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Abstract Introduction This study evaluated acute change in odor identification following atropine nasal spray challenge, and 8‐week change in odor identification ability, as a predictor of long‐term improvement in patients with mild to moderate Alzheimer's disease (AD) who received open‐label cholinesterase inhibitor treatment. Methods In patients with clinical AD, the University of Pennsylvania Smell identification Test (UPSIT) was administered before and after an anticholinergic atropine nasal spray challenge. Patients were then treated with donepezil for 52 weeks. Results In 21 study participants, acute atropine‐induced decrease in UPSIT was not associated with change in the Alzheimer's Disease Assessment Scale ‐ Cognitive Subscale (ADAS‐Cog) or Selective Reminding Test (SRT). Decline in odor identification performance from baseline to week 8 was indicative of a future decline in cognitive performance over 52 weeks. Discussion Change in odor identification with atropine challenge is not a useful predictor of treatment response to cholinesterase inhibitors. Short‐term change in odor identification performance needs further investigation as a potential predictor of cognitive improvement with cholinesterase inhibitor treatment.