The cholinergic hypothesis of cognitive aging revisited again: cholinergic functional compensation.

It is now possible to reevaluate the cholinergic hypothesis of age-related cognitive dysfunction based on a synthesis of new evidence from cholinergic stimulation studies and cognitive models. We propose that a change of functional circuitry that can be observed through a combination of pharmacologic challenge and functional neuroimaging is associated with age-related changes in cholinergic system functioning. Psychopharmacological manipulations using cholinergic agonists and antagonists have been consistent in replicating patterns of aging seen in functional imaging studies. In addition, studies of anticholinesterase drugs in patients with Alzheimer's disease and mild cognitive impairment show support for the proposal that cholinergic compensation causes alterations in task-related brain activity. Thus, the cholinergic hypothesis of age-related cognitive dysfunction deserves further consideration as new methodologies for evaluating its validity are increasingly being used. Future directions for testing hypotheses generated from this model are presented.