Change in Odor Identification Impairment is Associated with Improvement with Cholinesterase Inhibitor Treatment in Mild Cognitive Impairment

J Alzheimers Dis. 2017;60(4):1525-1531. doi: 10.3233/JAD-170497.


Background: Anticholinergic challenge can induce odor identification impairment that indicates Alzheimer's disease pathology.

Objective: To determine if decline in odor identification ability with anticholinergic challenge can predict improvement with donepezil, a cholinesterase inhibitor (ChEI), in patients with mild cognitive impairment (MCI).

Methods: At baseline, the University of Pennsylvania Smell identification Test (UPSIT) was administered before and after an anticholinergic atropine nasal spray challenge. Donepezil was started at 5 mg daily, increased to 10 mg daily if tolerated, and then the dose was kept constant for 52 weeks. Main outcomes were change in Selective Reminding Test (SRT) total immediate recall and ADAS-Cog total score from baseline to 26 and 52 weeks.

Results: In 37 participants, mean age 70.4 (SD 9.8) y, greater atropine-induced decrease in UPSIT score at baseline was associated with greater improvement in SRT total recall score from baseline to 26 and 52 weeks (p < 0.03). This effect remained after adjusting for time, age, education, gender, APOE ɛ4 status, and baseline cognitive score (p < 0.05). Decrease in UPSIT score was associated with global improvement (CIBIC-plus) over 52 weeks (p < 0.02). After excluding patients with congential anosmia, increase in UPSIT score from 0 to 8 weeks showed a trend-level association with improvement on the ADAS-Cog (p = 0.07).

Conclusions: Anticholinergic challenge-induced odor identification decline was associated with cognitive improvement, and short-term improvement in odor identification tended to predict longer term cognitive improvement. These simple inexpensive strategies have the potential to improve selection of patients with MCI for ChEI treatment.

Keywords: Acetylcholine; Alzheimer’s disease; mild cognitive impairment; olfaction.

MeSH terms

  • Aged
  • Atropine / administration & dosage*
  • Cholinesterase Inhibitors / therapeutic use*
  • Cognitive Dysfunction / diagnosis*
  • Cognitive Dysfunction / drug therapy
  • Cognitive Dysfunction / physiopathology
  • Donepezil
  • Female
  • Humans
  • Indans / therapeutic use*
  • Male
  • Memory / drug effects
  • Memory / physiology
  • Muscarinic Antagonists / administration & dosage*
  • Neuropsychological Tests
  • Odorants
  • Olfaction Disorders / drug therapy
  • Olfaction Disorders / physiopathology
  • Olfactory Perception / drug effects*
  • Olfactory Perception / physiology
  • Pattern Recognition, Physiological / drug effects
  • Pattern Recognition, Physiological / physiology
  • Piperidines / therapeutic use*
  • Prognosis
  • Psychotropic Drugs / therapeutic use
  • Treatment Outcome


  • Cholinesterase Inhibitors
  • Indans
  • Muscarinic Antagonists
  • Piperidines
  • Psychotropic Drugs
  • Atropine
  • Donepezil