Nicotine treatment of mild cognitive impairment (MCI): Efects of APOE4 genotype
South Hall A
Tuesday, Oct 20, 2009, 8:00 AM - 9:00 AM
*H. L. WILKINS
, E. LEVIN
, E. CODERRE
, H. WHITE
, D. HOWARD
, P. AISEN
, K. KELLAR
, K. WESNES
, P. NEWHOUSE
Univ. Vermont, Burlington, VT;
Duke Univ., Durham, NC;
Georgetown Univ., Washington, DC;
Cognitive Drug Res. Ltd., Goring-on-Thames, United Kingdom
A strong genetic risk factor for late onset Alzheimer's disease (AD) and mild cognitive impairment (MCI) is the presence of the E4 allele of the apolipoprotein E (APOE4) gene which encodes a protein involved in cholesterol metabolism and contributes to disease pathogenesis by modulating the metabolism of Aβ peptide. APOE4 status has been variably related to treatment effects in AD and MCI and has been reported to interact with nicotinic receptor activation. Mild Cognitive Impairment (MCI) may be an appropriate target for nicotinic treatment and thus we explored the effect of APOE genotype on the response to transdermal treatment with nicotine in MCI patients. 74 non-smoking subjects from 3 sites who met criteria for amnestic MCI were randomized to receive either double-blind transdermal nicotine (NIC) at 15 mg/day or placebo patch for the first 6 months of the study and open label nicotine patch for the second 6 months of the study. Subjects were cognitively assessed at baseline, 91, and 182 days utilizing the Cognitive Drug Research (CDR) battery, Conners CPT task and others. 32 of 72 subjects had at least one E4 allele. APOE4 genotype effects were seen on a CDR battery items including the power of attention composite measure (NIC x APOE, p=.048) with E4/E4 double allele subjects showing a highly significant (p=.02) NIC treatment benefit compared to single allele E4/E3 or E3/E3 subjects. For the Digit Vigilance task, there was a similar pattern with E4/E4 subjects showing a significant positive effect of nicotine compared to other genotypes on speed (p=.01) and false alarms (p=.03). Significant nicotine treatment (p<.01) effects were seen in the CPT task for E4/E4 subjects on omission and commission errors. For more complex tasks such as the Digit Symbol Substitution Task (DSST), genotype interacted with both treatment and baseline performance (p=.06 for treatment x genotype x baseline) such that lower performing E4+ subjects showed a significant (p=.02) improvement on nicotine compared to placebo. By contrast, for the paragraph recall task, immediate recall, subjects without the E4 allele showed a statistically significant (p<.01) benefit from nicotine at several levels of baseline performance whereas E4 subjects showed a trend level (p=.055) benefit only at the highest level of baseline performance. Clinical Global Impression (CGI) showed a trend (p=.08) for E4 subjects to be more likely to be rated as worse than baseline by six months. We conclude that nicotinic effects on cognitive performance may be influenced by APOE allelic status and long-term treatment results may be influenced by genotype
NIA R01 AG022462
[Authors]. [Abstract Title]. Program No. XXX.XX. 2009 Neuroscience Meeting Planner. Chicago, IL: Society for Neuroscience, 2009. Online.
2009 Copyright by the Society for Neuroscience all rights reserved. Permission to republish any abstract or part of any abstract in any form must be obtained in writing by SfN office prior to publication.
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