Evidence of neurodegeneration in obstructive sleep apnea: Relationship between obstructive sleep apnea and cognitive dysfunction in the elderly

Abstract

The incidence of dementia and obstructive sleep apnea (OSA) increases with age. Late-onset Alzheimer's disease (AD) is an irreversible neurodegenerative disease of the elderly characterized by amyloid β (Aβ) plaques and neurofibrillary tangles. The disease involves widespread synaptic loss in the neocortex and the hippocampus. Rodent and clinical studies suggest that OSA impairs the structural integrity of several brain regions, including the medial temporal lobe. Indeed, hypoxia, hypertension, hypoperfusion, endothelial dysfunction, inflammation, and oxidative stress noted in OSA patients also occur in AD patients. This Review highlights pathological commonality, showing that OSA upregulates Aβ, tau hyperphosphorylation, and synaptic dysfunction. Indeed, OSA and hypertension trigger hypoperfusion and hypometabolism of brain regions, including cortex and hippocampus. Several studies show that hypertension-driven brain damage and pathogenic mechanisms lead to an Aβ increase. The pathophysiological mechanism by which OSA enhances hypertension may be linked to sympathoexcitation, oxidative stress, and endothelial dysfunction. Strong pathophysiological similarities that exist between OSA and AD are underscored here. For example, the hippocampus is negatively impacted in both OSA and AD. OSA promotes hippocampal atrophy, which is associated with memory impairment. Cognitive impairment, even in the absence of manifest dementia, is an important independent predictor of mortality. However, several pathophysiological mechanisms in OSA are reversible with appropriate therapy. OSA, therefore, is a modifiable risk factor of cognitive dysfunction, and treating OSA prior to mild cognitive impairment may be an effective prevention strategy to reduce risk for cognitive decline and AD in middle-aged persons and the elderly.

The systemic nature of CKD

“…The circadian pattern of the blood pressure profile is often inverted in patients with kidney failure and nocturnal hypoxaemia 242 . Studies in animal models and clinical studies show that sleep apnoea causes neuro degeneration via hypoxia, hypertension, vascular dysfunction, inflammation, and oxidative stress 243 . Moreover, serum amyloid levels are more than doubled in patients with moderate to severe sleep apnoea compared with those with mild sleep apnoea or healthy controls 244 .…”

Intermittent hypoxia training protects cerebrovascular function in Alzheimer's disease

“…15,16 In contrast, therapeutic IHT utilizes exposures to moderately severe hypoxia produced in hypobaric chambers or by inspiring normobaric atmospheres with O 2 content lowered to approximately 10%. Typical normobaric IHT protocols utilized in our laboratories for human [93][94][95] and animal 96-100 research involve 5-8 cycles/ day of inspiration of 10% O 2 for 5-10 min, with intervening 4 min normoxia (21% O 2 ), over the course of 14-20 consecutive days.…”

“…13 In addition, several modifiable AD risk factors have been identified, including cigarette smoking, hypertension, type 2 diabetes mellitus, physical inactivity, dyslipidemia, adiposity, obstructive sleep apnea, and metabolic syndrome. 15,16 Since each of these modifiable risk factors has a cardiovascular component, 17 collectively they comprise vascular risk factors for AD, i.e. VRF.…”

Evidence For and Against a Pathogenic Role of Reduced γ-Secretase Activity in Familial Alzheimer’s Disease

“…It is possible that, under hypoxic stress, HIF1␣ promotes the endoproteolysis of a pre-existing pool of PSEN holoprotein to form active ␥-secretase. Hypoxia is a form of cellular stress increasingly identified in AD [164,165] and one implication of Villa and colleagues' analysis is that fAD mutations might affect the effectiveness of this cellular response via alteration of an interaction (direct or indirect) between PSEN holoprotein and HIF1␣. Hypoxia also upregulates autophagy [166] consistent with the role of PSEN1 holoprotein in lysosomal acidification and the concentration of PSEN proteins in the MAM.…”