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Approximately 4.5 million people in the U.S. have Alzheimers 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 Alzheimers 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 Alzheimers disease is expected to rise to 9 million by 2040.
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 Alzheimers, may provide more opportunities for an antioxidant compound.
Pathophysiology of Alzheimers
In a 2004 review on Alzheimers disease in the New England Journal of Medicine, Jeffrey Cummings described current knowledge of the pathophysiology of Alzheimers (Cummings 2004):
There is increasing consensus that the production and accumulation of beta-amyloid (AB) peptide is central to the pathogenesis of Alzheimers disease. Evidence for a pivotal role for AB includes the following: mutations in the amyloid precursor protein lead to early-onset Alzheimers disease All currently known mutations associated with Alzheimers disease increase the production of AB
In patients with trisomy 21 (Downs syndrome) and three copies of the gene for amyloid precursor protein, neuropathological characteristics of Alzheimers disease develop by midlife; AB is neurotoxic in vitro and leads to cell death
Overexpression of human amyloid precursor protein in transgenic mouse models of Alzheimers disease results in neuritic plaques similar to those seen in humans with Alzheimers disease
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 Alzheimers disease, leads to accelerated deposition of amyloid; and the generation of antiamyloid antibodies in humans with Alzheimers disease seems to ameliorate the disease process.
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 Alzheimers disease through identification of antiamyloid agents, antioxidants, and other drugs
Alternate hypotheses regarding the pathophysiology of Alzheimers disease place greater emphasis on the potential role of tau-protein abnormalities, heavy metals, vascular factors, or viral infections.
There are many studies of the role of oxidative stress in Alzheimers 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 Alzheimers disease includes the following.
Amyloid beta generates free radicals The Met35 amino acid residue of AB is responsible for free radical production
Oxidative damage appears to be one of the earliest pathophysiological events in Alzheimers preceding the formation of amyloid plaques and neurofibrillary tangles. Plasma levels of most antioxidants are lower in patients with Alzheimers and Mild Cognitive Impairment (MCI) compared to healthy age-matched controls.
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.
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.
Numerous studies have shown that free radicals cause neuron degeneration and death in vitro and in vivo, while antioxidants have been shown to protect against neurodegeneration and have shown efficacy in clinical trials for treating Alzheimers disease and in epidemiologic studies for reducing the risk of Alzheimers disease
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.
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.
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.
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 Alzheimers disease.
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.
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 alphatocopherol, 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.
On the basis of this study, many practitioners have added high-dose vitamin E supplements (2000 IU daily) to their standard treatment regimen for Alzheimers disease.
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.