Alzheimer Disease

Researchers from EuroEspes Biomedical Research Center report recent findings in pharmacology

Alzheimer Disease Library Library Home This article was published in Pain & Central Nervous System Week, which you can subscribe to online.

"The pharmacological treatment in AD accounts for 10-20% of direct costs, and less than 20% of AD patients are moderate responders to conventional drugs (donepezil, rivastigmine, galantamine, memantine), with doubtful cost-effectiveness. The neuropathological hallmark of AD (amyloid deposition in senile plaques, neurofibrillary tangle formation, and neuronal loss) are buth the phenotypic expression of a pathogenic process in which more than 200 genes and their products are potentially involved. Drug metabolism, and the mechanisms underlying drug efficacy and safety, are also genetically regulated complex traits in which hundreds of genes cooperatively participate. Structural and functional genomics studies demonstrate that genomic factors, probably induced by environmental factors, cerebrovascular dysfunction, and epigenetic phenomena, might be responsible for AD pathogenic events leading to premature neuronal death. The AD population exhibits a higher genetic variation rate than the control population, with absolute and relative genetic variations of 40-60% and 0.85-1.89%, respectively. AD patients also differ in their genomic architecture from patients with other forms of dementia. Functional genomics studies in AD reveal that age of onset, brain atrophy, cerebrovascular hemodynamics, brain bioelectrical activity, cognitive decline, apoptosis, immune function, lipid metabolism dyshomeostasis, and amyloid deposition are associated with AD-related genes. Pioneering pharmacogenomics studies also demonstrate that the therapeutic response in AD is genotype-specific, with APOE-4/4 carriers as the worst responders to conventional treatments. About 10-20% of Caucasians are carriers of defective CYP2D6 polymorphic variants that alter the metabolism and effects of AD drugs and many psychotropic agents currently administered to patients with dementia. There is a moderate accumulation of AD-related genetic variants of risk in CYP2D6 poor metabolizers and ultra-rapid metabolizers, which are the worst responders to conventional drugs. With diverse multifactorial therapies, combining different types of drugs and metabolic factors, it is partially possible to slow-down cognitive deterioration, improving non-cognitive symptoms, such as anxiety and depression, which currently aggravate cognition and increase the difficulties in disease management; however, the association of the APOE-4 allele with specific genetic variants of other genes (e.g., CYP2D6, ACE) negatively modulate the therapeutic response to multifactorial treatments affecting cognition, mood and behaviour. Pharmacogenetic and pharmacogenomic factors may account for 60-90% of drug variability in drug disposition and pharmacodynamics," wrote R. Cacabelos and colleagues, EuroEspes Biomedical Research Center.

The researchers concluded: "The incorporation of pharmacogenetic/pharmacogenomic protocols to AD research and clinical practice can foster therapeutics optimization by helping to develop cost-effective pharmaceuticals and improving drug efficacy and safety."

Cacabelos and colleagues published the results of their research in Methods and Findings In Experimental and Clinical Pharmacology (Molecular pathology and pharmacogenomics in Alzheimer's disease: polygenic-related effects of multifactorial treatments on cognition, anxiety and depression. Methods and Findings In Experimental and Clinical Pharmacology, 2007;29 Suppl A():1-91).

For additional information, contact R. Cacabelos, EuroEspes Biomedical Research Center, Institute for CNS Disorders, Bergondo, Coruna, Spain.

The publisher of the journal Methods and Findings In Experimental and Clinical Pharmacology can be contacted at: Prous Science, SA, PO Box 540, Provenza 388, 08025 Barcelona, Spain.

Keywords: Spain, Alzheimer Disease, Antidyskinetic, Antiparkinson, Anxiety Disorder, Biotechnology, Central Nervous System Agent, Cholinergic Agent, Clinical Pharmacology, Depression, Donepezil Hydrochloride, Dopamine Agent, Drugs, Excitatory Amino Acid Anta, Galantamine, Genetics, Genomics, Memantine, Mental Health, Nootropic Agent, Parasympathomimetic, Pharmaceuticals, Pharmacogenomic, Pharmacology, Rivastigmine, Therapies, Therapy, Treatment.

This article was prepared by Pain & Central Nervous System Week editors from staff and other reports. Copyright 2007, Pain & Central Nervous System Week via NewsRx.com.