Sleep, major depressive disorder, and Alzheimer disease

Huang, Jian; Zuber, Verena; Matthews, Paul M.; Elliott, Paul; Tzoulaki, Ioanna; Dehghan, Abbas

doi:10.1212/wnl.0000000000010463

Cited by 61 publications

(45 citation statements)

References 49 publications

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“…Apparent inconsistences between our nding and previous MR studies may be partly due to different de nitions, diagnostic criteria and forms of characterization of AD (such as cognitive impairment, memory loss, reaction time and so on) [53], different types of data (individual-level data or summary-level data) [53], different MR methods (linear MR or non-linear MR) [53], or different statistical analysis methods (genetic risk score) [54]. In addition, we found no causal relationship between AD and insomnia, whereas a recent MR study conducted by Huang et al found that higher risk of AD was associated with lower risk of insomnia (OR: 0.99, P IVW = 7 × 10 − 13 ) [55]. Given the consistency in population, sample size and statistical methods between the study by Huang et al and the present study, we consider that the difference in results is due to Huang et al adopted F-statistic > 10 to lter exposure-related SNPs to reduce the weak instrumental bias of using genotype data [55].…”

Section: Discussioncontrasting

confidence: 50%

Sleep and Alzheimer’s Disease: Shared Genetic Risk Factors, Drug Targets, Molecular Mechanisms, and Causal Effects

Chen

Wang

Jia

et al. 2021

Preprint

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Background: Alzheimer’s disease (AD) was associated with sleep-related phenotypes (SRPs). Whether they share common genetic etiology remains largely unknown. We explored the shared genetics and causality between AD and SRPs by using high-definition likelihood (HDL), cross phenotype association study (CPASSOC), transcriptome wide association study (TWAS), and bidirectional Mendelian randomization (MR) in summary-level data for AD (n = 79145) and summary-level data for seven SRPs (sample size ranges from 345552 to 386577). Results: AD shared strong genetic basis with insomnia (rg = 0.20; P = 9.70×10-5), snoring (rg = 0.13; P = 2.45×10-3), and sleep duration (rg = -0.11; P = 1.18×10-3). CPASSOC identifies 31 independent loci shared between AD and SRPs, including four novel shared loci. Functional analysis and TWAS showed shared genes were enriched in liver, brain, breast, and heart tissues, and highlighted the regulatory role of immunological disorders, very-low-density lipoprotein particle clearance, triglyceride-rich lipoprotein particle clearance, chylomicron remnant clearance and positive regulation of T cell mediated cytotoxicity pathways. Protein-protein interaction analysis provided three potential drug target genes (APOE, MARK4 and HLA-DRA) that interacted with known FDA-approved drug target genes. CPASSOC and TWAS demonstrated three regions 11p11.2, 6p22.3 and 16p11.2 may account for the shared basis between AD and sleep duration or snoring. MR showed AD had causal effect on sleep duration (βIVW = -0.056, PIVW = 1.03×10-3). Conclusion: Our findings provide strong evidence of shared genetics and causation between AD and sleep, and advance our understanding the genetic overlap between them. Identifying shared drug targets and molecular pathways can be beneficial to treat AD and sleep disorders more efficiently.

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Section: Discussioncontrasting

confidence: 50%

Sleep and Alzheimer’s Disease: Shared Genetic Risk Factors, Drug Targets, Molecular Mechanisms, and Causal Effects

Chen

Wang

Jia

et al. 2021

Preprint

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“…This speculation is supported by a recent Mendelian randomization (MR) analysis from the largest genome-wide association studies of the UK Biobank (N = 446,118), the Psychiatric Genomics Consortium (N = 18,759), and the International Genomics of Alzheimer's Project (N = 63,926). This MR analysis found that higher risk of AD, based on genetic risk score, was significantly associated with being a “morning person,” who prefers going to bed and waking earlier and is less active in the first half of the night ( 15 ). Other studies have reported the association between sleep timing and risk of cognitive impairment.…”

Section: Discussionmentioning

confidence: 99%

Sleep Timing and Risk of Dementia Among the Chinese Elderly in an Urban Community: The Shanghai Aging Study

Ding

Zhao

et al. 2021

Front. Neurol.

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Background: Growing evidence has suggested a link between poor sleep quality and increased risk of dementia. However, little is known about the association between sleep timing, an important behavior marker of circadian rhythms, and dementia risk in older adults, and whether this is independent of sleep duration or quality.Methods: We included data from 1,051 community-dwelling older men and women (aged≥ 60y) without dementia from the Shanghai Aging Study. At baseline, participants reported sleep timing, duration, and quality using the Chinese version of the Pittsburgh Sleep Quality Index (CPSQI). Dementia diagnosis over the following 7.3 years was determined by neurologists using DSM-IV criteria. We used Cox proportional hazards models to examine the association between bedtime (before 9 p.m., after 11 p.m. vs. 9–11 p.m.), rise time (before 6 a.m., after 8 a.m. vs. 6–8 a.m.), and risk of dementia.Results: A total of 238 (22.8%), 675 (64.5%), and 133 (12.7%) participants reported going to bed before 9 p.m., between 9 and 11 p.m., and after 11 p.m., respectively, while 272 (26%), 626 (59.9%), and 148 (14.2%) reported getting up before 6 a.m., between 6 and 8 a.m., and after 8 a.m., respectively. Participants who reported going to bed earlier had a lower education level, were less likely to be smokers, more likely to have hypertension or diabetes, and had longer sleep duration but poorer sleep quality compared to those who reported a later bedtime. We found 47 incidents of dementia among 584 participants followed up over an average of 7.3 years. After adjustment for demographics, education, income, body mass index, depressive symptoms, smoking, alcohol use, physical activity, comorbidities, APOE4 genotype, and baseline MMSE, those with a bedtime of before 9 p.m. were two times more likely to develop dementia [hazard ratio (HR)=2.16 (95%CI: 1.06–4.40)], compared to those going to bed between 9 and 11 p.m. Later bedtime (i.e., after 11 p.m.) showed the opposite but had a non-significant association with dementia risk (HR=0.15, 95%CI: 0.02–1.29). We did not find an association for rise time and risk of dementia.Conclusion: Earlier sleep timing in older adults without dementia was associated with an increased risk of dementia. Future studies should examine the underlying mechanisms of this association and explore the usefulness of sleep timing as a preclinical marker for dementia.

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“…Values of p < 0.0004 in two-tailed tests were considered significant (p=0.05 with Bonferroni correction for 123 potential exposures). We estimated effect size globally and by time between health condition exposure and AD diagnosis, as follows: (0 -2] years, (2 -10] years, and (10)(11)(12)(13)(14)(15) years. In this last category, no health condition was found to increase the risk of AD onset in both countries.…”

Section: Discussionmentioning

confidence: 99%

“…The lateness of these associations suggests that these conditions are probably prodromal symptoms of the disease rather than risk factors. For instance, a recent Mendelian randomised study 12 showed that AD was more likely to be the cause of sleep disorders rather than a consequence of these disorders.…”

Section: Discussionmentioning

confidence: 99%

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Data-driven identification of health conditions associated with incident Alzheimer’s disease dementia risk: a 15 years follow-up cohort from electronic health records in France and the United Kingdom

Nedelec

Couvy‐Duchesne

Monnet

et al. 2021

Preprint

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Importance. The identification of modifiable risk factors for Alzheimer s disease (AD) is paramount for early prevention and the targeting of new interventions. Objective. To assess the associations between health conditions diagnosed in primary care and the risk of incident AD over time. Design, Setting, and Participants. Data for 20,214 AD patients from the United Kingdom and 19,458 AD patients from France were extracted from The Health Improvement Network (THIN) database. For each AD case, a control was randomly assigned after matching for sex and age at dementia diagnosis. We agnostically tested the associations between 123 different ICD10 diagnoses extracted from health records and AD dementia, by conditional logistic regression. We focused on two time periods: 2 to 10 years vs. 0 to 2 years before the diagnosis of AD, to separate risk factors from early symptoms/comorbidities. Exposures. We considered all health conditions that had been recorded in more than 0.1% of visits per 1000 person-years in both cohorts, corresponding to 123 potential types of exposure. Main Outcomes and Measures. Odds ratios (ORs) for the association of AD with the various health conditions were calculated after Bonferroni correction for multiple comparisons. Results. Ten health conditions were significantly associated with high odds ratios for AD when diagnosed 2 to 10 years before AD, in the British and French samples: major depressive disorder (OR 95% confidence interval (UK):1.23-1.46)), anxiety (1.25-1.47), reaction to severe stress (1.24-1.59), hearing loss (1.11-1.28), constipation (1.22-1.41), spondylosis (1.14-1.39), abnormal weight loss (1.33-1.63), malaise and fatigue (1.14-1.32), memory loss (6.65-8.76) and syncope and collapse (1.1-1.37). Depression was the first comorbid condition associated with AD, appearing at least nine years before the first clinical diagnosis of AD, followed by, anxiety, constipation and abnormal weight loss. Conclusions and Relevance. These results from two independent primary care databases provide new evidence on the temporality of risk factors and early signs of Alzheimer s disease. These results could guide new dementia prevention strategies.

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Sleep, major depressive disorder, and Alzheimer disease

Cited by 61 publications

References 49 publications

Sleep and Alzheimer’s Disease: Shared Genetic Risk Factors, Drug Targets, Molecular Mechanisms, and Causal Effects

Sleep and Alzheimer’s Disease: Shared Genetic Risk Factors, Drug Targets, Molecular Mechanisms, and Causal Effects

Sleep Timing and Risk of Dementia Among the Chinese Elderly in an Urban Community: The Shanghai Aging Study

Data-driven identification of health conditions associated with incident Alzheimer’s disease dementia risk: a 15 years follow-up cohort from electronic health records in France and the United Kingdom

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