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Relationships of Hypnotics with Incident Dementia and Alzheimer’s Disease: A Longitudinal Study and Meta-Analysis

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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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Authors and Affiliations

  1. Department of Neurology, Qingdao Municipal Hospital, Qingdao University, Qingdao, China, Donghai Middle Road, No.5, Qingdao, China

    J.-H. Hou, C.-C. Tan, Y.-M. Huang, L. Tan & Wei Xu

  2. Jining Medical University, Jining, China

    S.-L. Sun

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  2. S.-L. Sun
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  3. C.-C. Tan
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  4. Y.-M. Huang
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Alzheimer’s Disease Neuroimaging Initiative

Contributions

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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Correspondence to Wei Xu.

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Conflict of interests: The authors declare that they have no competing interests.

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Data Sharing

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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