John P. Blass and Gary Gibson led this live discussion on 15 April 2002. Readers are invited to submit additional comments by using our Comments form at the bottom of the page.

View Transcript of Live Discussion — Posted 29 August 2006

Background Text
By John P. Blass and Gary Gibson, Weill Cornell College of Medicine

Our group has proposed that the cerebrometabolic deficiency in Alzheimer's disease(AD) is the proximate cause of the clinical disability. Several sets of observations support this hypothesis.

1. Impaired brain metabolism essentially always occurs in clinically significant AD, and the degree of clinical disability is proportional to the degree of metabolic impairment. The earliest, mildest changes in brain metabolism occur even before the onset of measurable cognitive impairment or atrophy. This observation disproves the now outdated assumption that the decreased metabolism is simply a consequence of decreased mental function or of atrophy. One of the important mechanisms reducing brain metabolism in AD appears to be damage to key mitochondrial components.

2. Inducing impairments of brain metabolism causes changes in mentation that mimic the clinical disabilities in AD, in both humans and experimental animals.

3. Preliminary results from several units suggest that treatment directed at the impairment of brain metabolism can improve neuropsychological functions in AD patients. This hypothesis does not negate the importance of other mechanisms in AD, such as amyloid accumulation, vascular compromise, and free radical action. However, those other abnormalities can occur in people whose mentation is still clinically unimpaired. Approximately half the people over the age of 85 who have the full panoply of the neuropathology of AD are clinically well. The frequently-advanced hypothesis that they would have developed dementia "if they had lived long enough" is not testable. In contrast, once significant decrease in the rate of brain metabolism occurs, mentation essentially invariably becomes defective. That statement is supported by robust experimental observations in both humans and other animals.

References
1. Snowden DA. Aging and Alzheimer's disease: Lessons from the Nun study. Gerontologist 1997;(37):150-156. Abstract.

2. Blass JP. Immunological treatment of Alzheimer's disease. New Eng J Med 1999;(22):1694-1695. Abstract.

3. Robinson SR, Bishop GM. A-β as a bioflocculant: implications for the amyloid hypothesis of Alzheimer's disease. Neurobiol Aging, in press.

4. Gibson GE, Park LC, Zhang H, Sorbi S, Calingasan NY. Oxidative stress and a key metabolic enzyme in Alzheimer brains, cultured cells, and an animal model of chronic oxidative deficits. Ann N Y Acad Sci 1999;(893):79-94. Abstract.

5. Gibson GE, Blass JP. Metabolism and neurotransmission. In Handbook of Neurochemistry, A. Lajtha ed, Vol. 3, 2nd Ed. Plenum Press, New York, 1982, pp. 633-651.

6. Blass JP, Gibson GE. Cerebrometabolic aspects of delirium in relationship to dementia. Dement Geriatr Cogn Disord 1999;(10):335-338. Abstract.

7. Hirsch JA, Gibson GE. Selective alteration of neurotransmitter release by low oxygen in vitro. Neurochem Res 1984;(9):1039-1049. Abstract.

8. Blass JP. Pathophysiology of the Alzheimer's syndrome. Neurology 1993;(43):S25-S38.

9. Blass JP. The mitochondrial spiral: An adequate cause of dementia in the Alzheimer syndrome. Ann NY Acad Sci 2000;(924):170-183. Abstract.

10. Floyd RA. Antioxidants, oxidative stress, and degenerative neurological disorders. Proc Soc Exp Biol Med 1999;(222):236-245. Abstract.

11. Frey KA, Minoshima S, Kuhl DE. Neurochemical imaging of Alzheimer's disease and other degenerative dementias. Q J Nucl Med 1998;(42):166-168. Abstract.

12. de Leon MJ, Convit A, Wolf OT, Tarshish CY, DeSanti S, Rusinek H, Tsui W, Kandil E, Schere H, Roche A, Imossi A, Thorn E, Bobinski M, Caraos C, Lesbre P, Schyler D, Poirier J, Resiberg B, Fowler J. Prediction of cognitive decline in normal elderly subjects with 2-[18F]fluoro-2-deoxyglucose/positron-emission tomography (FDC/PET). Proc Natl Acad Sci USA 2001;(98):10966-10971. Abstract.

13. Kumar A, Schapiro MB, Grady G, Haxby JV, Wagner E, Salerno JA, Friedland RP, Rapoport SI. High resolution PET studies in Alzheimer's disease. Neuropsychopharmacology 1991;(4):35-46. Abstract.

14. Fukuyama H, Ogawa M, Yamauchi H, Yamaguchi S, Kimura J, Yonekura Y, Konishi J. Altered cerebral energy metabolism in Alzheimer's disease: A PET study. J Nuclear Med 1994;(35):1-6. Abstract.

15. Frolich L, Blum-Degen D, Bernstein HG, Engelsberger S, Humfrich J, Laufer S, Muschner D, Thalheimer A, Trk A, Hoyer S, Zchling R, Boissl KW, Jellinger K, Riederer O. Insulin and insulin receptors in the brain in aging and sporadic Alzheimer's disease. J Neural Transm 1998;(105):423-438. Abstract.

16. Henneberg N, Hoyer S. Desensitization of the neuronal insulin receptor: a new approach in the etiopathogenesis of late-onset sporadic dementia of the Alzheimer type (SDAT)? Arch Gerontol Geriatr 1995;(21):63-74.

17. Hoyer S. Is sporadic Alzheimer disease the brain type of non-insulin dependent diabetes mellitus? A challenging hypothesis. J Neural Transm 1998;(105):415-422. Abstract.

18. Sorbi S, Bird ED, Blass JP. Decreased pyruvate dehydrogenase complex activity in Huntington and Alzheimer brain. Ann Neurol 1983;(13):72-78. Abstract.

19. Gibson GE, Sheu K-FR, Blass JP. Abnormalities of mitochondrial enzymes in Alzheimer disease. J Neural Transmission 1998;(105):855-870. Abstract.

20. Gibson GE, Haroutunian V, Zhang H, Park LC, Shi Q, Lesser M, Mohs RC, Sheu RK-F, Blass JP, Mitochondrial damage in Alzheimer's disease varies with apolipoprotein E genotype. Ann Neurol 2000;(48):297-303. Abstract.

21. Kish SJ, Mastrogiacomo F, Guttman M, Furukawa Y, Taanman JW, Dozic S, Pandolfo M, Lam L, Distefano L, Chang LJ. Decreased brain protein levels of cytochrome oxidase subunits in Alzheimer's disease and hereditary spinocerebellar ataxia disorders: a nonspecific change? J Neurochem 1999;(72):700-707. Abstract.

22. Sheu K-FR, Blass JP. The a-ketoglutarate dehydrogenase complex. Ann NY Acad Sci 1999;(893):61-78. Abstract.

23. Blass JP, Sheu K-FR, Piacentini S, Sorbi S. Inherent abnormalities in oxidative metabolism in AD: Interaction with vascular abnormalities. Ann NY Acad Sci 1997;(826):382-385. Abstract.

24. Calingasan NY, Baker H, Sheu K-F, Gibson GE. Distribution of the a-ketoglutarate dehydrogenase complex in rat brain. J Comp Neurol 1994;(346):461-479. Abstract.

25. Ko L, Sheu K-FR, Thaler HT, Markesbery WR, Blass JP. Selective loss of KGDHC-enriched neurons in Alzheimer temporal cortex: does mitochondrial variation contribute to selective vulnerability? J Molec Neurosci 2001;(17):361-369. Abstract.

26. Curti D, Rognoni F, Gasparini L, Cattaneo A, Paolillo M, Racchi M, Zanni L, Bianchetti A, Trabucci A, Bergamaschi S, Govoni S. Oxidative metabolism in cultured fibroblasts from sporadic Alzheimer's disease. Neurosci Lett 1997;(236):13-16. Abstract.

27. Butterfield DA, Yatin SM, Link CD. In vitro and in vivo protein oxidation induced by Alzheimer's disease amyloid beta-peptide (1-42). Ann NY Acad Sci 1999;(42):265-268. Abstract.

	Comments on Live Discussion
	Comment by:  Siegfried Hoyer
	Submitted 14 April 2002  |  Permalink	Posted 14 April 2002
	"A central issue in medicine is the grouping of disorders on the basis of their etiology, yet one common clinico-pathologic feature of diseases does not indicate a common etiology. Therefore, from a nosological point of view, Alzheimer's disease is no one single disorder. Rather, type I/ disease I is due to mutation within three genes (5 percent of all AD cases); whereas type II/ disease II is sporadic in origin without any mutations (95 percent of cases). Both susceptibility genes and adult life-style risk factors, such as aging, participate in the origin of the latter AD type. Thus, I fully support the view of John Blass and Gary Gibson that sporadic AD is an age-associated cerebrometabolic disorder. It appears necessary to make a clear distinction between these two heterogenous pathologic conditions. In its early pathogenesis, perhaps in its etiology, normal functions of insulin and insulin signal transduction were found to be severely perturbed in the brain, causing acetylcholine reduction, an ATP deficit, disturbed AbPP trafficking in the endoplasmic reticulum and Golgi...  Read more "A central issue in medicine is the grouping of disorders on the basis of their etiology, yet one common clinico-pathologic feature of diseases does not indicate a common etiology. Therefore, from a nosological point of view, Alzheimer's disease is no one single disorder. Rather, type I/ disease I is due to mutation within three genes (5 percent of all AD cases); whereas type II/ disease II is sporadic in origin without any mutations (95 percent of cases). Both susceptibility genes and adult life-style risk factors, such as aging, participate in the origin of the latter AD type. Thus, I fully support the view of John Blass and Gary Gibson that sporadic AD is an age-associated cerebrometabolic disorder. It appears necessary to make a clear distinction between these two heterogenous pathologic conditions. In its early pathogenesis, perhaps in its etiology, normal functions of insulin and insulin signal transduction were found to be severely perturbed in the brain, causing acetylcholine reduction, an ATP deficit, disturbed AbPP trafficking in the endoplasmic reticulum and Golgi apparatus, tau hyperphosphorylation, and reduced activities of enzymes associated with the cell cycle." -Siegfried Hoyer, University of Heidelberg, Germany. View all comments by Siegfried Hoyer
	Comment by:  Archibaldo Donoso
	Submitted 22 April 2002  |  Permalink	Posted 29 August 2006
	Of course, metabolism and function are the two faces of a coin. But metabolic failure exists not only in Alzheimer's disease, but in any brain disease. So, if we want to define the disease we must use the peculiar characteristics (NFT and so on) and not the metabolism. View all comments by Archibaldo Donoso

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