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Increased Mental Slowing Associated With the APOE 4 Allele After Trihexyphenidyl Oral Anticholinergic Challenge in Healthy Elderly

From the Geriatric Psychiatry Program (NP, KB, JJS), Nathan Kline Institute for Psychiatric Research, Orangeburg, NY; and the Department of Psychiatry (NP, JJS), New York University School of Medicine, New York.

Objectives: The objectives of this study were to examine the relationship between APOE 4 and subjective effects of trihexyphenidyl on measures reflecting sedation and confusion and to investigate the relationship between trihexyphenidyl-induced subjective effects and objective memory performance.

Methods: This study comprised 24 cognitively intact, health elderly adults (12 APOE 4 carriers) at an outpatient geriatric psychiatry research clinic. This was a randomized, double blind, placebo-controlled, three-way, crossover experimental design. All participants received 1.0 mg or 2.0 mg trihexyphenidyl or placebo administered in counterbalanced sequences over a period of three consecutive weeks. Bond and Lader’s visual analog scales and alternate versions of the Buschke Selective Reminding Test were administered in a repeated measures design at baseline, 1, 2.5, and 5 hours postdrug administration.

Results: A 2.0-mg oral dose of trihexyphenidyl resulted in increased subjective ratings of mental slowness in carriers of the APOE 4 allele only. Drug effects as determined by difference scores between 2.0 mg trihexyphenidyl and placebo on ratings of mental slowness significantly correlated with total and delayed recall on the Buschke Selective Reminding Test in carriers of the APOE 4 allele only. However, no significant effects were found with other visual analog scales reflecting subjective sedation and clear-headedness.

Conclusion: The 4 allele in healthy elderly was associated with increased subjective mental slowing after trihexyphenidyl anticholinergic challenge.

Key Words: APOE polymorphisms • anticholinergic challenge • muscarinic antagonists • memory • subjective ratings • elderly