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

For the past 20 years the scientific community and the pharmaceutical indus try have been searching for treatments to neutralize the devastating effect s of Alzheimer disease (AD). During this period important changes in the et iopathogenic concept of AD have occurred and, as a consequence, the pharmac ological approach for treating AD has also changed. During the past 2 decad es 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 neuropro tecting agents in dementia alone or in combination with cholinesterase inhi bitors. The interest of the pharmaceutical industry has also shifted from t he cholinergic hypothesis which led to the development of cholinesterase in hibitors to enhance the bioavailability of acetylcholine at the synaptic cl eft to a more "molecular approach" based on new data on the pathogenic even ts underlying neurodegeneration in AD. In our opinion, the pharmacological treatment of AD should rely on a better understanding of AD etiopathogenesi s in order to use current drugs that protect the AD brain against deleterio us events and/or to develop new drugs specifically designed to inhibit and/ or regulate those factors responsible for premature neuronal death in AD. T he most relevant pathogenic events in AD can be classified into 4 main cate gories: primary events (genetic factors, neuronal apoptosis), secondary eve nts (beta-amyloid deposition in senile plaques and brain vessels, neurofibr illary tangles due to hyperphosphorylation of tau proteins, synaptic loss), tertiary events (neurotransmitter deficits, neurotrophic alterations, neur oimmune dysfunction, neuroinflammatory reactions) and quaternary events (ex citotoxic reactions, calcium homeostasis miscarriage, free radical formatio n, primary and/or reactive cerebrovascular dysfunction). All of these patho genic events are potential targets for treatment in AD. Potential therapeut ic strategies for AD treatment include palliative treatment with nonspecifi c neuroprotecting agents, symptomatic treatment with psychotropic drugs for noncognitive symptoms, cognitive treatment with cognition enhancers, subst itutive treatment with cholinergic enhancers to improve memory deficits, mu ltifactorial treatment using several drugs in combination and etiopathogeni c treatment designed to regulate molecular factors potentially associated w ith AD pathogenesis. This review discusses the conventional cholinergic enh ancers (cholinesterase inhibitors, muscarinic agonists), noncholinergic str ategies that have been developed with other compounds, novel combination dr ug 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 t he treatment of gene-related brain damage and neuroregeneration. The identi fication of an increasing number of genes associated with neuronal dysfunct ion 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 ide ntify candidates for prevention among first-degree relatives in families wi th transgenerational dementia. (C) 2000 Prous Science. All rights reserved.