Inherent abnormalities in energy metabolism in Alzheimer disease. Interaction with cerebrovascular compromise.
Alzheimer disease (AD) is a form of the dementia syndrome. AD appears to have a variety of fundamental etiologies that lead to the neuropathological manifestations which define the disease. Patients who are at high risk to develop AD typically show impairments of cerebral metabolic rate in vivo even before they show any evidence of the clinical disease on neuropsychological, electrophysiological, and neuroimaging examinations. Therefore, impairment in energy metabolism in AD can not be attributed to loss of brain substance or to electrophysiological abnormalities. Among the characteristic abnormalities in the AD brain are deficiencies in several enzyme complexes which participate in the mitochondrial oxidation of substrates to yield energy. There include the pyruvate dehydrogenase complex (PDHC), the alpha-ketoglutarate dehydrogenase complex (KGDHC), and Complex IV of the electron transport chain (COX). The deficiency of KGDHC may be due to a mixture of causes including damage by free radicals and perhaps to genetic variation in the DLST gene encoding the core protein of this complex. Inherent impairment of glucose oxidation by the AD brain may reasonably be expected to interact synergistically with an impaired supply of oxygen and glucose to the AD brain, in causing brain damage. These considerations lead to the hypothesis that cerebrovascular compromise and inherent abnormalities in the brain's ability to oxidize substrates can interact to favor the development of AD, in individuals who are genetically predisposed to develop neuritic plaques.
Blass
J P
JP
Dementia Research Service, Burke Medical Research Institute, Weill Medical College of Cornell University, White Plains, New York 10605, USA. jpblass@mail.med.cornell.edu
Sheu
R K
RK
Gibson
G E
GE
D000544:Alzheimer Disease / Q000378:metabolism* / Q000503:physiopathology*; D001921:Brain / Q000098:blood supply / Q000378:metabolism* / Q000503:physiopathology; D002560:Cerebrovascular Circulation / Q000502:physiology*; D004734:Energy Metabolism; D006801:Humans; D007655:Ketoglutarate Dehydrogenase Complex / Q000378:metabolism; D008959:Models, Neurological; D009410:Nerve Degeneration; D010101:Oxygen Consumption
D007655:Ketoglutarate Dehydrogenase Complex