Rationale: The APOE epsilon4 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 epsilon4 allele influences lorazepam-induced memory deficits in this population.
Materials and methods: Forty-one non-demented, HIV-1 seropositive adults (15 epsilon4 carriers, mean age = 43.47 +/- 8.25; 26 epsilon4 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 epsilon4 group by time interaction was also found such that the APOE-epsilon4-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 epsilon4 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.