Over a decade ago, John Blass and his colleagues proposed that AD was caused by compromised metabolism. Today, this theory has gained support from a convergence of numerous therapeutic, pathological and biochemical studies pointing to a metabolic dimension to Alzheimer's disease (AD)-the subject of this roundtable.

Siegfried Hoyer (Abstract 15) focused on glucose, the primary energy source of the brain. He found that glucose utilization initially drops during the course of the disease, with a compensatory increase in use of other substrates such as fatty and amino acids. Increased amino acid metabolism is supported by increased ammonia secretion from the brain in AD. Hoyer feels that the switch from glucose is a result of deficiencies in the insulin receptor, actually suggesting that AD may be a kind of cerebral diabetes. However, while the insulin receptor is reduced in normal aging, its level is not substantially further reduced in AD. Nonetheless, the theory gains support from the observation that changes in insulin receptor activation can lead to tau phosphorylation. What's more, its expression level is high in hippocampus and hypothalamus-areas affected in AD.

George Perry (Abstract 16) presented the extensive evidence that he, Mark Smith, and others have amassed showing that increased oxidative damage specifically involves vulnerable neurons in AD. Since no cytopathology has been ascribed to these neurons (i.e., no neurofibrillary tangles), the increased radicals cannot be lesion-based. To understand whether mitochondria might be that source, they performed in situ hybridization for mtDNA, both wild-type and with the 5kb common deletion, in AD and control samples. Perry reported a two- to threefold increase in mtDNA specific for vulnerable neurons. Cytochrome oxidase immunoreactivity is similarly increased while cytochrome oxidase activity is unchanged. These findings suggest a profound alteration in mitochondrial metabolism leading to mtDNA proliferation in AD. Perry also presented the first evidence of oxidative damage to RNA in AD and further showed that its level was positively correlated with mtDNA during normal aging but not during AD. Instead, in AD cases, the best predictor of RNA oxidation was amyloid-β, and it was inversely related suggesting amyloid-β may be playing a protective, rather than a toxic, role.

Christian Pike (Abstract 17) presented cell culture models of amyloid-β toxicity to analyze whether amyloid-β-related death is mediated by oxidative stress. He compared iron, a true oxidative insult, with amyloid-β and found that while both yield similar profiles of death in ~15 hours, iron, but not amyloid-β, can be blocked by probucol. Pike proposes that amyloid-β leads to reactive oxygen production, and interprets amyloid-β-related oxidative stress as a feature, but not the critical feature, of neuronal death in his model of amyloid-β toxicity. Several questions were raised about the relevance of culture studies, because compartmentation and redox state will play key roles in amyloid-β toxicity if it acts as a pro/antioxidant. Certainly in vivo models have shown no amyloid-β toxicity.

Ahmad Salehi (Abstract 18) presented a compelling argument that metabolism is vastly reduced for neurons in AD. His assessment is based on the finding of Nicholas Gonatas that there is a reduction in the area occupied by Golgi apparatus in AD versus controls. A further premise of their studies is that apolipoprotein E plays a role in protecting neurons from death in AD, and that that role is to protect neurons by increasing their metabolism. Consistent with this view is the finding that the reduction in the Golgi appartus is greatest in cases with apolipoprotein E4. Salehi further suggested that Trk4 abnormalities may underlie the metabolic abnormalities he has noted. Not discussed is that vulnerable neurons in AD are heterotypic regarding growth factors, making an argument for a single growth factor abnormality difficult to understand.

Leon Thal (Abstract 20) discussed the recently completed trial of vitamin E (1000U/day) and selegiline (5mg). The results show a clear delay of deterioration in milestones of daily living for both vitamin E and selegiline treated patients, e.g., 25 percent reduction in institutionalization, while there was little difference in mental improvement between any group. Interestingly, the group receiving both vitamin E and selegiline showed no improvement beyond either agent administered separately. These findings clearly present the value of two weak antioxidants as therapeutics. While it might be criticized that all cases to enter the study were already moderately demented, this is essential to detect changes over a two-year study period. Significantly, no toxicity was noted for either vitamin E or selegiline.

Hans Gutzmann (Abstract 19) presented the results of a clinical trial with idebenone, a coenzyme Q derivative with strong antioxidant activity specifically related to its reduction in the mitochondria. As such, idebenone protects cells from oxygen radicals at a primary source of production. Idebenone significantly slowed the decline of patients, particularly those less who were demented. Switching patients receiving placebo from the first year to idebenone in the second year also slowed their decline, but never resulted in a "catching-up" to the group receiving idebenone for both years. Significantly, patients responded rapidly to idebenone, seemingly protecting them from further deterioration. These promising findings suggest that carefully targeted antioxidants can be efficacious in the treatment of AD.

Masaomi Miyamoto presented the pharmacology of idebenone, stating that it rapidly passes the blood-brain barrier. It is the reduced form of idebenone that terminates damaging radicals. However, because idebenone can only be reduced in the mitochondria, between sites I and III coupled with complex II, it does not participate in redox cycling-a problem associated with most other strong antioxidants. Redox cycling would lead to increased radicals rather than radical quenching. The low toxicity of idebenone as well as strong antioxidant properties are ascribed to its ability to prolong the lifespan of rats, a property that vitamin E, a weak antioxidant, does not share.

Idebenone administration has been shown to increase cerebral blood flow and glucose utilization in models of infarction and basal forebrain lesions. In consideration of the major reduction in cerebral blood flow in AD, one can wonder if the clinical benefit of idebenone to patients might involve increased brain perfusion. In summary, idebenone, by acting as an antioxidant and increasing electron transport and cerebral blood flow, improves brain metabolism.

Ken Nagata presented intriguing positron emission tomography studies that show that cerebral blood flow is reduced by 30% in AD while the extracted oxygen fraction is reduced by only 10%. The sum of these findings is that brain perfusion is not reduced as a result of lowered oxygen demand but rather that brain perfusion is limiting in AD. These findings are particularly important in light of recent studies showing strong relationships between arteriosclerosis and hypoperfusion and AD, and certainly gives pause to the importance of apolipoprotein E genotype in AD, since apolipoprotein E genotype is a major risk factor not only in AD but also in arteriosclerosis.

In summary, the roundtable made a convincing case for metabolic insufficiency and subsequent compensation playing a central role in AD. Further these findings not only supported the clinical efficacy of antioxidants, but suggest that greater effects will be noted with agents that also improve electron transport and increase cerebral blood flow, leading to enhancement of cerebral energy metabolism.—George Perry, Institute of Pathology, Case Western Reserve University (Note: Dr. Perry was also a speaker at this roundtable.)

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