Related Experiment Video
Updated: Jul 10, 2026
09:37
A Phenotyping Regimen for Genetically Modified Mice Used to Study Genes Implicated in Human Diseases of Aging
Published on: July 14, 2016
Apolipoprotein E genotype and gender influence response to tacrine therapy
M R Farlow1, D K Lahiri, J Poirier
1Department of Neurology, Indiana University School of Medicine, Indianapolis 46202-5111, USA.
Annals of the New York Academy of Sciences
|December 16, 1996
Summary
Apolipoprotein E (APOE) genotype influences Alzheimer's disease (AD) treatment response to tacrine. APOE epsilon 4 carriers showed less cognitive improvement, particularly women, suggesting APOE genotyping for cholinergic therapy trials.
Area of Science:
- Neuroscience
- Genetics
- Pharmacology
Background:
- Alzheimer's disease (AD) is a neurodegenerative disorder characterized by cognitive decline.
- Tacrine, a cholinesterase inhibitor, has shown variable efficacy in AD patients.
- Apolipoprotein E (APOE) genotype, particularly the epsilon 4 allele, is linked to AD risk and pathology.
Purpose of the Study:
- To investigate the association between APOE genotype and clinical response to tacrine treatment in AD patients.
- To determine if APOE epsilon 4 carriers exhibit differential responses to tacrine compared to non-carriers.
- To explore potential interactions between APOE genotype, gender, and treatment response.
Main Methods:
- Retrospective analysis of a 30-week, randomized, double-blind, placebo-controlled trial of tacrine in 460 AD patients with available APOE genotype data.
- APOE genotyping performed on plasma samples.
- Clinical outcomes assessed using Alzheimer's Disease Assessment Scale (ADAS), ADAS-Cognitive (ADAS-Cog), Clinician's Interview-Based Impression (CIBI), Global Deterioration Scale (GDS), and Clinical Global Impression of Change (CGIC).
Main Results:
- Non-APOE epsilon 4 carriers (E2,3) demonstrated significantly greater improvement on tacrine versus placebo compared to APOE epsilon 4 carriers (E4) for ADAS (p=0.04) and ADAS-Cog (p=0.05).
- A trend for greater treatment effect in E2,3 patients was observed for CIBI, GDS, and CGIC, though not statistically significant.
- The interaction between gender and APOE genotype was significant for ADAS-Cog (p=0.03), with E2-3 women showing the most improvement and E4 women the least.
Conclusions:
- APOE genotype may serve as a predictor of clinical response to tacrine in AD patients.
- APOE epsilon 4 allele is associated with a reduced likelihood of cognitive improvement with tacrine.
- Incorporating APOE genotyping into future clinical trials of cholinergic therapies for AD is recommended, especially considering gender-specific effects.
More Related Videos
09:38Generalized Psychophysiological Interaction (PPI) Analysis of Memory Related Connectivity in Individuals at Genetic Risk for Alzheimer's Disease
Published on: November 14, 2017
04:22Biomarker Identification for Gender Specificity of Alzheimer's Disease Based on the Glial Transcriptome Profiles
Published on: May 20, 2024
Related Concept Videos
01:27Pharmacodynamics in Geriatric Patients: Effects of Age
Age-related pharmacokinetic changes are extensively documented, but understanding age-related pharmacodynamic alterations is relatively limited. This knowledge gap can be partly attributed to the complexity of developing appropriate measures of drug responses compared to bioanalytical methods for determining drug concentrations.Most information regarding age-related differences in human pharmacodynamics originates from cross-sectional studies. However, these studies assume that observed mean...
01:29Pharmacogenetic Phenotypes: Alterations in Pharmacokinetics, Drug Targets and Biologic Milieu
Genetic variations significantly influence drug response through pharmacokinetics, receptor interactions, and biologic milieu modifications. Pharmacokinetic alterations impact drug metabolism and clearance, affecting efficacy and toxicity. Variants in drug-metabolizing enzymes, such as CYP2C9 and CYP2C19, alter drug activation and elimination. For example, CYP2C9 loss-of-function variants require lower warfarin doses to prevent excessive bleeding, while CYP2C19 variants reduce clopidogrel...
01:27Pharmacogenetics of Drug Metabolism: Overview
Genetic polymorphism in drug metabolism is crucial to the inter-individual variability observed in drug responses. Drug metabolism primarily involves the chemical modification of drugs and other xenobiotics to enhance their elimination by increasing their polarity. Two main classes of enzymes mediate this biotransformation process: Phase I enzymes, primarily cytochrome P450s, catalyze oxidation and reduction reactions, while other enzymes, such as esterases, mediate hydrolysis, and Phase II...
01:11Pharmacogenetics of Drug Targets: β₂-Adrenergic Receptors, Apo E, Thymidylate Synthase
Genetic polymorphisms in drug targets have emerged as critical determinants of interindividual variability in drug response and toxicity. Pharmacogenomic investigations increasingly focus on identifying these variations to personalize and optimize therapeutic interventions. A drug target may be a receptor, enzyme, or signaling protein involved in pharmacologic responses or disease-related pathways. While early pharmacogenetic studies focused primarily on drug metabolism, current research...
01:24Drug Toxicity: Risk factors
Adverse Drug Reactions (ADRs) are potential complications that arise during pharmacotherapy, influenced by multiple risk factors. Age plays a significant role; both neonates and the elderly are at heightened risk due to their respective immature and diminished metabolic and elimination processes. Gender also impacts ADRs, with females experiencing a 1.5 to 1.7-fold greater risk than males, which may be linked to pharmacokinetic, pharmacodynamic, and hormonal differences. Notably, neonates, the...
01:16Drug toxicity: Idiosyncratic Reactions
Idiosyncratic drug reactions represent abnormal chemical responses that vary significantly among individuals, ranging from extreme sensitivity to low doses to insensitivity to high doses. These reactions often occur due to the drug's covalent binding with serum proteins, forming a foreign hapten that triggers an immunotoxicological response. The variability in drug reactions has a strong pharmacogenetic foundation, with genetic differences crucial in how individuals metabolize drugs. For...