1. Alzheimer's disease Beta amyloid protein and the potential for anti-oxidants drugs

2. Approximately 4.5 million people in the U.S. have Alzheimer’s disease (AD). It is the 4th or 5th leading cause of death. The prevalence is 3% for persons 65-74 years old, 19% for those 75-84 years old and 47% for those over 85 years old. The cost of care for patients with Alzheimer’s disease in the U.S. is $83.9 billion annually (in 1996 dollars) and rising. With the aging U.S. population, the number of people in the U.S. with Alzheimer’s disease is expected to rise to 9 million by 2040.

3. Current therapies have extremely limited efficacy, with a typical benefit of 6 to 12 months delay in the progression of symptoms. Evidence that oxidative damage occurs in patients with mild cognitive impairment (MCI), a precursor of Alzheimer’s, may provide more opportunities for an anti- oxidant compound.

4. Pathophysiology of Alzheimer’s In a 2004 review on Alzheimer’s disease in the New England Journal of Medicine, Jeffrey Cummings described current knowledge of the pathophysiology of Alzheimer’s (Cummings 2004):

5. There is increasing consensus that the production and accumulation of beta-amyloid (AB) peptide is central to the pathogenesis of Alzheimer’s disease. Evidence for a pivotal role for AB includes the following: mutations in the amyloid precursor protein lead to early-onset Alzheimer’s disease All currently known mutations associated with Alzheimer’s disease increase the production of AB

6. In patients with trisomy 21 (Down’s syndrome) and three copies of the gene for amyloid precursor protein, neuropathological characteristics of Alzheimer’s disease develop by midlife; AB is neurotoxic in vitro and leads to cell death

7. Overexpression of human amyloid precursor protein in transgenic mouse models of Alzheimer’s disease results in neuritic plaques similar to those seen in humans with Alzheimer’s disease

8. Transgenic mice overexpressing the human amyloid precursor protein have evidence of learning and memory deficits, in concert with the accumulation of amyloid; the apolipoprotein E4 genotype, a major risk factor for Alzheimer’s disease, leads to accelerated deposition of amyloid; and the generation of antiamyloid antibodies in humans with Alzheimer’s disease seems to ameliorate the disease process.

9. Formation of neurofibrillary tangles, oxidation and lipid peroxidation, glutamatergic excitotoxicity, inflammation, and activation of the cascade of apoptotic cell death are considered secondary consequences of the generation and deposition of AB. This hypothesized amyloid cascade underlies attempts to modify the onset and course of Alzheimer’s disease through identification of antiamyloid agents, antioxidants, and other drugs

10. Alternate hypotheses regarding the pathophysiology of Alzheimer’s disease place greater emphasis on the potential role of tau-protein abnormalities, heavy metals, vascular factors, or viral infections.

11. There are many studies of the role of oxidative stress in Alzheimer’s disease and more specifically the activity of AB in production of reactive oxygen species (ROS). Evidence supporting the role of AB and oxidative stress in Alzheimer’s disease includes the following.

12. Amyloid beta generates free radicals The Met35 amino acid residue of AB is responsible for free radical production

13. Researchers have found a variety of oxidative damage in AD brains increased lipid peroxidation and decreased polyunsaturated fatty acids in the AD brain, and increased 4-hydroxynonenal, an aldehyde product of lipid peroxidation in AD ventricular fluid increased protein and DNA oxidation in the AD brain; diminished energy metabolism and decreased cytochrome c oxidase in the brain in AD advanced glycation end products (AGE), malondialdehyde, carbonyls, peroxynitrite, heme oxygenase-1 and SOD

14. Oxidative damage appears to be one of the earliest pathophysiological events in Alzheimer’s preceding the formation of amyloid plaques and neurofibrillary tangles. Plasma levels of most antioxidants are lower in patients with Alzheimer’s and Mild Cognitive Impairment (MCI) compared to healthy age-matched controls.

15. Transgenic mice expressing AB reproduce the clinical symptoms and pathological progression of AD including oxidative stress. In beta-amyloid transgenic mice, memory impairment is correlated with increased levels of beta amyloid Active and passive beta-amyloid-directed immunization removes beta-amyloid plaques and restores memory.

16. In transgenic mice expressing both AB and presenilin 1, gene expression profiles using microarrays and Q-PCR showed reduced expression of genes required for long-term potentiation and memory formation. In studies of cortical tissue AD patients, the same memory-associated genes are down-regulated.

17. Numerous studies have shown that free radicals cause neuron degeneration and death in vitro and in vivo, while anti- oxidants have been shown to protect against neurodegeneration and have shown efficacy in clinical trials for treating Alzheimer’s disease and in epidemiologic studies for reducing the risk of Alzheimer’s disease

18. not proven that AB or ROS directly cause Alzheimer’s disease. “Because tissue injury itself can induce reactive oxygen species (ROS) generation, it is not known whether this is a primary or secondary event [in Alzheimer’s disease]. Even if free radical generation is secondary to other initiating causes, they are deleterious and part of a cascade of events that can lead to neuron death, suggesting that therapeutic efforts aimed at removal of ROS or prevention of their formation may be beneficial in AD” (Markesbery 1997).

19. Many but not all anti-oxidants have been shown to cross the blood-brain barrier and to have neuroprotective effects in vitro and/or in vivo in humans or in animal models. The major limitations of these anti-oxidants appear to be their relatively short half-life in vivo (ALA), their (possibly) relatively low bioavailability at the sites of free-radical production (Vitamins C and E) and the lack of patent protection.

20. Alzheimer’s drug development Many pharmaceutical companies are pursuing new treatments for Alzheimer’s, with a wide variety of targets, including AB and anti-oxidants. In a 2004 NEJM review, Cummings describes current research on treatments of Alzheimer’s:

21. Antiamyloid therapies No antiamyloid therapies are currently available. The enzymes responsible for liberating AB, a toxic fragment of 42 amino acids, from the amyloid precursor protein are b and g secretases. Inhibitors of these enzymes are under active study. The metabolism of cholesterol is intimately involved in the generation of AB, and preliminary evidence suggests that statins may be beneficial in reducing the accumulation of AB.

22. Neuroprotective approaches AB protein seems to exert its neurotoxic effects through a variety of secondary mechanisms, including oxidative injury and lipid peroxidation of cell membranes, inflammation, hyperphosphorylation of tau protein, and increased glutamatergic excitotoxicity. Neuroprotective strategies have targeted these mechanisms in an effort to reduce the cell injury associated with the generation and aggregation of AB.

23. Antioxidants The principal antioxidant strategy has involved treatment with alpha-tocopherol (vitamin E). A randomized, placebo-controlled trial compared the effect of vitamin E, selegiline, the two drugs together, and placebo in patients with Alzheimer’s disease.

24. When the severity of cognitive decline at baseline was included as a covariate, a significant delay in the primary outcomes (time to death, placement in a nursing home, development of severe dementia, or a defined severity of impairment of activities of daily living) was observed for patients in the selegiline, alpha-tocopherol, and combination-therapy groups, as compared with the placebo group.

25. The increase in median time to one of the primary outcomes, as compared with the time in patients receiving placebo, was 230 days for patients receiving alpha- tocopherol, 215 days for those treated with selegiline, and 145 days for those receiving both agents. No differences in cognitive function were evident among the four groups.

26. On the basis of this study, many practitioners have added high-dose vitamin E supplements (2000 IU daily) to their standard treatment regimen for Alzheimer’s disease.

27. Rutten: review of antioxidant clinical trials in Alzheimer’s disease Recent prospective studies have indicated that dietary intake of several exogenous antioxidants is associated with a lower risk for Alzheimer's disease. This suggests that people at risk for developing Alzheimer's disease or being in the early phases of this disease may benefit from intervention with exogenous antioxidants. The clinical studies carried out so far, however, do not provide the final answer to whether antioxidants are truly protective against Alzheimer's disease

28. There is compelling evidence that oxidative stress is involved in Alzheimer's disease pathogenesis, and several lines of evidence indicate that administration of antioxidants may be useful in prevention and treatment of Alzheimer's disease. Further clinical studies, based on larger cohorts studied over a longer period of time, are needed, however, to test this hypothesis. Furthermore, for the future one might expect balanced upregulation of both exogenous and endogenous antioxidants as one of the best treatment strategies for preventing or at least slowing down the progression of Alzheimer's disease.