Einfluss von Diabetes mellitus, Übergewicht und Bewegungsmangel auf Morbus Alzheimer – Interaktion von Insulin mit Amyloid und phosphoryliertem Tau–Protein

Mehrere prospektive epidemiologische Untersuchungen belegen, dass Diabetes mellitus das Risiko, an einer Demenz vom Alzheimer–Typ zu erkranken, um etwa den Faktor 1,6 bis 1,9 steigert. Weitere metabolische Risikofaktoren der Alzheimer–Demenz sind Übergewicht und Bewegungsmangel im mittleren Lebensalter. Die neurobiologische Basis dieses epidemiologischen Zusammenhangs ist eine komplexe Beteiligung des neuronalen Glukose– und Insulinstoffwechsels an synaptischer Plastizität und Gedächtnisprozessen. Die intrazelluläre neuronale Signaltransduktionskette von Insulin ist aber bei Alzheimer–Demenz in ähnlicher Weise gestört wie bei peripherer Insulinresistenz im Rahmen des Diabetes mellitus. Insulin interagiert an verschiedenen Stellen mit der Bildung von Amyloid und phosphoryliertem Tau–Protein. In der Zukunft besteht die Hoffnung, dass sich aus der Kenntnis dieser Zusammenhänge neue kausal wirksame Therapieprinzipien für die Alzheimer–Demenz entwickeln lassen. Bereits jetzt sollte beim einzelnen Patienten und in populationsbasierten Ansätzen die Möglichkeit genützt werden, das Alzheimer–Risiko durch vermehrte körperliche Aktivität und Vermeidung von Übergewicht um mehr als die Hälfte zu senken. Bei Diabetikern muss dem erhöhten Demenzrisiko durch eine möglichst frühzeitige Diagnostik sowie durch sorgfältige Stoffwechseleinstellung Rechnung getragen werden.

According to a growing body of evidence from prospective population–based studies, the risk of incident AlzheimerŽs disease in diabetic patients is increased by an odds ratio of approximately 1,6 to 1,9. Mid–life obesity and a sedentary life style are additional risk factors of AlzheimerŽs dementia. As a neurobiological correlate, neuronal glucose and insulin metabolism is involved in regulation of synaptic plasticity and memory processes. In AlzheimerŽs disease, intracellular signalling of insulin in neurons is impaired in a similar fashion as it is in peripheral cells from insulin resistant diabetic patients. Insulin interacts with the metabolic pathways that participate in the formation of AlzheimerŽs plaques and neurofibrillary tangles. Hopefully, this knowledge will eventually result in the design of new targets for prevention and treatment of AlzheimerŽs disease. For the time being, this evidence must be translated into individual and population–based life–style interventions that will help to reduce the risk of incident AlzheimerŽs dementia by more than 50  %. In diabetic patients, routine cognitive testing is warranted as part of the diagnostic screening for diabetes–related complications, and antihyperglycemic treatment must be optimized in order to lower the risk of cognitive decline.

Key words

Diabetes mellitus - Alzheimer's disease - obesity - prevention

Literatur

• 1 Bucht G, Adolfsson R, Lithner F, Winblad B.. Changes in blood glucose and insulin secretion in patients with senile dementia of Alzheimer type.  Acta Med Scand. 1983;  213 387-392
• 2 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
• 3 Kopf D, Frölich L.. Risk of incident Alzheimer's disease in diabetic patients: A systematic review of prospective trials. J Alzh Dis 2009; im Druck
• 4 Xu W, Qiu C, Winblad B, Fratiglioni L.. The effect of borderline diabetes on the risk of dementia and Alzheimer's disease.  Diabetes. 2007;  56 211-216
• 5 Rönnemaa E, Zethelius B, Sundelöf J. et al. . Impaired insulin secretion increases the risk of Alzheimer disease.  Neurology. 2008;  71 1065-1071
• 6 Luchsinger JA, Tang MX, Shea S, Mayeux R.. Hyperinsulinemia and risk of Alzheimer disease.  Neurology. 2004;  63 1187-1192
• 7 Bergmann C, Sano M.. Cardiac risk factors and potential treatments in Alzheimer's disease.  Neurol Res. 2006;  28 595-604
• 8 Whitmer RA.. The epidemiology of adiposity and dementia.  Curr Alzheimer Res. 2007;  4 117-122
• 9 Whitmer RA, Karter AJ, Yaffe K. et al. . Hypoglycemic episodes and risk of dementia in older patients with type 2 diabetes mellitus.  JAMA. 2009;  301 1565-1572
• 10 Peters A, Schweiger U, Pellerin L. et al. . The selfish brain: competition for energy resources.  Neurosci Biobehav Rev. 2004;  28 143-180
• 11 McEwen BS, Reagan LP.. Glucose transporter expression in the central nervous system: relationship to synaptic function.  Eur J Pharmacol. 2004;  490 13-24
• 12 Schulingkamp RJ, Pagano TC, Hung D, Raffa RB.. Insulin receptors and insulin action in the brain: review and clinical implications.  Neurosci Biobehav Rev. 2000;  24 855-872
• 13 Banks WA.. The source of cerebral insulin.  Eur J Pharmacol. 2004;  490 5-12
• 14 Zhao WQ, Chen H, Quon MJ, Alkon DL.. Insulin and the insulin receptor in experimental models of learning and memory.  Eur J Pharmacol. 2004;  490 71-81
• 15 Paulus K, Schulz C, Lehnert H.. Central nervous effects of leptin and insulin on hippocampal leptin and insulin receptor expression following a learning task in Wistar rats.  Neuropsychobiology. 2005;  51 100-106
• 16 Benedict C, Hallschmid M, Hatke A. et al. . Intranasal insulin improves memory in humans.  Psychoneuroendocrinology. 2004;  29 1326-1334
• 17 Needham BE, Wlodek ME, Ciccotosto GD. et al. . Identification of the Alzheimer's disease amyloid precursor protein (APP) and its homologue APLP2 as essential modulators of glucose and insulin homeostasis and growth.  J Pathol. 2008;  215 155-163
• 18 Grimm MO, Grimm HS, Tomic I. et al. . Independent inhibition of Alzheimer disease beta– and gamma–secretase cleavage by lowered cholesterol levels.  J Biol Chem. 2008;  283 11302-11311
• 19 De Felice FG, Vieira MN, Bomfim TR. et al. . Protection of synapses against Alzheimer's–linked toxins: insulin signaling prevents the pathogenic binding of Abeta oligomers.  Proc Natl Acad Sci USA. 2009;  106 1971-1976
• 20 Frölich L, Blum–Degen D, Riederer P, Hoyer S.. A disturbance in the neuronal insulin receptor signal transduction in sporadic Alzheimer's disease.  Ann N Y Acad Sci. 1999;  893 290-293
• 21 Qiu WQ, Folstein MF.. Insulin, insulin–degrading enzyme and amyloid–beta peptide in Alzheimer's disease: review and hypothesis.  Neurobiol Aging. 2006;  27 190-198
• 22 Elliott E, Ginzburg I.. The role of neurotrophins and insulin on tau pathology in Alzheimer's disease.  Rev Neurosci. 2006;  17 635-642
• 23 Rovio S, Kåreholt I, Helkala EL. et al. . Leisure–time physical activity at midlife and the risk of dementia and Alzheimer's disease.  Lancet Neurol. 2005;  4 705-711
• 24 Lautenschlager NT, Cox KL, Flicker L. et al. . Effect of physical activity on cognitive function in older adults at risk for Alzheimer disease: a randomized trial.  JAMA. 2008;  300 1027-1037
• 25 Yaffe K, Blackwell T, Whitmer RA. et al. . Glycosylated hemoglobin level and development of mild cognitive impairment or dementia in older women.  J Nutr Health Aging. 2006;  10 293-295
• 26 Beeri MS, Schmeidler J, Silverman JM. et al. . Insulin in combination with other diabetes medication is associated with less Alzheimer neuropathology.  Neurology. 2008;  71 750-757
• 27 Watson GS, Cholerton BA, Reger MA. et al. . Preserved cognition in patients with early Alzheimer disease and amnestic mild cognitive impairment during treatment with rosiglitazone: a preliminary study.  Am J Geriatr Psychiatry. 2005;  13 950-958
• 28 Hanyu H, Sato T, Kiuchi A. et al. . Pioglitazone improved cognition in a pilot study on patients with Alzheimer's disease and mild cognitive impairment with diabetes mellitus.  J Am Geriatr Soc. 2009;  57 177-179
• 29 Risner ME, Saunders AM, Altman JF. et al. . Rosiglitazone in Alzheimer's Disease Study Group. Efficacy of rosiglitazone in a genetically defined population with mild–to–moderate Alzheimer's disease.  Pharmacogenomics J. 2006;  6 246-254
• 30 Leibson CL, Rocca WA, Hanson VA. et al. . Risk of dementia among persons with diabetes mellitus: a population–based cohort study.  Am J Epidemiol. 1997;  145 301-308
• 31 MacKnight C, Rockwood K, Awalt E, McDowell I.. Diabetes mellitus and the risk of dementia, Alzheimer's disease and vascular cognitive impairment in the Canadian Study of Health and Aging.  Dement Geriatr Cogn Disord. 2002;  14 77-83
• 32 Ott A, Stolk RP, van Harskamp F. et al. . Diabetes mellitus and the risk of dementia: The Rotterdam Study.  Neurology. 1999;  53 1937-1942
• 33 Peila R, Rodriguez BL, Launer LJ.. Honolulu–Asia Aging Study. Type 2 diabetes, APOE gene, and the risk for dementia and related pathologies: The Honolulu–Asia Aging Study.  Diabetes. 2002;  51 1256-1262

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