Faculty Bibliography

RATIONALE: The APOE varepsilon4 allele, an established genetic risk factor for late-onset Alzheimer's disease, has been linked to an increased risk for dementia especially in older individuals with HIV-1 infection. This allele has also been associated with increased memory impairment following oral lorazepam challenge in healthy elderly. Lorazepam and other benzodiazepines are widely prescribed in individuals with HIV-1 infection who are at increased risk for cognitive impairment. OBJECTIVE: The aim of this study was to examine if the varepsilon4 allele influences lorazepam-induced memory deficits in this population. MATERIALS AND METHODS: Forty-one non-demented, HIV-1 seropositive adults (15 varepsilon4 carriers, mean age = 43.47 +/- 8.25; 26 varepsilon4 non-carriers, mean age = 46.77 +/- 8.56) participated in a double-blind, placebo-controlled crossover design, receiving single acute oral doses of lorazepam 0.5, 1.0 mg, or placebo over three sessions, each 1 week apart. Standardized neuropsychological assessments, including measures of immediate and delayed verbal recall, were conducted at baseline and at 1, 2.5, and 5 h post-drug administration in each condition. RESULTS: Acute lorazepam administration produced dose- and time-dependent impairments in measures of verbal recall. However, the e4 allele did not modulate these adverse effects. An APOE varepsilon4 group by time interaction was also found such that the APOE-varepsilon4-positive subjects had significantly better immediate and delayed verbal recall than the negative subjects at baseline assessment, but the groups did not significantly differ at any subsequent time point. CONCLUSION: Future studies should clarify the role of varepsilon4 in the modulation of drug-induced cognitive toxicity and baseline performance and their relationship to progressive decline, especially in older individuals with HIV-1 infection, a group at increased risk for dementia

Objectives: The objectives of this study were to examine the relationship between APOE epsilon4 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 epsilon4 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 epsilon4 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 epsilon4 allele only. However, no significant effects were found with other visual analog scales reflecting subjective sedation and clear-headedness. Conclusion: The epsilon4 allele in healthy elderly was associated with increased subjective mental slowing after trihexyphenidyl anticholinergic challenge