Abstract
Alzheimer’s disease (AD) is a progressive neurodegenerative disorder. The human brain is extremely sensitive to hypoxia, ischemia, and glucose depletion. Impaired delivery of oxygen in obstructive sleep apnea (OSA) alters neuronal homeostasis, induces pathology, and triggers neuronal degeneration/death. This article systematically delineates the steps in the complex cascade leading to AD, focusing on pathology caused by chronic intermittent hypoxia, hypertension, brain hypoperfusion, glucose dysmetabolism, and endothelial dysfunction. Hypoxia/hypoxemia underpins several pathological processes including sympathetic activation, chemoreflex activity, neuroinflammation, oxidative stress, and a host of perturbations leading to neurodegeneration. The arterial blood flow reduction in OSA is profound, being about 76 % in obstructive hypopneas and 80 % in obstructive apneas; this leads to cerebral ischemia promoting neuronal apoptosis in neocortex and brainstem. OSA pathology also includes gray matter loss in the frontal, parietal, temporal, and occipital cortices, the thalamus, hippocampus, and key brainstem nuclei including the nucleus tractus solitarius. (18)F-FDG PET studies on OSA and AD patients, and animal models of AD, have shown reduced cerebral glucose metabolism in the above mentioned brain regions. Owing to the pathological impact of hypoxia, hypertension, hypoperfusion and impaired glucose metabolism, the adverse cardiovascular, neurocirculatory and metabolic consequences upregulate amyloid beta generation and tau phosphorylation, and lead to memory/cognitive impairment—culminating in AD. The framework encompassing these factors provides a pragmatic neuropathological approach to explain onset of Alzheimer’s dementia. The basic tenets of the current paradigm should influence the design of therapeutic strategies to ameliorate AD.
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Abbreviations
- AGEs:
-
Advanced glucose endproducts
- AD:
-
Alzheimer’s disease
- Aβ:
-
Amyloid-β
- APP:
-
Amyloid precursor protein
- APAP:
-
Autotitrating positive airway pressure
- AHI:
-
Apnea-hypopnea index
- BACE:
-
β-site amyloid precursor protein cleavage enzyme
- BFB:
-
Basal forebrain
- BOLD:
-
Blood-oxygenation-level-dependent
- BP:
-
Blood pressure
- CAA:
-
Amyloid angiopathy
- CBFV:
-
Cerebral artery blood flow velocity
- CIC:
-
Circulating inflammatory cytokines
- CIH:
-
Chronic intermittent hypoxia
- CMRO2 :
-
Cerebral metabolic rate of oxygen
- COX-2:
-
Cycloxygenase-2
- CRP:
-
C-reactive protein
- CPAP:
-
Continuous positive airway pressure
- DM:
-
Type 2 diabetes mellitus
- DMV:
-
Dorsal motor nucleus V cranial nerve
- DMNV:
-
Dorsal motor nucleus of the vagus
- EDS:
-
Excessive daytime sleepiness
- ERC:
-
Entorhinal cortex
- GMV:
-
Gray matter volume
- HEP:
-
High energy phosphates
- HIF:
-
Hypoxia-inducible factor
- ICAM-1 and -2:
-
Intercellular adhesion molecule-1 and -2
- IGF-1R:
-
IGF-1 receptor
- IH:
-
Intermittent hypoxia
- IR:
-
Insulin receptor
- IL-1β:
-
Interleukin-1β
- LDL:
-
Low-density lipoprotein
- MMP:
-
Matrix metalloproteinase 2
- MTL:
-
Medial temporal lobe
- NMDARs:
-
N-methyl-D-aspartate receptors
- MCAV:
-
Middle cerebral artery velocity
- MCI:
-
Mild cognitive impairment
- NA:
-
Nucleus ambiguus
- NIRS:
-
Near-infrared spectroscopy
- NFTs:
-
Neurofibrillary tangles
- NO:
-
Nitric oxide
- NREM:
-
Non-rapid eye movement sleep
- NF-κB:
-
Nuclear factor kappa B
- NTS:
-
Nucleus of the solitary tract
- OSA:
-
Obstructive sleep apnea
- PCC:
-
Posterior cingulate cortex
- PECAM:
-
Platelet endothelial cell adhesion molecule-1
- PFC:
-
Prefrontal cortex
- RAGE:
-
AGE receptor
- RAS:
-
Renin-angiotensin system
- ROS:
-
Reactive oxygen species
- SAA:
-
Serum amyloid A
- SDB:
-
Sleep disordered breathing
- SHR:
-
Hypertensive rat
- SPs:
-
Amyloid senile plaques
- SPECT:
-
Single photon emission computed tomography
- TNF-α:
-
Tumor necrosis factor-α
- UA:
-
Upper airway
- VBM:
-
Voxel-based morphometry
- VEGF:
-
Vascular endothelial growth factor
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Daulatzai, M.A. Quintessential Risk Factors: Their Role in Promoting Cognitive Dysfunction and Alzheimer’s Disease. Neurochem Res 37, 2627–2658 (2012). https://doi.org/10.1007/s11064-012-0854-6
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DOI: https://doi.org/10.1007/s11064-012-0854-6