Self‐reported obstructive sleep apnea, amyloid and tau burden, and Alzheimer's disease time‐dependent progression

Abstract

Introduction Obstructive sleep apnea (OSA) is associated with Alzheimer's disease (AD) biomarkers in cognitively normal (CN) and mild cognitive impaired (MCI) participants. However, independent and combined effects of OSA, amyloid beta (Aβ) and tau‐accumulation on AD time‐dependent progression risk is unclear. Methods Study participants grouped by biomarker profile, as described by the A/T/N scheme, where “A” refers to aggregated Aβ, “T” aggregated tau, and “N” to neurodegeneration, included 258 CN (OSA‐positive [OSA+] [A+TN+ n = 10, A+/TN− n = 6, A−/TN+ n = 10, A−/TN− n = 6 and OSA‐negative [OSA‐] [A+TN+ n = 84, A+/TN− n = 11, A−/TN+ n = 96, A−/TN− n = 36]) and 785 MCI (OSA+ [A+TN+ n = 35, A+/TN− n = 15, A−/TN+ n = 25, A−/TN− n = 16] and OSA− [A+TN+ n = 388, A+/TN− n = 28, A−/TN+ n = 164, A−/TN− n = 114]) older‐adults from the Alzheimer's Disease Neuroimaging Initiative cohort. Cox proportional hazards regression models estimated the relative hazard of progression from CN‐to‐MCI and MCI‐to‐AD, among baseline OSA CN and MCI patients, respectively. Multi‐level logistic mixed‐effects models with random intercept and slope investigated the synergistic associations of self‐reported OSA, Aβ, and tau burden with prospective cognitive decline. Results Independent of TN‐status (CN and MCI), OSA+/Aβ+ participants were approximately two to four times more likely to progress to MCI/AD (P < .001) and progressed 6 to 18 months earlier (P < .001), compared to other participants combined (ie, OSA+/Aβ−, OSA−/Aβ+, and OSA−/Aβ−). Notably, OSA+/Aβ− versus OSA−/Aβ− (CN and MCI) and OSA+/TN− versus OSA−/TN− (CN) participants showed no difference in the risk and time‐to‐MCI/AD progression. Mixed effects models demonstrated OSA synergism with Aβ (CN and MCI [β = 1.13, 95% confidence interval (CI), 0.74 to 1.52, and β = 1.18, 95%CI, 0.82 to 1.54]) respectively, and with tau (MCI [β = 1.31, 95% CI, 0.87 to 1.47]), P < .001 for all. Discussion OSA acts in synergism with Aβ and with tau, and all three acting together result in synergistic neurodegenerative mechanisms especially as Aβ and tau accumulation becomes increasingly abnormal, thus leading to shorter progression time to MCI/AD in CN and MCI‐OSA patients, respectively.

WITHDRAWN: Sleep Treatment Improves Neuropsychological Symptoms and Reduces Blood Aβ42/pTau Protein in Alzheimer's Disease Patients: a Longitudinal Study

“…Aberrant accumulation of amyloid peptides and aggregation of phosphorylated Tau protein are the major pathogenic factors in the development and progression of Alzheimer's disease 3,8 . Studies in mouse models of Alzheimer's disease and in humans have convincingly demonstrated a tight association between sleep disorder and Alzheimer's disease in terms of amyloid peptides and Tau proteins 14,15,[43][44][45][46] . Increased cerebrospinal fluid and blood levels of amyloid peptides and phosphorylated Tau protein were reported in patients with sleep disturbances 9,16,17,[47][48][49] and have been considered as biomarkers for disease progression 11 .…”

“…These sleep behavior changes began in the prodromal phase of Alzheimer's disease while patients only suffered from mild cognitive impairment, possibly due to amyloid/Tau pathology before cognition decline 14 . Recent studies showed that sleep deprivation or disturbances increased A peptides and Tau proteins in CSF solution compared to normal sleep controls 9,[15][16][17] due to elevated production of A peptides 18 , which was supported by studies from transgenic mouse models of Alzheimer's disease 19 . On the other hand, a healthy sleep cycle was shown to facilitate A clearance from the brain tissue 20 .…”

The Link Between Obstructive Sleep Apnoea and Neurodegeneration and Cognition

“…In the other direction, OSA has been proposed as a risk factor for AD as it promotes or enhances AD-related subclinical pathological processes. In fact, multiple recent studies based on large cohorts have shown that subjects with OSA are, depending on the study, between 1.49 and 2.21 times more likely to develop AD than individuals not suffering from OSA [16,17,[39][40][41]. Furthermore, Bubu et al (2021) showed that individuals with OSA have shorter progression times between cognitively normal (CN) to mild cognitive impairment (MCI) or MCI to AD [17].…”

“…In fact, multiple recent studies based on large cohorts have shown that subjects with OSA are, depending on the study, between 1.49 and 2.21 times more likely to develop AD than individuals not suffering from OSA [16,17,[39][40][41]. Furthermore, Bubu et al (2021) showed that individuals with OSA have shorter progression times between cognitively normal (CN) to mild cognitive impairment (MCI) or MCI to AD [17]. One proposed mechanism through which OSA could have an effect on AD pathology is via a dysregulation of the Aβ metabolism caused by intermittent hypoxia and reduced clearance from interstitial to cerebrospinal fluid (CSF) caused by sleep fragmentation, resulting in decreased CSF Aβ 40 and 42 levels and increased Aβ plaque formation.…”

“…Alternatively, oral devices or, in extreme cases, surgical procedures are available [2]. A growing body of evidence has shown the impact of OSA on reduced cognition [5][6][7][8][9], brain morphology [3,[10][11][12][13], and neurodegenerative pathophysiology [11,[14][15][16][17][18]. Furthermore, it has been shown that the treatment of OSA mitigates some of its negative consequences [13,16,[19][20][21], suggesting that, with readily available treatment options, OSA is a promising target to delay the onset of neurodegenerative disorders such as dementia, Alzheimer's disease (AD), or Parkinson's disease (PD).…”