Are Acetylcholinesterase Inhibitors Appropriate in General Mild Cognitive Impairment?


Medications used to treat Alzheimer's-induced mild cognitive impairment are often used to potentially improve the symptoms of general mild cognitive impairment.

Mild cognitive impairment is the clinical stage of cognitive decline between normal aging and dementia.1

Because this form of impairment is not severe, the patient still retains the capability to independently continue his or her activities of daily living with minor concerns.


Based on clinical characteristics, the patient may be diagnosed with either general mild cognitive impairment or Alzheimer’s-induced mild cognitive impairment.1

Those with the former diagnosis experience changes in cognition, show 1 or more objective pieces of evidence of impairment in cognitive function, perform activities of daily living independently, and show no significant social or occupational impairment. Meanwhile, those with Alzheimer’s-induced mild cognitive impairment present with significant memory impairment, progressive cognitive decline, lack of Parkinsonism, visual hallucinations, extensive cerebrovascular disease, lack of behavior, and even language disorders.1

Brain imaging can be used to easily differentiate between these 2 types, as patients diagnosed with Alzheimer’s-induced mild cognitive impairment tend to have an increased presence of both cerebrovascular complications and Lewy bodies.1 Any cognitive dysfunction is defined by changes in memory, language, visuospatial function, attention, and executive function; however, the degree of change, accompanied by other risk factors, will truly determine the stage and clinical diagnosis of the dysfunction.


Treatment varies based on the origin of the mild cognitive impairment. While there are established clinical guidelines for the treatment of patients with a history of Alzheimer’s disease, no current drug therapies have proven to be effective for the treatment of general mild cognitive impairment.1

Acetylcholinesterase inhibitors such as donepezil (Aricept) and galantamine (Razadyne) have limited statistical significance and show no clinically significant effects on cognitive improvement with short-term use in clinical studies. Evidence also suggests that acetylcholinesterase inhibitors do not reduce the risk of mild cognitive impairment progression to dementia at 1 and 3 years.1

A 2012 meta-analysis examined 9 studies from 8 separate sources to understand the safety and efficacy associated with acetylcholinesterase inhibitor use in patients with mild cognitive impairment. This analysis included patients treated with donepezil, galantamine, or rivastigmine for cognitive impairment.2

In one randomized, controlled trial, patients experienced varying exposure times to different acetylcholinesterase inhibitor therapy: donepezil for 24 weeks to 3 years, galantamine for 16 weeks to 24 months, and rivastigmine for 24 weeks to 48 months.2

The meta-analysis authors concluded that patients in the acetylcholinesterase inhibitor groups experienced significantly greater adverse events such as nausea, vomiting, muscle spasms, syncope, and headaches (RR= 1.09; 95% CI 1.02 to 1.16) and also showed no difference in improvement of cognition, function, or behavior compared with placebo.2,3 There was also very little evidence to suggest that acetylcholinesterase inhibitors may reduce the risk of progression to dementia.

At 4 consecutive years of treatment, there was no significant improvement in patient cognition and no effect on progression to dementia at 3 years.2,3 Two studies examined in the meta-analysis showed significantly different outcomes, indicating a possible reduction in mild cognitive impairment with an RR of 0.67; however, this minor difference is unlikely to be clinically significant.2

In another meta-analysis, the benefit of using donepezil 10 mg/day was compared with placebo in order to understand its importance in the treatment of mild cognitive impairment. Based on the outcomes, the authors concluded that there was a “modest treatment effect in cognitive function,” but no outcome improvements at other domains of cognitive function such as language, visuospatial ability, recent memory, and executive function.4

Patients on donepezil also presented with significantly greater gastrointestinal side effects than those taking placebo. Of the 133 patients on donepezil, approximately 116 of them experienced any of the following adverse effects at 24 weeks of therapy: diarrhea, nausea, vomiting, leg cramps, and abnormal dreams (OR = 2.52, 95% CI 1.34 to 4.76; p = 0.004). A total of 29 patients withdrew prematurely due to intolerable adverse events.4

At 3 years of treatment, there were 63 patients on donepezil diagnosed with dementia, compared with 73 on placebo; however, this difference was not statistically significant (p = 0.4). It was revealed that, just like other acetylcholinesterase inhibitors, donepezil showed no improvement in the delay of dementia onset or other outcomes in patients with general mild cognitive impairment.4


Based on available clinical data, acetylcholinesterase inhibitors appear to be ineffective in treating general mild cognitive impairment and associated with higher rates of adverse events. Therefore, their use should not be recommended unless the patient has established Alzheimer’s disease.


  • Langa KM, Levine DA. The diagnosis and management of mild cognitive impairment: a clinical review. JAMA. 2014;312(23):2551-1561.
  • Russ TC, Morling JR. Cholinesterase inhibitors for mild cognitive impairment. Cochrane Database Syst Rev. 2012;9:CD009132.
  • Russ TC. Cholinesterase inhibitors should not be prescribed for mild cognitive impairment. Evid Based Med. 2014 Jun;19(3):101. doi: 10.1136/eb-2013-101687. Epub 2014 Jan 30.
  • Birks J, Flicker L. Donepezil for mild cognitive impairment. Cochrane Database Syst Rev. 2006;(3):CD006104.

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