Alzheimer’s Disease Biomarkers and Complement Proteins Mediate the Impact of Sleep Fragmentation on Cognitive Impairment in Obstructive Sleep Apnea Patients Without Dementia
Restricted accessResearch articleFirst published online October 10, 2023
Alzheimer’s Disease Biomarkers and Complement Proteins Mediate the Impact of Sleep Fragmentation on Cognitive Impairment in Obstructive Sleep Apnea Patients Without Dementia
Cognitive impairment is common in patients with obstructive sleep apnea (OSA). Previous studies indicated that intermittent hypoxia, sleep fragmentation, and depressive symptoms were associated with cognitive impairment in OSA patients.
Objective:
The study aimed to investigate whether sleep characteristics and depressive symptoms affected cognitive abilities mediated by Alzheimer’s disease (AD) biomarkers and complement proteins in OSA patients without dementia.
Methods:
A total of 317 subjects without dementia who had undergone polysomnography, cognitive and neuropsychological evaluations, were recruited. Neuronal-derived exosomes (NDEs) levels for amyloid-β (Aβ), total tau (T-tau), and tau phosphorylated 62 at threonine 181 (P-T181-tau) and astrocyte-derived exosomes (ADEs) levels for complement proteins were measured. Mediation analysis were performed to explore the mediation effects of AD biomarkers (Aβ42, T-tau, P-T181-tau) and complement proteins (C3b and C5b-9) on cognition.
Results:
The findings revealed that the association between sleep fragmentation and cognition was mediated by Aβ42 (the percentage varied from 18.25% to 30.6%), P-T181-tau (the percentage varied from 24.36% to 32.3%), and C5b-9 (the percentage varied from 30.88% to 60.7%). The influence of depressive symptoms on cognition was only mediated via C3b (the percentage varied from 24.1% to 36.6%).
Conclusions:
In OSA patients without dementia, Aβ42 and P-T181-tau levels in NDEs, and C5b-9 levels in ADEs mediated the impact of sleep fragmentation on cognitive impairment, and C3b levels in ADEs mediated the impact of depressive symptoms on cognitive impairment.
HninK, MukherjeeS, AnticNA, CatchesideP, Chai-CoetzerCL, McEvoyD, VakulinA (2018) The impact of ethnicity on the prevalence and severity of obstructive sleep apnea. Sleep Med Rev41, 78–86.
4.
PeppardPE, YoungT, BarnetJH, PaltaM, HagenEW, HlaKM (2013) Increased prevalence of sleep-disordered breathing in adults. Am J Epidemiol177, 1006–1014.
5.
OlaitheM, BucksRS, HillmanDR, EastwoodPR (2018) Cognitive deficits in obstructive sleep apnea: Insights from a meta-review and comparison with deficits observed in COPD, insomnia, and sleep deprivation. Sleep Med Rev38, 39–49.
6.
BubuOM, AndradeAG, Umasabor-BubuOQ, HoganMM, TurnerAD, de LeonMJ, OgedegbeG, AyappaI, Jean-LouisGG, JacksonML, VargaAW, OsorioRS (2020) Obstructive sleep apnea, cognition and Alzheimer’s disease: A systematic review integrating three decades of multidisciplinary research. Sleep Med Rev50, 101250.
ZhouJ, CamachoM, TangX, KushidaCA (2016) A review of neurocognitive function and obstructive sleep apnea with or without daytime sleepiness. Sleep Med23, 99–108.
9.
AlomriRM, KennedyGA, WaliSO, AhejailiF, RobinsonSR (2021) Differential associations of hypoxia, sleep fragmentation, and depressive symptoms with cognitive dysfunction in obstructive sleep apnea. Sleep44, zsaa213.
OlaitheM, SkinnerTC, HillmanD, EastwoodPE, BucksRS (2015) Cognition and nocturnal disturbance in OSA: The importance of accounting for age and premorbid intelligence. Sleep Breath19, 221–230.
12.
GarbarinoS, BardwellWA, GuglielmiO, ChiorriC, BonanniE, MagnavitaN (2020) Association of anxiety and depression in obstructive sleep apnea patients: A systematic review and meta-analysis. Behav Sleep Med18, 35–57.
13.
LengY, McEvoyCT, AllenIE, YaffeK (2017) Association of sleep-disordered breathing with cognitive function and risk of cognitive impairment: A systematic review and meta-analysis. JAMA Neurol74, 1237–1245.
14.
LiguoriC, MaestriM, SpanettaM, PlacidiF, BonanniE, MercuriNB, GuarnieriB (2021) Sleep-disordered breathing and the risk of Alzheimer’s disease. Sleep Med Rev55, 101375.
KongW, ZhengY, XuW, GuH, WuJ (2021) Biomarkers of Alzheimer’s disease in severe obstructive sleep apnea-hypopnea syndrome in the Chinese population. Eur Arch Otorhinolaryngol278, 865–872.
18.
KuoCY, HsiaoHT, LoIH, NikolaiT (2020) Association between obstructive sleep apnea, its treatment, and Alzheimer’s disease: Systematic mini-review. Front Aging Neurosci12, 591737.
19.
KuoCY, StachivI, NikolaiT (2020) Association of late life depression, (non-) modifiable risk and protective factors with dementia and Alzheimer’s disease: Literature review on current evidences, preventive interventions and possible future trends in prevention and treatment of dementia. Int J Environ Res Public Health17, 7475.
20.
OwenJE, BenediktsdottirB, CookE, OlafssonI, GislasonT, RobinsonSR (2021) Alzheimer’s disease neuropathology in the hippocampus and brainstem of people with obstructive sleep apnea. Sleep44, zsaa195.
21.
SunH, GaoY, LiM, ZhangS, ShenT, YuanX, ShangX, LiZ, ZhangJ (2022) Altered amyloid-beta and tau proteins in neural-derived plasma exosomes in obstructive sleep apnea. Sleep Med94, 76–83.
22.
LiuX, MaY, OuyangR, ZengZ, ZhanZ, LuH, CuiY, DaiZ, LuoL, HeC, LiH, ZongD, ChenY (2020) The relationship between inflammation and neurocognitive dysfunction in obstructive sleep apnea syndrome. J Neuroinflammation17, 229.
23.
ShahA, KishoreU, ShastriA (2021) Complement system in Alzheimer’s disease. Int J Mol Sci22, 13647.
24.
WinstonCN, GoetzlEJ, SchwartzJB, ElahiFM, RissmanRA (2019) Complement protein levels in plasma astrocyte-derived exosomes are abnormal in conversion from mild cognitive impairment to Alzheimer’s disease dementia. Alzheimers Dement (Amst)11, 61–66.
25.
KalluriR, LeBleuVS (2020) The biology, function, and biomedical applications of exosomes. Science367, eaau6977.
26.
JiaL, QiuQ, ZhangH, ChuL, DuY, ZhangJ, ZhouC, LiangF, ShiS, WangS, QinW, WangQ, LiF, WangQ, LiY, ShenL, WeiY, JiaJ (2019) Concordance between the assessment of Abeta42, T-tau, and P-T181-tau in peripheral blood neuronal-derived exosomes and cerebrospinal fluid. Alzheimers Dement15, 1071–1080.
27.
Delgado-PerazaF, Nogueras-OrtizCJ, VolpertO, LiuD, GoetzlEJ, MattsonMP, GreigNH, EitanE, KapogiannisD (2021) Neuronal and astrocytic extracellular vesicle biomarkers in blood reflect brain pathology in mouse models of Alzheimer’s disease. Cells10, 933.
28.
ChenKL, XuY, ChuAQ, DingD, LiangXN, NasreddineZS, DongQ, HongZ, ZhaoQH, GuoQH (2016) Validation of the Chinese version of montreal cognitive assessment basic for screening mild cognitive impairment.. J Am Geriatr Soc64, e285–e290.
29.
LiH, JiaJ, YangZ (2016) Mini-Mental State examination in elderly Chinese: A population-based normative study. J Alzheimers Dis53, 487–496.
30.
GagnonK, BarilAA, MontplaisirJ, CarrierJ, ChamiS, GauthierS, LafondC, GagnonJF, GosselinN (2018) Detection of mild cognitive impairment in middle-aged and older adults with obstructive sleep apnoea. Eur Respir J52, 1801137.
31.
WinbladB, PalmerK, KivipeltoM, JelicV, FratiglioniL, WahlundLO, NordbergA, BackmanL, AlbertM, AlmkvistO, AraiH, BasunH, BlennowK, de LeonM, DeCarliC, ErkinjunttiT, GiacobiniE, GraffC, HardyJ, JackC, JormA, RitchieK, van DuijnC, VisserP, PetersenRC (2004) Mild cognitive impairment–beyond controversies, towards a consensus: Report of the International Working Group on Mild Cognitive Impairment. J Intern Med256, 240–246.
32.
ZimmermanM, MartinezJH, YoungD, ChelminskiI, DalrympleK (2013) Severity classification on the Hamilton Depression Rating Scale. J Affect Disord150, 384–388.
33.
BerryRB, AlbertarioCL, HardingSM, LloydRM, PlanteDT, QuanSF, TroesterMM, VaughnBV, American Academy of Sleep Medicine (2018) The AASM Manual for the Scoring of Sleep and Associated Events: Rules, Terminology and Technical Specifications. Version 2.5. American Academy of Sleep Medicine, Darien, IL.
34.
LiM, SunH, ShenT, XueS, ZhaoY, LengB, ZhangJ, LiZ, XiaZ (2021) Increased serum levels of cyclophilin a and matrix metalloproteinase-9 are associated with cognitive impairment in patients with obstructive sleep apnea. Sleep Med93, 75–83.
35.
ZhangJ, ChiH, WangT, ZhangS, ShenT, LengB, SunH, LiZ, LiF (2021) Altered amyloid-beta and tau proteins in neural-derived plasma exosomes of type 2 diabetes patients with orthostatic hypotension. J Alzheimers Dis82, 261–272.
YanL, ParkHR, KezirianEJ, YookS, KimJH, JooEY, KimH (2021) Altered regional cerebral blood flow in obstructive sleep apnea is associated with sleep fragmentation and oxygen desaturation. J Cereb Blood Flow Metab41, 2712–2724.
38.
Shokri-KojoriE, WangGJ, WiersCE, DemiralSB, GuoM, KimSW, LindgrenE, RamirezV, ZehraA, FreemanC, MillerG, ManzaP, SrivastavaT, De SantiS, TomasiD, BenvenisteH, VolkowND (2018) Beta-amyloid accumulation in the human brain after one night of sleep deprivation. Proc Natl Acad Sci U S A115, 4483–4488.
39.
CordoneS, AnnarummaL, RossiniPM, De GennaroL (2019) Sleep and beta-amyloid deposition in Alzheimer disease: Insights on mechanisms and possible innovative treatments. Front Pharmacol10, 695.
40.
BarthelemyNR, LiuH, LuW, KotzbauerPT, BatemanRJ, LuceyBP (2020) Sleep deprivation affects tau phosphorylation in human cerebrospinal fluid. Ann Neurol87, 700–709.
41.
d’Oleire UquillasF, JacobsHIL, HanseeuwB, MarshallGA, ProperziM, SchultzAP, LaPointMR, JohnsonKA, SperlingRA, VanniniP (2018) Interactive versus additive relationships between regional cortical thinning and amyloid burden in predicting clinical decline in mild AD and MCI individuals. Neuroimage Clin17, 388–396.
42.
VilleneuveS, ReedBR, WirthM, HaaseCM, MadisonCM, AyaktaN, MackW, MungasD, ChuiHC, DeCarliC, WeinerMW, JagustWJ (2014) Cortical thickness mediates the effect of beta-amyloid on episodic memory. Neurology82, 761–767.
43.
DigmaLA, MadsenJR, ReasET, DaleAM, BrewerJB, BanksSJ; Alzheimer’s Disease Neuroimaging Initiative (2019) Tau and atrophy: Domain-specific relationships with cognition. Alzheimers Res Ther11, 65.
44.
TidemanP, StomrudE, LeuzyA, Mattsson-CarlgrenN, PalmqvistS, HanssonO; Alzheimer’s Disease Neuroimaging Initiative (2022) Association of beta-amyloid accumulation with executive function in adults with unimpaired cognition. Neurology98, e1525–e1533.
45.
JonesDT, Graff-RadfordJ, LoweVJ, WisteHJ, GunterJL, SenjemML, BothaH, KantarciK, BoeveBF, KnopmanDS, PetersenRC, JackCRJr (2017) Tau, amyloid, and cascading network failure across the Alzheimer’s disease spectrum. Cortex97, 143–159.
46.
PelkmansW, LegdeurN, Ten KateM, BarkhofF, YaqubMM, HolstegeH, van BerckelBNM, ScheltensP, van der FlierWM, VisserPJ, TijmsBM (2021) Amyloid-beta, cortical thickness, and subsequent cognitive decline in cognitively normal oldest-old. Ann Clin Transl Neurol8, 348–358.
47.
MueedZ, RaiPK, KamalMA, PoddarNK (2021) Decoding the inter-relationship between sleep disorders and Alzheimer’s disease pathogenesis. CNS Neurol Disord Drug Targets20, 723–735.
48.
HajishengallisG, ReisES, MastellosDC, RicklinD, LambrisJD (2017) Novel mechanisms and functions of complement. Nat Immunol18, 1288–1298.
49.
WadhwaM, PrabhakarA, AnandJP, RayK, PrasadD, KumarB, PanjwaniU (2019) Complement activation sustains neuroinflammation and deteriorates adult neurogenesis and spatial memory impairment in rat hippocampus following sleep deprivation. Brain Behav Immun82, 129–144.
50.
LiM, SunC, XueS, LengB, SunH, ShenT, LiuX, LiZ, ShangX, ZhangJ (2023) Complement protein levels in serum astrocyte-derived exosomes are associated with cognitive impairment in obstructive sleep apnea. J Clin Sleep Med19, 727–739.
51.
ShoibS, MalikJA, MasoodiS (2017) Depression as a manifestation of obstructive sleep apnea. J Neurosci Rural Pract8, 346–351.
52.
BeurelE, ToupsM, NemeroffCB (2020) The bidirectional relationship of depression and inflammation: Double trouble. Neuron107, 234–256.
