Genetic Risk of Alzheimer's Disease and Sleep Duration in Non‐Demented Elders

Abstract

Growing evidence has suggested an association between sleep duration and Alzheimer's disease (AD), but it is unclear if sleep duration is a manifestation of the AD disease process. We studied whether genetic liability for AD predicts sleep duration using a genetic risk score (GRS) for AD (AD‐GRS), in 406,536 UK Biobank participants with European ancestry and without dementia at enrollment. Higher AD‐GRS score was associated with shorter sleep (b = −0.014, 95% confidence interval [CI] = −0.022 to −0.006), especially in those aged 55+. Using AD‐GRS as an instrumental variable for AD diagnosis, incipient AD reduced sleep duration by 1.87 hours (95% CI = 0.96, 2.78). Short sleep duration might be an early marker of AD. ANN NEUROL 2021;89:177–181

The Genetic Architecture of Alzheimer’s Disease Risk: A Genomic Structural Equation Modelling Study

“…This factor might reflect only an apparent protective effect of these factors on AD due to premature mortality and survival bias [35][36][37], or could simply reflect a clustering of these traits independent of AD. Factor 3 included positive loadings for AD and a subset of risk factors that have complex relationships with AD in that they have all been hypothesised to be disease prodromes as well as causal risk factors [6][7][8][9]38]. Moreover, systolic blood pressure negatively loaded onto this factor, and whereas risk of dementia is associated with higher blood pressure in mid-life, blood pressure declines during the period prior to cognitive symptoms and dementia diagnosis [39][40][41][42].…”

“…However, the mechanisms by which these factors influence dementia risk, and whether they are truly causal, remain incompletely understood. Some factors such as sleep disturbance, social isolation, depression and hearing difficulty could, at least partly, serve as prodromal risk markers rather than causal risk factors [6][7][8][9]. An improved understanding of the causal pathways to clinical dementia development is urgently needed to support prevention efforts through the prioritisation of targets for intervention studies.…”

Applications of brain organoids in neurodevelopment and neurological diseases

“…AD currently affects more than 40 million people worldwide, and patients suffer from varying degrees of cognitive decline and severe memory impairment [72]. Researchers have been committed to understanding the pathological process of Alzheimer's disease and developing effective drugs [73,74]. Mutations in the amyloid-β precursor protein (APP) [75] and presenilin (PS) 1 genes [76] have been found to contribute to familial AD (FAD).…”

“…PD is characterized by the loss of dopamine in the substantia nigra and the dysregulation of fine motor control localized in the basal ganglia, which leads to the clinical parkinsonian symptoms, including bradykinesia, muscular rigidity, and resting tremors [82]. The LRRK2 G2019S gene mutation was reported to be associated with the progressive loss of dopamine neurons in the PD pathological process [73]. Recently, Kim et al generated 3D midbrain organoids derived from iPSCs with the LRRK2 G2019S mutation to gain a deeper understanding of the role of the LRRK2 mutation in the pathogenic mechanisms of PD [69].…”

Methods to Address Self-Selection and Reverse Causation in Studies of Neighborhood Environments and Brain Health

“…In our second case study, we evaluate the possibility of reverse causation. We use an instrumental variable to study the association between episodic memory as the predictor and neighborhood greenness as the outcome, modeled after a similar method employed in prior studies [ 65 , 66 , 67 ]. Data came from 243 participants from the University of California, Davis Alzheimer’s Disease Research Center (ADRC) in Northern California.…”