Researchers noted that further examinations are needed of the genetic heterogeneity depression syndromes to test for causal relationships between distinct subtypes of depression and Alzheimer disease.
Data from bi-directional 2-sample Mendelian randomization (MR) analyses suggest that Alzheimer disease (AD) may causally influence sleep patterns, despite no evidence to support a causal role of disturbed sleep patterns for AD or evidence of a causal relationship between major depressive disorder (MDD) and AD.
Conducted by Jian Huang, PhD, MRC Centre for Environment and Health, Imperial College London, and colleagues, the study contained genetic associations from the largest genome-wide association studies currently available, including UK Biobank (n = 446,118), the Psychiatric Genomics Consortium (n = 18,759), and the International Genomics of Alzheimer’s Project (n = 63,926).
Huang and co-investigators found that a higher risk of AD was significantly associated with being a “morning person” (odds ratio [OR], 1.01; P = .001) and shorter sleep duration (self-reported ß = —0.006; P = 1.9x10-4; accelerometer-based ß = —0.015; P = 6.9x10-5) after adjusting for multiple comparisons. Chronotype was considered as the proclivity for earlier or later timing of sleep and the distinction of being a “morning person” was answered by each of the individuals and defined as an individual who prefers going to bed and waking earlier.
Further results showed that after adjusting for multiple comparisons, the risk of AD was significantly associated with those who were less likely to report long sleep (ß = —0.003; P = 7.3x10-7), earlier timing of the least active 5 hours (ß = —0.024; P = 1.7x10-13), and a smaller number of sleep episodes (ß = —0.025; P = 5.7x10-14).
An increased risk of AD was also associated with lower risk of insomnia (OR, 0.99; P = 7x10-13). There was no evidence to suggest that these abnormal sleep patterns were causally related to AD or for a significant causal relationship between MDD and a risk of AD.
“Previous studies considered multiple sleep-related phenotypes together as a global concept of sleep disturbances, while we investigated a number of the commonly characterized sleep-related phenotypes separately,” Huang and colleagues noted. “Our concern was that, given the complexity of sleep, the different sleep-related phenotypes provide measures of different elements of sleep behavior.”
In addition to the inverse variance weighted (IVW) Mendelian randomization method to estimate causal effects, researchers used weighted median (WM) and MR-Egger for sensitivity analyses to test for pleiotropic effects. Investigators also compared data to a genome-wide association study (GWAS), those of which showed no evidence for shared genetic architecture between depression and AD.
MR findings using IVW, WM, and MR-Egger were consistent. Results based on the GWAS of AD/AD-by-proxy cases were also similar, except that accelerometer-based sleep duration was the only significant sleep phenotype that appeared to be potentially caused by AD using IVW after adjusting for multiple comparisons.
Huang and colleagues also performed sensitivity analysis that excluded APOE4 single nucleotide polymorphisms (SNPs; rs7412 and rs429358), an ancestral gene with pleotropic effects that can contribute to AD risk. Without APOE4, the causal associations of AD with self-reported and accelerometer-based sleep duration were not significant. However, all other causal associations of AD on sleep phenotypes examined were supported.
“As a first step toward better understanding the basis for observed associations between depression and AD, future work could explore the genetic heterogeneity of depression syndromes to test for causal relationships between potentially etiologically distinct sub-types of depression and AD,” the study authors concluded.
The associations of sleep pattern disruption with AD has been well documented. In February, the FDA approved an expanded indication for suvorexant (Belsomra; Merck) for the treatment of insomnia in patients with mild to moderate AD. The oral orexin receptor antagonist, previously approved for the treatment of insomnia, has made a staple as the 1 of the leading drugs impacting quality of life measures for those with AD.2
Pimavanserin (Nuplazid), a treatment for hallucinations and delusions associated with dementia-related psychosis (DRP) recently had its supplemental new drug application (sNDA) accepted by the FDA and awaits a scheduled prescription drug user fee act (PDUFA) date of April 3, 2021. If approved, pimavanserin would be the first therapy indicated for the treatment of hallucinations and delusions associated with DRP.3
1. Huang J, Zuber V, Matthews PM, Elliot P, Tzoulaki J, Dehghan A. Sleep, major depressive disorder and Alzheimer’s disease: a Mendelian randomization study. Neurology. Published online August 19, 2020. doi: 10.1212/WNL.0000000000010463
2. Merck receives approval for belsomra (suvorexant) C-IV label update to include findings from study of insomnia in patients with mild-to-moderate Alzheimer’s disease [news release]. Kenilworth, NJ: Merck. February 3, 2020. mrknewsroom.com/news-release/prescription-medicine-news/merck-receives-approval-belsomra-suvorexant-c-iv-label-updat. Accessed August 20, 2020.
3. Acadia Pharmaceuticals announces US FDA accepted for filing the supplemental new drug application for Nuplazid (pimavanserin) for the treatment of hallucinations and delusions associated with dementia-related psychosis [news release]. San Diego, CA. Acadia Pharmaceuticals. Published online July 20, 2020. Accessed July 22, 2020. ir.acadia-pharm.com/news-releases/news-release-details/acadia-pharmaceuticals-announces-us-fda-accepted-filing?field_nir_news_date_value%5Bmin%5D=