Neurochemical Research

, Volume 37, Issue 12, pp 2627–2658 | Cite as

Quintessential Risk Factors: Their Role in Promoting Cognitive Dysfunction and Alzheimer’s Disease

  • Mak Adam Daulatzai


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.


Alzheimer’s disease Amyloid-β Obstructive sleep apnea Hypoxia Hypoxemia Hypertension Neuroinflammation Cerebral hypoperfusion Nucleus of the solitary tract 



Advanced glucose endproducts


Alzheimer’s disease



Amyloid precursor protein


Autotitrating positive airway pressure


Apnea-hypopnea index


β-site amyloid precursor protein cleavage enzyme


Basal forebrain




Blood pressure


Amyloid angiopathy


Cerebral artery blood flow velocity


Circulating inflammatory cytokines


Chronic intermittent hypoxia


Cerebral metabolic rate of oxygen




C-reactive protein


Continuous positive airway pressure


Type 2 diabetes mellitus


Dorsal motor nucleus V cranial nerve


Dorsal motor nucleus of the vagus


Excessive daytime sleepiness


Entorhinal cortex


Gray matter volume


High energy phosphates


Hypoxia-inducible factor

ICAM-1 and -2

Intercellular adhesion molecule-1 and -2


IGF-1 receptor


Intermittent hypoxia


Insulin receptor




Low-density lipoprotein


Matrix metalloproteinase 2


Medial temporal lobe


N-methyl-D-aspartate receptors


Middle cerebral artery velocity


Mild cognitive impairment


Nucleus ambiguus


Near-infrared spectroscopy


Neurofibrillary tangles


Nitric oxide


Non-rapid eye movement sleep


Nuclear factor kappa B


Nucleus of the solitary tract


Obstructive sleep apnea


Posterior cingulate cortex


Platelet endothelial cell adhesion molecule-1


Prefrontal cortex


AGE receptor


Renin-angiotensin system


Reactive oxygen species


Serum amyloid A


Sleep disordered breathing


Hypertensive rat


Amyloid senile plaques


Single photon emission computed tomography


Tumor necrosis factor-α


Upper airway


Voxel-based morphometry


Vascular endothelial growth factor


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Copyright information

© Springer Science+Business Media, LLC 2012

Authors and Affiliations

  1. 1.Sleep Disorders Group, Department of EEE/MSEThe University of MelbourneParkvilleAustralia

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