The "cholinergic hypothesis" postulates that loss of cholinergic function in the cerebral cortex underlies age-related cognitive decline. Indeed, previous experiments in older adults had suggested that boosting acetylcholine (ACh) levels (with drugs like such as donepezil that inhibit a synaptic ACh scavenging esterase) can improve performance on memory and recognition tasks.

Jerome Yesavage and colleagues at the Palo Alto (Calif.) Veterans Affairs Health Care System and several other institutions noted that pressure is beginning to mount on clinicians to prescribe AChE inhibitors to older adults (without AD or even mild cognitive impairment) for whom age-related cognitive decline can interfere with normal living. A controversial case in point is that of pilots, who are currently forced to stop flying regular passenger routes at the age of 60.

As the authors point out, the flight simulator tests required for commercial pilots are ideal for studying the effects of any number of drugs. The tests allow for the collection of reliable, highly quantifiable data, and also can be designed to focus on particular cognitive areas, such as sustained attention, working memory, or psychomotor speed.

In the double-blind, parallel study, the pilots (n = 18; avg. age 52) first practiced a series of complex piloting tasks on a simulator. Half the subjects then took donepezil 5 mg/day for thirty days, while the other half took placebos. After 30 days, the pilots who had taken donepezil showed little loss of performance on the tests learned at baseline, while the placebo group showed a significant decrement in performance. The strongest effects were on emergency tasks and approach to landing, both of which require dividing attention between a series of stimuli.

"The association of cholinergic drugs with better attention has led investigators to suggest that part of the benefit of cholinergic drugs on memory performance may be mediated through attentional components involved in working memory," write the authors, noting that their own results support this suggestion. -- Hakon Heimer

Reference:Yesavage JA, Mumenthaler MS, Taylor JL, Friedman L, O'Hara R, Sheikh J, Tinklenberg J, Whitehouse PJ. Donepezil and flight simulator performance: Effects on retention of complex skills. Neurol. Jul 2002;59:123-5. Abstract