Increased Anticholinergic Challenge-Induced Memory Impairment Associated with the APOE-ε4 Allele in the Elderly: A Controlled Pilot Study

Abstract

The degree to which elderly adults experience cognitive impairments from centrally acting anticholinergic drugs is variable, but the cause of this variability is unknown. The present study examined the ε4 allele as a possible modulator of the effects of trihexyphenldyl hydrochloride (Artane™), an anticholinergic drug, on memory functioning. Of the 24 cognitively intact, elderly participants (age range 62-76), 12 who possessed the ε4 allele, participated in a double-blind, randomized, placebo-controlled, crossover, three-way study. All participants were tested after receiving a single oral dose of trihexyphenidyl (1 or 2mg) or placebo, with a 7-day washout period between sessions. Memory and psychomotor tests were administered at baseline, and at 1, 2.5, and 5 h post-treatment. Results showed that participants with the ε4 allele demonstrated significant impairments in delayed recall after both 1 and 2mg doses of trihexyphenidyl while the non-ε4 group did not. Additionally, while acute administration of the 2 mg dose significantly impaired total recall in both ε4 and non-ε4 carriers, the ε4 carriers showed a more persistent impairment. These findings held when participants with the ε2 allele were excluded from the analyses. The ε4 groups did not differ with respect to psychomotor performance or plasma drug levels. These results provide evidence suggesting that the ε4 allele plays a significant role in increasing cognitive sensitivity to trihexyphenidyl and that a temporal component of memory consolidation may be especially vulnerable, A larger study is warranted to confirm these preliminary findings.