[en] Study objectives: Sleep disturbances and genetic variants have been identified as risk factors for Alzheimer's disease. Our goal was to assess whether genome-wide polygenic risk scores (PRS) for AD associate with sleep phenotypes in young adults, decades before typical AD symptom onset.
Methods: We computed whole-genome Polygenic Risk Scores (PRS) for AD and extensively phenotyped sleep under different sleep conditions, including baseline sleep, recovery sleep following sleep deprivation and extended sleep opportunity, in a carefully selected homogenous sample of healthy 363 young men (22.1 y ± 2.7) devoid of sleep and cognitive disorders.
Results: AD PRS was associated with more slow wave energy, i.e. the cumulated power in the 0.5-4 Hz EEG band, a marker of sleep need, during habitual sleep and following sleep loss, and potentially with large slow wave sleep rebound following sleep deprivation. Furthermore, higher AD PRS was correlated with higher habitual daytime sleepiness.
Conclusions: These results imply that sleep features may be associated with AD liability in young adults, when current AD biomarkers are typically negative, and the notion that quantifying sleep alterations may be useful in assessing the risk for developing AD.
Disciplines :
Genetics & genetic processes
Author, co-author :
Muto, Vincenzo ✱; Université de Liège - ULiège > CRC In vivo Imaging-Sleep and chronobiology
Koshmanova, Ekaterina ✱; Université de Liège - ULiège > CRC In vivo Imaging-Sleep and chronobiology
Musiek ES, Holtzman DM. Three dimensions of the amyloid hypothesis: time, space and "wingmen." Nat Neurosci. 2015;18(6):800-806. doi:10.1038/nn.4018
Jack CR Jr, et al. NIA-AA research framework: toward a biological definition of Alzheimer?s disease. Alzheimers Dement. 2018;14(4):535-562.
Scheltens P, et al. Alzheimer?s disease. Lancet. 2016;388(10043):505-517.
Norton S, et al. Potential for primary prevention of Alzheimer?s disease: an analysis of population-based data. Lancet Neurol. 2014;13(8):788-794.
Van Egroo M, et al. Sleep-wake regulation and the hallmarks of the pathogenesis of Alzheimer?s disease. Sleep. 2019;42(4). doi:10.1093/sleep/zsz017
Al-Qassabi A, et al. Sleep disturbances in the prodromal stage of Parkinson disease. Curr Treat Options Neurol. 2017;19(6):22.
Mander BA, et al. ?-amyloid disrupts human NREM slow waves and related hippocampus-dependent memory consolidation. Nat Neurosci. 2015;18(7):1051-1057.
Lucey BP, et al. Reduced non-rapid eye movement sleep is associated with tau pathology in early Alzheimer?s disease. Sci Transl Med. 2019;11(474):eaau6550. doi:10.1126/ SCITRANSLMED.AAU6550
Branger P, et al. Relationships between sleep quality and brain volume, metabolism, and amyloid deposition in late adulthood. Neurobiol Aging. 2016;41:107-114. doi:10.1016/j. neurobiolaging.2016.02.009
Pase MP, et al. Sleep architecture and the risk of incident dementia in the community. Neurology. 2017;89(12). doi: 10.1212/WNL.0000000000004373
Lim AS, et al. Sleep fragmentation and the risk of incident Alzheimer?s disease and cognitive decline in older persons. Sleep. 2013;36(7):1027-1032.
Holth JK, et al. The sleep-wake cycle regulates brain interstitial fluid tau in mice and CSF tau in humans. Science. 2019;363:880-884. doi:10.1126/science.aav2546
Ooms S, et al. Effect of 1 night of total sleep deprivation on cerebrospinal fluid ?-amyloid 42 in healthy middle-aged men: a randomized clinical trial. JAMA Neurol. 2014;71(8):971-977.
Ju YS, et al. Slow wave sleep disruption increases cerebrospinal fluid amyloid-? levels. Brain. 2017;140(8):2104-2111.
Mather M, et al. The locus coeruleus: essential for maintaining cognitive function and the aging brain. Trends Cogn Sci. 2016;20(3):214-226.
Braak H, Del Tredici K. The pathological process underlying Alzheimer?s disease in individuals under thirty. Acta Neuropathol. 2011;121(2):171-181. doi:10.1007/ s00401-010-0789-4
Gatz M, et al. Role of genes and environments for explaining Alzheimer disease. Arch Gen Psychiatry. 2006;63(2):168-174.
Ertekin-Taner N. Genetics of Alzheimer disease in the preand post-GWAS era. Alzheimers Res Ther. 2010;2(1):3.
Ge T, et al. Polygenic prediction via Bayesian regression and continuous shrinkage priors. Nat Commun. 2019;10(1):1776.
Martiskainen H, et al. Effects of Alzheimer?s diseaseassociated risk loci on cerebrospinal fluid biomarkers and disease progression: a polygenic risk score approach. J Alzheimers Dis. 2015;43(2):565-573.
Ge T, et al. Dissociable influences of APOE ?4 and polygenic risk of AD dementia on amyloid and cognition. Neurology. 2018;90(18):e1605-e1612.
Sabuncu MR, et al. The association between a polygenic Alzheimer score and cortical thickness in clinically normal subjects. Cereb Cortex. 2012;22(11):2653-2661.
Marden JR, et al. Using an Alzheimer disease polygenic risk score to predict memory decline in Black and White Americans over 14 years of follow-up. Alzheimer Dis Assoc Disord. 2016;30(3):195-202.
Mormino EC, et al. Polygenic risk of Alzheimer disease is associated with early-and late-life processes. Neurology. 2016;87(5):481-488.
Foley SF, et al. Multimodal brain imaging reveals structural differences in Alzheimer?s disease polygenic risk carriers: a study in healthy young adults. Biol Psychiatry. 2017;81(2):154-161.
Beck AT, et al. Psychometric properties of the Beck Depression Inventory: twenty-five years of evaluation. Clin Psychol Rev. 1988;8:77-100. doi: 10.1016/0272-7358(88)90050-5
Buysse DJ, et al. The Pittsburgh Sleep Quality Index: a new instrument for psychiatric practice and research. Psychiatry Res. 1989;28(2):193-213.
Johns MW. A new method for measuring daytime sleepiness: The Epworth Sleepiness Scale. Sleep. 1991;14(6):540-545. doi:10.1016/j.sleep.2007.08.004
John, Raven J. Raven progressive matrices. In: Handbook of Nonverbal Assessment. Boston, MA: Springer; 2003:223-237. doi:10.1007/978-1-4615-0153-4_11
Berthomier C, et al. Exploring scoring methods for research studies: accuracy and variability of visual and automated sleep scoring. J Sleep Res. 2020:1-11. doi: 10.1111/jsr.12994
?t Wallant DC, et al. Automatic artifacts and arousals detection in whole-night sleep EEG recordings. J Neurosci Methods. 2016;258:124-133.
Skorucak J, et al. Response to chronic sleep restriction, extension, and total sleep deprivation in humans: adaptation or preserved sleep homeostasis? Sleep. 2018;41(1). doi: 10.1093/sleep/zsy078
Schmidt C, et al. Age-related changes in sleep and circadian rhythms: impact on cognitive performance and underlying neuroanatomical networks. Front Neurol. 2012;3:118.
Dijk D-J, Landolt H-P. Sleep physiology, circadian rhythms, waking performance and the development of sleep-wake therapeutics. In: Dijk DJ, Landolt HP, eds. Handbook of Experimental Pharmacology. Berlin, Heidelberg: Springer; 2019:1-41. doi: 10.1007/164_2019_243
Purcell S, et al. PLINK: a tool set for whole-genome association and population-based linkage analyses. Am J Hum Genet. 2007;81(3):559-575.
Altshuler DL, et al. A map of human genome variation from population-scale sequencing. Nature. 2010;467(7319):1061-1073. doi:10.1038/nature09534
Yengo L, et al. Meta-analysis of genome-wide association studies for height and body mass index in ?700000 individuals of European ancestry. Hum Mol Genet. 2018;27(20):3641-3649.
Marioni RE, et al. GWAS on family history of Alzheimer?s disease. Transl Psychiatry. 2018;8(1):99.
Sudlow C, et al. UK biobank: an open access resource for identifying the causes of a wide range of complex diseases of middle and old age. PLoS Med. 2015;12(3):e1001779.
Lambert JC, et al. Meta-analysis of 74,046 individuals identifies 11 new susceptibility loci for Alzheimer?s disease. Nat Genet. 2013;45(12):1452-1458.
Sleegers K, et al. A 22-single nucleotide polymorphism Alzheimer?s disease risk score correlates with family history, onset age, and cerebrospinal fluid A?42. Alzheimers Dement. 2015;11(12):1452-1460.
Escott-Price V, et al. Common polygenic variation enhances risk prediction for Alzheimer?s disease. Brain. 2015;138(Pt 12):3673-3684.
Faul F, et al. G * Power 3: a flexible statistical power analysis program for the social, behavioral, and biomedical sciences. Behav Res Methods. 2007;39(2):175-191.
Santoro ML, et al. Polygenic risk score analyses of symptoms and treatment response in an antipsychotic-naive first episode of psychosis cohort. Transl Psychiatry. 2018;8(1):174.
Dudbridge F. Power and predictive accuracy of polygenic risk scores. PLoS Genet. 2013;9(3):e1003348.
Ettore E, et al. Relationships between objectives sleep parameters and brain amyloid load in subjects at risk to Alzheimer?s disease: the INSIGHT-preAD Study. Sleep. 2019;42:1-9. doi: 10.1093/sleep/zsz137
Carrier J, et al. Sleep slow wave changes during the middle years of life. Eur J Neurosci. 2011;33(4):758-766.
Kunkle BW, et al. Author correction: genetic meta-analysis of diagnosed Alzheimer?s disease identifies new risk loci and implicates A?, tau, immunity and lipid processing. Nat Genet. 2019;51(9):1423-1424.
Dijk DJ, et al. Contribution of the circadian pacemaker and the sleep homeostat to sleep propensity, sleep structure, electroencephalographic slow waves, and sleep spindle activity in humans. J Neurosci. 1995;15(5 Pt 1):3526-3538.
Steriade M, et al. Slow sleep oscillation, rhythmic K-complexes, and their paroxysmal developments. J Sleep Res. 1998;7 Suppl 1:30-35.
Klerman EB, et al. Interindividual variation in sleep duration and its association with sleep debt in young adults. Sleep. 2005;28(10):1253-1259.
Viola AU, et al. PER3 polymorphism predicts sleep structure and waking performance. Curr Biol. 2007;17(7):613-618.
Tononi G, et al. Sleep and the price of plasticity: from synaptic and cellular homeostasis to memory consolidation and integration. Neuron. 2014;81(1):12-34.
Scammell TE, et al. Neural circuitry of wakefulness and sleep. Neuron. 2017;93(4):747-765.
Huber R, et al. Human cortical excitability increases with time awake. Cereb Cortex. 2013;23(2):332-338.
Ly JQM, et al. Circadian regulation of human cortical excitability. Nat Commun. 2016;7:11828.
Dash MB, et al. Long-term homeostasis of extracellular glutamate in the rat cerebral cortex across sleep and waking states. J Neurosci. 2009;29(3):620-629.
Hefti K, et al. Increased metabotropic glutamate receptor subtype 5 availability in human brain after one night without sleep. Biol Psychiatry. 2013;73(2):161-168.
Bero AW, et al. Neuronal activity regulates the regional vulnerability to amyloid-? deposition. Nat Neurosci. 2011;14(6):750-756.
Bero AW, et al. Bidirectional relationship between functional connectivity and amyloid-? deposition in mouse brain. J Neurosci. 2012;32(13):4334-4340.
Thal DR, et al. Phases of A beta-deposition in the human brain and its relevance for the development of AD. Neurology. 2002;58(12):1791-1800.
Braak H, et al. The preclinical phase of the pathological process underlying sporadic Alzheimer?s disease. Brain. 2015;138(Pt 10):2814-2833.
Roh JH, et al. Disruption of the sleep-wake cycle and diurnal fluctuation of ?-amyloid in mice with Alzheimer?s disease pathology. Sci Transl Med. 2012;4(150):150ra122.
Chai X, et al. Constitutive secretion of tau protein by an unconventional mechanism. Neurobiol Dis. 2012;48(3):356-366.
Yamada K, et al. Neuronal activity regulates extracellular tau in vivo. J Exp Med. 2014;211(3):387-393.
Schultz MK Jr, et al. Pharmacogenetic neuronal stimulation increases human tau pathology and trans-synaptic spread of tau to distal brain regions in mice. Neurobiol Dis. 2018;118:161-176.
Crimins JL, et al. Electrophysiological changes precede morphological changes to frontal cortical pyramidal neurons in the rTg4510 mouse model of progressive tauopathy. Acta Neuropathol. 2012;124(6):777-795.
Nilsen LH, et al. Glutamate metabolism is impaired in transgenic mice with tau hyperphosphorylation. J Cereb Blood Flow Metab. 2013;33(5):684-691.
Holth JK, et al. Tau loss attenuates neuronal network hyperexcitability in mouse and Drosophila genetic models of epilepsy. J Neurosci. 2013;33(4):1651-1659.
Polydoro M, et al. Soluble pathological tau in the entorhinal cortex leads to presynaptic deficits in an early Alzheimer?s disease model. Acta Neuropathol. 2014;127(2):257-270.
Van der Jeugd A, et al. Cognitive defects are reversible in inducible mice expressing pro-aggregant full-length human Tau. Acta Neuropathol. 2012;123(6):787-805.
Sydow A, et al. Tau-induced defects in synaptic plasticity, learning, and memory are reversible in transgenic mice after switching off the toxic Tau mutant. J Neurosci. 2011;31(7):2511-2525.
Oddo S, et al. Triple-transgenic model of Alzheimer?s disease with plaques and tangles. Neuron. 2003;39(3):409-421. doi:10.1016/S0896-6273(03)00434-3
Fein JA, et al. Co-localization of amyloid beta and tau pathology in Alzheimer?s disease synaptosomes. Am J Pathol. 2008;172(6):1683-1692.
Svetnik V, et al. EEG spectral analysis of NREM sleep in a large sample of patients with insomnia and good sleepers: effects of age, sex and part of the night. J Sleep Res. 2017;26(1):92-104.
Horne JA, et al. A self-assessment questionnaire to determine morningness-eveningness in human circadian rhythms. Int J Chronobiol. 1976;4(2):97-110.