A Possible Link between Alzheimer's Disease and Diabetes- Part XXVII of a XXVII Article on AD

A Possible Link between Alzheimer's Disease and Diabetes- Part XXVII of a XXVIII Part Article on AD

(10/06)- Insulin Sensitizer Rosiglitazone (Avandia) and APOE4 in Alzheimer’s Disease-According to the Clinical Trials.gov site (viewed Aug. 1, 2006), GlaxoSmithKline is set to launch a study of Rosiglitazone (Extended Release Tablets) as adjunctive therapy for subjects with mild to moderate Alzheimer’s disease (Clinical Trials. Gov Identifier NCT00348309). The study will be a randomized, double-blind, placebo control, parallel assignment efficacy study to investigate the efficacy of rosiglitazone (Rosiglitazone is sold under the brand name Avandia) as adjunctive therapy to donepezil on cognition and overall clinical response in APOE e4-stratified subjects with mild to moderate Alzheimer’s disease. They expect to enroll 1392 subjects at a number of sites throughout the USA.

In the publication CNS Drugs 2003,17(1):27-45, G. S. Watson and S. Craft (Geriatric Research, Education and Clinical Center, Veterans Affairs Puget Sound Health Care System, Seattle WA) reviewed evidence suggesting that insulin resistance plays a role in the pathophysiology and clinical symptoms of Alzheimer disease. Based on this evidence, these researchers proposed that the treatment of insulin resistance may reduce the risk or retard the development of Alzheimer’s disease. This has lead to investigators looking at the role of insulin sensitizers as a treatment. Insulin resistance refers to clinical condition in which the biologic response to insulin is diminished to below normal levels.

"University of Buffalo endocrinologists, led by Paresh Dandona, M.D., professor of medicine and head of the Division of Endocrinology in the UB School of Medicine and Biomedical Sciences, have been studying the anti-inflammatory properties of insulin and insulin sensitizers and their potential use in treatment and prevention of atherosclerosis, one of the leading causes of heart attacks.

Atherosclerosis, or hardening of the arteries, begins as an inflammation of the blood-vessel wall. Persons with diabetes are at increased risk of developing atherosclerosis and heart disease. Dandona’s lab has shown in research with a small group of obese non-diabetic volunteers that rosiglitazone decreased the levels of oxygen free radicals, which can begin the inflammation cascade by injuring blood-vessel linings. The drug also decreased the levels of several blood markers of inflammation." (Information accessed Aug. 2, 2006 at www.innovations-report.de/html/berichte/medizin_gesunheit/bericht-10622.htm)

Alzheimer’s disease patients treated with rosiglitazone maleate, an insulin sensitizer and mitochondrial stimulator appear to have improved cognition. (See: M.E. Risner et al, "Efficacy of rosiglitazone in a genetically defined population with mild to moderate Alzheimer’s disease, Pharmacogenomics J. (in press) 2006 and S. Ye et al., “Apolipoprotein (apo) E4 enhances amyloid β peptide production in cultured neuronal cells: APOE structure as a potential therapeutic target." Proc Natl Acad Sci 2005; 102:18700-5.)

The scientific community is hard at work looking at the properties and function of APOE. They now know that APOE plays a basic role in the transport of lipids in the body as well as in the repair of neurons. Human APOE is 299 amino acids long and its gene is found on chromosome 19. The three variants of APOE are called alleles-ApoE2, ApoE3, ApoE4. The latter allele is considered a major risk factor for Alzheimer’s disease. Robert Mahley and Xadong Huang writing in The Scientist, 2006; 20(4):49-54 believe "that apoE4 works in concert with a variety of insults or so-called second hits to lead to neuropathology".

These three alleles differ only at two positions, 112 and 158. The differences result in different biophysical properties that likely contribute to the finding that ApoE4 imposes malfunctioning cell machinery leading to pathology. It appears to "enhance amyloid beta production, potentiate amyloid beta-induced lysomal leakage and apoptosis, and enhance neuron-specific proteolysis (the directed degradation (digestion) of proteins by cellular enzymes called proteases or by intramolecular digestion, ed. insert) resulting in translocation of neurotoxic apoE4 fragments into the cytosol (the internal fluid of the cell, and a portion of cell metabolism occurs here, ed. insert) where they are associated with cytoskeletal disruption and mitochondrial dysfunction". (The Scientist. ibid) The goal of those researchers looking at a drug therapy for Alzheimer’s disease is to convert the apoE4 to apoE3-like molecule. If this could be done, the apoE3 allele is not neuropathologically detrimental, thus reducing the risk of developing Alzheimer’s disease. The question remains whether rosiglitazone is a promise of a cure for one of our most debilitating ills. Meanwhile, research continues on many different fronts to deal with Alzheimer’s disease, that, as the elderly population increases, is looming as a large health crisis in the near future.

(7/27/06)- Several new studies suggest that diabetes increases the risk of Alzheimer's disease. The studies involve only Type 2 diabetes, the most common kind, which is related to obesity.

A corollary to this finding may be that by controlling diabetes the medical profession may stumble across an answer as to the cause of Alzheimer's disease. The current findings were presented by the Alzheimer's Association at a 6-day conference in Madrid, with 5,000 researchers from around the world present.

Alzheimer's affects 1 in 10 people over the age of 65 and nearly half of those over 85. About 4.5 million Americans suffer from the disease. Not everyone with Alzheimer's has diabetes and not all diabetes sufferers have Alzheimer's disease. Both Alzheimer's and diabetes sufferers have build up of amyloid deposits. In the case of Alzheimer patients it is in the brain, whereas in the case of diabetes Type 2 sufferers the buildup of the amyloid deposits is in the pancreas.

Patients with Type 2 diabetes often have a condition called insulin resistance, in which their cells can't properly use insulin, the hormone needed to help glucose leave the blood and enter cells that need it. Oftentimes the pancreas makes extra insulin, which can reach high levels in the blood.

About 20 million Americans have Type 2 diabetes. There are about 230 million people worldwide who suffer from diabetes.

Researchers from the Karolinska Institute in Sweden and the Stockholm Gerontology Research Center studied 1,175 people 75 and older. This study concluded that people who even had borderline diabetes were 70% more likely to develop Alzheimer's disease. The higher risk occurred only in those who did not carry the gene apo E4, which is associated with some cases of AD.

Another study on this topic involved 22,852 patients with Type 2 diabetes who were followed for 8 years by the Division of Research at the Kaiser Permanente in Oakland, California. Rachel A.Whitmer led this study.

Initially, none had dementia. The researchers looked at glycosylated hemoglobin, a blood test that reflects blood sugar levels for the previous two months. Normal is 7 or lower. The researchers concluded that when the blood sugar level rose to 10 to 11.9 lever, the risk of dementia increased by 13 %. From 12 to 14.9 the risk was 24% higher. Over 15, the risk jumped to 83 %.

Another study that was discussed at the meeting involved the class of diabetes drug commonly called a glitazone. Some small studies have indicated that the drug may lower the risk of Alzheimer's disease. The National Institute on Aging is sponsoring some further studies in this area. In this particular study, the records of 142,328 patients in the Veterans Affairs system who did not have dementia but were just starting to take a glitazone or insulin were scrutinized.

The patients were tracked for a 6-year period of time. Compared with those taking insulin, among the patients who took pioglitazone (Actos) or rosiglitazone (Avandia) there were nearly 20% fewer cases of AD. The glitizone had a similar advantage over another diabetes drug, metformin. Glitizone lowers blood sugar levels.

GlaxoSmithKline, the maker of rosiglitazone, sponsored the study, but did not control the way it was done or interpreted.

For some additional articles on Alzheimer's disease please see the following:

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Allan Rubin
posted July 27, 2006

http://www.therubins.com

To e-mail: hrubin12@nyc.rr.com or rubin@brainlink.com

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