Pharmacological treatment of Alzheimer disease: from psychotropic drugs and cholinesterase inhibitors to pharmacogenomics.

For the past 20 years the scientific community and the pharmaceutical industry have been searching for treatments to neutralize the devastating effects of Alzheimer disease (AD). During this period important changes in the etiopathogenic concept of AD have occurred and, as a consequence, the pharmacological approach for treating AD has also changed. During the past 2 decades only 3 drugs for AD have been formally approved by the FDA, although in many countries there are several drugs which are currently used as neuroprotecting agents in dementia alone or in combination with cholinesterase inhibitors. The interest of the pharmaceutical industry has also shifted from the cholinergic hypothesis which led to the development of cholinesterase inhibitors to enhance the bioavailability of acetylcholine at the synaptic cleft to a more "molecular approach" based on new data on the pathogenic events underlying neurodegeneration in AD. In our opinion, the pharmacological treatment of AD should rely on a better understanding of AD etiopathogenesis in order to use current drugs that protect the AD brain against deleterious events and/or to develop new drugs specifically designed to inhibit and/or regulate those factors responsible for premature neuronal death in AD. The most relevant pathogenic events in AD can be classified into main categories: primary events (genetic factors, neuronal apoptosis), secondary events (beta-amyloid deposition in senile plaques and brain vessels, neurofibrillary tangles due to hyperphosphorylation of tau proteins, synaptic loss), tertiary events (neurotransmitter deficits, neurotrophic alterations, neuroimmune dysfunction, neuroinflammatory reactions) and quaternary events (excitotoxic reactions, calcium homeostasis miscarriage, free radical formation, primary and/or reactive cerebrovascular dysfunction). All of these pathogenic events are potential targets for treatment in AD. Potential therapeutic strategies for AD treatment include palliative treatment with nonspecific neuroprotecting agents, symptomatic treatment with psychotropic drugs for noncognitive symptoms, cognitive treatment with cognition enhancers, substitutive treatment with cholinergic enhancers to improve memory deficits, multifactorial treatment using several drugs in combination and etiopathogenic treatment designed to regulate molecular factors potentially associated with AD pathogenesis. This review discusses the conventional cholinergic enhancers (cholinesterase inhibitors, muscarinic agonists), noncholinergic strategies that have been developed with other compounds, novel combination drug strategies and future trends in drug development for AD treatment. Stem-cell activation, genetically manipulated cell transplantation, gene therapy and antisense oligonucleotide technology constitute novel approaches for the treatment of gene-related brain damage and neuroregeneration. The identification of an increasing number of genes associated with neuronal dysfunction along the human genome together with the influence of specific allelic associations and polymorphisms indicate that pharmacogenomics will become a preferential procedure for drug development in polygenic complex disorders. Furthermore, genetic screening of the population at risk will help to identify candidates for prevention among first-degree relatives in families with transgenerational dementia.