Pharmacological Reversal of Attention Deficits in Non-Human Primates: Implications for Alzheimer's Disease

Attention deficits emerge early in Alzheimers disease (AD), where cholinergic dysfunction compromises goal-directed behavior and cognitive control. Therefore, attentional impairments may serve as early indicators of cognitive decline, and also as meaningful targets for therapeutic intervention. Despite their clinical importance, attention deficits remain under- targeted by current treatments, which offer only modest benefit. To support development of more effective therapies, preclinical models that closely mirror human neurobiology and behavior are essential. Non-human primates (NHPs), with their high degree of cortical and functional similarity to humans, particularly in prefrontal regions, offer a uniquely translational platform for evaluating cognitive enhancers. We assessed pharmacological interventions targeting sustained attention using the Continuous Performance Test (CPT) in adult male cynomolgus macaques. Monkeys were trained to detect target stimuli while ignoring distractors, achieving individualized stable performance. To simulate cholinergic dysfunction, we administered scopolamine, a muscarinic acetylcholine receptor antagonist, which produced dose-dependent declines in accuracy and reaction time. Mild and severe impairment levels were identified within each animal. We then tested three compounds: nicotine, guanfacine, and donepezil. Nicotine, a nicotinic receptor agonist, fully restored performance across both impairment levels, suggesting potential benefit in both early and advanced AD. Guanfacine, an 2A adrenergic agonist, improved accuracy only under mild impairment, while donepezil, an acetylcholinesterase inhibitor, showed inconsistent effects. None of the compounds reversed scopolamine-induced slowing of reaction time, indicating specificity for attentional control. These findings highlight the utility of the NHP CPT as a pharmacologically sensitive model for detecting attentional dysfunction and evaluating pro-cognitive therapeutics in aging and neurodegeneration.