Abstract
Background
Evidence describing the association between hypnotics use and dementia risk is conflicting. It is unknown if the controversy is related to the type or dose of hypnotics or if hypnotics affect different populations.
Objectives
We sought to derive lessons learned and future projections based on evidence from longitudinal studies.
Measurements
In the Alzheimer’s Disease Neuroimaging Initiative (ADNI) cohort, 1,543 older adults without dementia (mean age = 73.3 years, female = 45%) were followed for four years. The association between hypnotics and the risk of Alzheimer’s disease (AD) was investigated using Cox proportional hazards regressions. Next, electronic databases were searched until March 2022 to conduct the evidence synthesis of the associations of hypnotics with incident risk of dementia.
Results
In the ADNI cohort, ever use of hypnotics was associated with an increased risk of AD (hazard ratio = 1.96, 95% confidence intervals = 1.23–3.11, p < 0.01). This association was significant for benzodiazepines and Z-drugs but not for melatonin. The association was stronger in long-term (more than one year) users and those with high cumulative doses. A meta-analysis of 26 longitudinal studies with 3,942,018 participants revealed a correlation between the use of hypnotics and the risk of dementia (relative risk = 1.23, 95% confidence intervals = 1.13–1.33, p < 0.001, median risk difference = 4%). It is a linear dose-response relationship, if a person takes the daily recommended dose for 100 days, their risk of developing dementia increases by 5% relative to non-users. According to subgroup analyses, neither association was significant among patients with a history of insomnia.
Conclusions
Individuals who use hypnotics, especially high-dose or long-term users, are at a higher risk of dementia and AD. The main issue with conclusion credibility is heterogeneity.
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Abbreviations
- AD:
-
Alzheimer’s disease
- ACD:
-
all-cause dementia
- ADNI:
-
Alzheimer’s Disease Neuroimaging Initiative
- Aβ:
-
Amyloid β
- BZDs:
-
Benzodiazepines
- BMI:
-
Body mass index
- CI:
-
Confidence interval
- CNS:
-
Central nervous system
- DDD:
-
defined daily dose
- CDDD:
-
Cumulative defined daily dose
- CBT:
-
Cognitive behavioral therapy
- GABA:
-
Gamma-aminobutyric acid
- HR:
-
Hazard ratio
- MCI:
-
Mild cognitive impairment
- NOS:
-
Newcastle-Ottawa Quality Assessment Scale
- NC:
-
Normal cognition
- OR:
-
Odds ratio
- PRISMA:
-
Preferred Reporting Items for Systematic Reviews and Meta-Analyses 2020 guidelines
- PI:
-
Prediction interval
- RR:
-
Relative risk
- VD:
-
vascular dementia.
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Funding
Funding: This study was supported by grants from the National Natural Science Foundation of China (82001136 and 81901121). This work was supported by grants from the National Natural Science Foundation of China (82001136) and Taishan Young Scholarship.
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Dr. Wei Xu: conceptualization and design of the study and revision of the manuscript. Dr. Jia-Hui Hou: analysis of the data, drafting, and revision of the manuscript, and preparing all the figures. Dr. Chen-Chen Tan: extraction of data and revision of the manuscript. Dr. Shi-Li Sun, Dr Yi-Ming Huang, and Prof. Lan Tan: revision of the manuscript.
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Any data generated in the analysis process can be requested from the corresponding author.
The cohort data used in preparation for this article were obtained from the Alzheimer’s Disease Neuroimaging Initiative database (adni.loni.usc.edu). As such, the investigators within the ADNI contributed to the design and implementation of ADNI and/or provided data but did not participate in the analysis or writing of this report. A complete listing of ADNI investigators can be found at: http://adni.loni.usc.edu/wp-content/uploads/how_to_apply/ADNI_Acknowledgement_List.pdf.
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Hou, JH., Sun, SL., Tan, CC. et al. Relationships of Hypnotics with Incident Dementia and Alzheimer’s Disease: A Longitudinal Study and Meta-Analysis. J Prev Alzheimers Dis 11, 117–129 (2024). https://doi.org/10.14283/jpad.2023.78
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DOI: https://doi.org/10.14283/jpad.2023.78