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CMAJ. 2008 June 17; 178(13): 1687.
PMCID: PMC2413319

Hypoxia and Alzheimer disease

Sujoy Khan, MB BS* and Ioan B. Davies, MB ChB PhD

Christopher Patterson and colleagues reviewed the modifiable risk factors for Alzheimer disease but did not mention that hypoxia may stimulate the development of this illness.1 Cigarette smoking, severe head injury with loss of consciousness and systolic hypertension in older people are risk factors that may cause hypoxia directly or induce it via neuronal ischemia; the disruption of neurovascular coupling has been implicated in hypertension,2 ischemic stroke and Alzheimer disease. We are interested in the authors' views on this issue as many patients with Alzheimer disease also have vascular infarctions3 and these patients deteriorate faster.4

Prolonged or chronic hypoxia has been shown to alter the excitability and functional expression of ion channels, which possibly contributes to neurodegeneration. Reduced oxygen levels result in the formation of β-amyloid protein through amyloidogenic processing of amyloid precursor protein, leading to upregulation of native L-type calcium channels and disruption of calcium homeostasis.5 Cholinergic neurons may be especially vulnerable to β-amyloid protein toxicity.6 The dysregulated calcium expression following hypoxia in central neurons may contribute to the neurotoxicity of β- amyloid protein and subsequent development of Alzheimer disease.

Patients with chronic obstructive pulmonary disease and obstructive sleep apnea syndrome often complain of memory lapses, which may result from intermittent or chronic hypoxic injury to the forebrain. Sun and colleagues defined the molecular mechanism of hypoxia leading to dementia and showed that hypoxia leads to increased β-secretase activity and production of β-amyloid protein.7 Until specific therapy becomes available, simple measures to prevent chronic hypoxic injury to the brain may help to prevent Alzheimer disease or may benefit people who already have the condition.

Footnotes

Competing interests: None declared.

REFERENCES

1. Patterson C, Feightner JW, Garcia A, et al. Diagnosis and treatment of dementia: 1. Risk assessment and primary prevention of Alzheimer disease. CMAJ2008;178:548-56. [PMC free article] [PubMed]
2. Girouard H, Ladecola C. Neurovascular coupling in the normal brain and in hypertension, stroke and Alzheimer disease. J Appl Physiol2006;100:328-35. [PubMed]
3. Schneider JA, Arvaaitakis Z, Bang W, et al. Mixed brain pathologies account for most dementia cases in community dwelling older persons. Neurology2007;11:2197-204. [PubMed]
4. Sheng B, Cheng LF, Law CB, et al. Coexisting cerebral infarction in Alzheimer's disease is associated with fast dementia progression: applying the NINDS-ARIEN neuroimaging criteria in Alzheimer's disease with concomitant infarction. J Am Geriatr Soc2007;55:918-22. [PubMed]
5. Kawahara M, Kuroda Y. Molecular mechanism of neurodegeneration induced by Alzheimer's beta-amyloid protein: channel formation and disruption of calcium homeostasis. Brain Res Bull2000;53:389-97. [PubMed]
6. Zeng WH, Bastianetto S, Mennicken F, et al. Amyloid beta peptide induces tau phosphorylation and loss of cholinergic neurons in rat primary septal cultures. Neuroscience2002;115:201-11. [PubMed]
7. Sun X, He G, Qing H, et al. Hypoxia facilitates Alzheimer's disease pathogenesis by up-regulating BACE1 gene expression. Proc Natl Acad Sci USA2006;49:18727-32. [PubMed]

Articles from CMAJ : Canadian Medical Association Journal are provided here courtesy of Canadian Medical Association