Dear Editor,
We read with great interest the study by Peng et al. 1 which showed the longitudinal change of daytime napping inferred objectively by actigraphy, and the association with incident Alzheimer's dementia. However, a prospective study from Wong et al. 2 reported that there was little evidence to suggest that long sleep duration and regular napping are associated with long‐term dementia risk. Short sleep duration was modestly associated with dementia risk, but residual confounding cannot be excluded. It is difficult to infer causal effects only from observational studies because of confounding. Therefore, we try to use Mendelian randomization (MR) analysis to verify the authors' findings from the genetic perspective.
MR analysis uses genetic variation as an instrumental variable to estimate causal effects, independent of factors that may disrupt observational studies, and is not prone to confounding biases and reverse causality. In this study, we used R (V4.2.1) and TwoSampleMR R package, and inverse variance weighted (IVW) method was used as the primary approach. In addition, weighted median and MR‐Egger methods were adopted as sensitivity analyses. Single‐nucleotide polymorphisms (SNPs) at P < 5×10−8 were selected as instrumental variables. The linkage disequilibrium (LD) threshold was set to r 2 = 0.001 within a distance of 10,000 kb.
Summary genetic association estimates for Alzheimer's disease and daytime napping were obtained from the IEU OpenGWAS project. 3 All summary data used in this work were publicly available and were obtained with relevant participant consent and ethical approval. The IEU GWAS ID related to daytime napping were respectively ukb‐b‐4616 (N = 462,400), ukb‐b‐5776 (N = 460,913), and ukb‐a‐12 (N = 337,074). And the IEU GWAS ID associated with Alzheimer's disease were respectively ieu‐a‐824 (N = 1,489), ebi‐a‐GCST90012878 (N = 408,942), finn‐b‐F5_DEMENTIA_INCLAVO (N = 218,792), ieu‐b‐2 (N = 63,926), ebi‐a‐GCST90001390 (N = 6,618), and finn‐b‐KRA_PSY_DEMENTIA (N = 218,782). The population used in the study was European.
TABLE 1.
Results of Mendelian randomization analysis
| Exposure | Outcome | nSNP | OR (95%CI) | p‐Value |
|---|---|---|---|---|
| Daytime napping | Alzheimer's disease | 33 | 75.62(4.64‐1232.59) | 0.0024 |
| Family history of Alzheimer's disease | 31 | 1.06(1.01‐1.11) | 0.0096 | |
| Dementia, including AvoHilmo | 31 | 3.14(1.04‐9.48) | 0.0423 | |
| Alzheimer's disease | Daytime napping | 18 | 0.993(0.990‐0.997) | 0.0002 |
| Family history of Alzheimer's disease | 12 | 0.88(0.83‐0.94) | 0.00006 | |
| Dementia with Lewy bodies | 6 | 0.995(0.990‐0.999) | 0.0120 | |
| Any dementia | 6 | 0.993(0.990‐0.997) | 0.0004 |
Abbreviations: CI, confidence interval; OR, odds ratio; SNP, single‐nucleotide polymorphism.
The MR analysis (Table 1) showed that there was consistent evidence that daytime napping was causally associated with Alzheimer's disease [OR = 75.62 (95% CI: 4.64‐1232.59), p = 0.0024], 33 SNPs were used as instrumental variables. Our results showed the potential association between daytime napping and Alzheimer's disease that excessive daytime napping was a risk factor for Alzheimer's disease. The reverse MR study was also performed. It showed that genetic predisposition to Alzheimer's disease was also causally associated with daytime napping [OR = 0.993 (95% CI: 0.990‐0.997), p = 0.0002], 18 SNPs were used as instrumental variables. It reported that genetic predisposition to Alzheimer's disease could lower the risk of excessive daytime napping. There was neither heterogeneity nor horizontal pleiotropy in MR estimates (Cochran's Q p‐value > 0.05 and MR‐Egger intercept p‐value > 0.05).
In conclusion, we confirmed a bidirectional causal relationship between excessive daytime napping and Alzheimer's dementia using large‐scale genetic summary data. Peng et al. 1 suggested that longer and more frequent daytime naps are associated with a higher risk of Alzheimer's dementia, which was consistent with our results. However, the results of our analysis cannot verify that the progression of Alzheimer's dementia accelerates the annual increase in nap time/frequency in older adults. Further investigations should be encouraged to be carried out with a larger sample size which can give robust casual estimates.
CONFLICT OF INTEREST STATEMENT
The authors declare no conflicts of interest. Author disclosures are available in the supporting information.
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ACKNOWLEDGMENTS
None. This research did not receive any specific grant from funding agencies in the public, commercial, or not‐for‐profit sectors.
Shu Ran and Xitong Lin contributed equally to this study.
REFERENCES
- 1. Peng L, Lei G, Lei Y, et al. Daytime napping and Alzheimer's dementia: a potential bidirectional relationship. Alzheimer's Dementia. 2022;19(1):158‐168. [DOI] [PMC free article] [PubMed] [Google Scholar]
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