses were performed from November 2018 to April 2019.

Exposures  Diagnosis of stress-related disorders (PTSD, acute stress reaction, adjustment disorder, and other stress reactions).

Main Outcomes and Measurements  Neurodegenerative diseases were identified through the National Patient Register and classified as primary or vascular. Alzheimer disease, Parkinson disease, and amyotrophic lateral sclerosis were evaluated separately. Cox proportional hazards regression models were used to estimate hazard ratios (HRs) with 95% CIs after controlling for multiple confounders.

Results  The population-matched cohort included 61 748 exposed individuals and 595 335 matched unexposed individuals. A total of 44 839 exposed individuals and their 78 482 unaffected full siblings were included in the sibling cohort analysis. The median (interquartile range) age at the start of follow-up was 47 (41-56) years, and 24 323 (39.4%) of the exposed individuals were male. The median (interquartile range) follow-up was 4.7 (2.1-9.8) years. Compared with unexposed individuals, individuals with a stress-related disorder were at an increased risk of neurodegenerative diseases (HR, 1.57; 95% CI, 1.43-1.73). The risk increase was greater for vascular neurodegenerative diseases (HR, 1.80; 95% CI, 1.40-2.31) than for primary neurodegenerative diseases (HR, 1.31; 95% CI, 1.15-1.48). A statistically significant association was found for Alzheimer disease (HR, 1.36; 95% CI, 1.12-1.67) but not Parkinson disease (HR, 1.20; 95% CI, 0.98-1.47) or amyotrophic lateral sclerosis (HR, 1.20; 95% CI, 0.74-1.96). Results from the sibling cohort corroborated results from the population-matched cohort.

Conclusions and Relevance  This study showed an association between stress-related disorders and an increased risk of neurodegenerative diseases. The relative strength of this association for vascular neurodegenerative diseases suggests a potential cerebrovascular pathway.

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CME Disclosure Statement: Unless noted, all individuals in control of content reported no relevant financial relationships. If applicable, all relevant financial relationships have been mitigated.

Article Information

Accepted for Publication: December 30, 2019.

Corresponding Author: Huan Song, MD, PhD, West China Biomedical Big Data Center, West China Hospital, Sichuan University, Guo Xue Lane 37, Chengdu, China (huan@hi.is; huan.song@ki.se).

Published Online: March 9, 2020. doi:10.1001/jamaneurol.2020.0117

Author Contributions: Dr Song and Ms Sieurin contributed equally to this work and should be considered co-first authors. Drs Song and Fang had full access to all of the data in the study and take responsibility for the integrity of the data and the accuracy of the data analysis.

Concept and design: Song, Wirdefeldt, Larsson, Valdimarsdóttir, Fang.

Acquisition, analysis, or interpretation of data: Song, Sieurin, Wirdefeldt, Pedersen, Almqvist, Valdimarsdóttir, Fang.

Drafting of the manuscript: Song, Sieurin, Fang.

Critical revision of the manuscript for important intellectual content: All authors.

Statistical analysis: Song, Sieurin, Valdimarsdóttir, Fang.

Obtained funding: Wirdefeldt, Almqvist, Larsson, Valdimarsdóttir, Fang.

Administrative, technical, or material support: Fang.

Supervision: Wirdefeldt, Pedersen, Larsson, Valdimarsdóttir, Fang.

Conflict of Interest Disclosures: Dr Wirdefeldt reported receiving grants from the Swedish Research Council during the conduct of the study. Dr Pedersen reported receiving grants from the Swedish Research Council during the conduct of the study. Dr Almqvist reported receiving grants from the Swedish Research Council during the conduct of the study. Dr Larsson reported receiving grants and personal fees from Shire/Takeda and personal fees from Evolan outside the submitted work. Dr Valdimarsdóttir reported receiving grants from the European Research Council and the Icelandic Research Fund during the conduct of the study. Dr Fang reported receiving grants from the Swedish Research Council and Karolinska Institutet during the conduct of the study. No other disclosures were reported.

Funding/Support: This study was funded by grants 2019-01088 and 2017-02175 from the Swedish Research Council (Vetenskapsrådet); grant 163362-051 from Grant of Excellence, Icelandic Research Fund; grant 726413 from the European Research Council Consolidator Grant (StressGene); a Senior Researcher Award and Strategic Research Area in Epidemiology from the Karolinska Institutet; grant 340-2013-5867 from the Swedish Initiative for Research on Microdata in the Social and Medical Sciences framework; and grant ZYJC18010 from the 1.3.5 Project for Disciplines of Excellence, West China Hospital, Sichuan University.

Role of the Funder/Sponsor: The funders had no role in the design and conduct of the study; collection, management, analysis, and interpretation of the data; preparation, review, or approval of the manuscript; and decision to submit the manuscript for publication.

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