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Alzheimer’s disease (AD) is a progressive, incurable, uniformly fatal neurological disorder. It is the number six cause of death in the United States presently diagnosed in more than six million people in the U. S. The prevalence of the disease markedly increases after the age of 60 doubling every five years and estimated to be present in 40% or more of those who are 85 and older. AD is thought to begin with a pre-symptomatic stage. It progresses to significant memory loss, depression, psychosis, executive dysfunction and the loss of the ability to ambulate, speak, and swallow, etc.The exact cause of AD is not known. One of the major hypotheses is that the disease is related to the excess buildup of amyloid beta causing neuronal degeneration. The presence of APOE4 may be a major genetic risk factor for AD. The diagnosis of AD is based on clinical, neuropsychological and neuroimaging assessments. A number of advanced imaging techniques are used including 3D volumetric measurements and positron emission tomography (PET), scanning with radiopharmaceutical compounds such as Flurodeoxyglucose (FDG PET) and amyloid imaging using (PiB) PET.
Over 1000 clinical studies have been reported in the treatment of AD. The cholinesterase inhibitors (tacrine, donepezil, rivastigmine, galantamine) are presently the mainstay of treatment. They increase cholinergic transmission by inhibiting the cholinesterase which breaks down the acetylcholine at the synaptic cleft. The results have been modest at best although there is a decrease in the trajectory of cognitive decline and increasing the time before institutionalization of the patient.
Memantadine is an NMDA receptor agonist and is thought to be neuroprotective for learning and memory. Its effects have been modest in patients with moderate-to- severe AD. Vitamin E and seligilene (monomine oxidase inhibitor) are thought to have antioxidant properties but are of questionable effectiveness. Estrogens have been evaluated as a treatment for dementia with little evidence of benefit, and as hormone replacement therapy for primary prevention of dementia, may even be harmful.
Ginkgo biloba an herbal extract supplement and the dietary supplements Vitamin B and Omega-3 fatty acids have not been shown to have any clinical benefit in the treatment of dementia. Statins have been studied and to date have not been shown to have a role in the treatment of dementia. Anti-inflammatory agents have been studied as a treatment based on amyloid induced inflammatory reaction and are not recommended. EVP-6124, an alpha-7 nicotinic agonist designed to increase the effects of acetylcholine, has been demonstrated to have cognitive benefits in mild to moderate AD. Sovenaid, a medical food product that may improve synapse function, has shown an improvement in memory performance. Citicoline, a dietary supplement, increases availability of neurotransmitters such as acetylcholine may be of benefit. One major area of research involves treating the underlying pathology of AD by reducing the amyloid beta levels. It was hypothesized that the immune system could be employed to recognize and attack the amyloid, altering the progressive course. One vaccine ACC-001 was under study but due to adverse effects in the subjects was suspended in 2008.
The most anticipated study of the past few years was the use of bapineuzumab, an antibody designed as identical to the naturally induced anti-amyloid antibody. Unfortunately, recent reports are disappointing. The bapineuzumab failed to meet the co-primary endpoints in a phase III study conducted in mild-to-moderate Alzheimer’s disease in patients who did not carry the ApoE4 genotype, with no change in cognitive and functional performance compared to placebo. An earlier report also was negative where bapineuzumab failed to meets its co-primary end points in a phase III study in patients with mild-to-moderate Alzheimer’s disease who carried the ApoE4 genotype. Exercise does appear to lessen the severe decline in memory in AD and should be encouraged. Major strides have been made regarding our scientific understanding of AD. It is hoped that these findings will soon lead to more effective therapy.
