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Gérard Emilien, PhD; Konrad Beyreuther, PhD; Colin L. Masters, MD; Jean-Marie Maloteaux, MD, PhD

Arch Neurol. 2000;57:454-459.

Alzheimer disease (AD) involves neuronal degeneration with impaired cholinergic transmission in the cerebral cortex and hippocampus in areas of the brain particularly associated with memory and higher intellectual functioning. Other neurotransmitter deficits also occur, but the mechanisms underlying the widespread impairment of synaptic functions remain uncertain. Research on the molecular basis of AD has elucidated a pathogenic pathway from which a range of rational pharmacological interventions has emerged. Although at least 3 cholinesterase inhibitors (tacrine hydrochloride, donepezil, and rivastigmine tartrate) are now available and provide patients with modest relief, the most promising strategy involves approaches to retarding, halting, or preventing the formation or accumulation of -amyloid (A) plaques. Estrogen is believed to have antioxidant or other anti-A effects, as hormonal replacement therapy in women with menopause is associated with a reduced risk or delayed onset of AD. The association between nonsteroidal anti-inflammatory drugs and a reduced risk of AD has not yet been confirmed, but these agents may protect the brain from the reactive glial and microglial responses associated with A deposition. Also, recent studies suggested that antioxidants, such as vitamin E taken alone or in combination with selegiline hydrochloride, can delay the progression of AD. Despite these encouraging results, no current therapy has been shown to halt or reverse the underlying disease process. The proof of the principle that anti-A drugs will work in the transgenic models of AD is eagerly awaited with the expectation that they will eventually prove successful in humans.

From the Laboratory of Pharmacology (Drs Emilien and Maloteaux) and Department of Neurology (Dr Maloteaux), Université Catholique de Louvain Cliniques Universitaires Saint Luc, Brussels, Belgium; the Centre for Molecular Biology, University of Heidelberg, Heidelberg, Germany (Dr Beyreuther); and the Department of Pathology, University of Melbourne, and the Mental Health Research Institute, Parkville, Australia (Dr Masters).

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