A Review of Cholinesterase Inhibitors in Treating Mild-to-Moderate Alzheimer's Disease

 

Why these medications are used:

Alzheimer’s disease and some other dementias involve a drop in acetylcholine, a brain chemical needed for memory and thinking. AChEIs work by slowing the breakdown of acetylcholine, giving brain cells a little more of this chemical to use.

 

 

Cognitive and functional benefits:

Multiple randomized clinical trials and systematic reviews (including Cochrane analyses) show that roughly 1 in 5–8 patients  (12-20%) experience a noticeable, small, consistent, benefit that wouldn’t have occurred without the drug. (1, 9, 10)

 

The statistically significant, but modest improvements, are:

 

  • Average improvement of 2–3 points on a 70-point memory/thinking tests (ADAS-Cog scale). (1,2,6)
    • For mild AD: a change of +3 points on the ADAS-Cog is often meaningful.
    • For mild cognitive impairment: a 2-3 point change on the ADAS-Cog is often considered a minimal clinically important difference

 

  • A 2-3 change impacts areas such memory, language, or the application of knowledge and ideas, which directly impact daily life, such as:

    • Dressing with less help

    • Eating

    • Handling finances

    • Having a little more clarity

    • Being in a better mood

    • Steadier daily routine

    • Following a conversation a bit better

    • Remembering appointments

 

 

WHAT TO EXPECT:

Most people see the clearest benefit in the first year; some continue to do better than expected for several years. These medicines slow decline rather than cure the disease.  

 

 

INDIVIDUAL VARIATION:

Responses vary widely—some people show noticeable changes, others show only small slowing of decline. Side effects and overall health influence continuation.

 

 

0–18 MONTHS (STRONG EVIDENCE):

Randomized clinical trials consistently show modest benefits on thinking, daily function, and global measures within the first 6–18 months. 

 

1.5–3 YEARS (MODERATE EDVIDENCE):

Extension and observational studies suggest benefits often continue for 2–3 years, though effects usually shrink over time.  

 

GREATER THAN 3 YEARS (LIMITED EVIDENCE):

Long-term observational studies (3–5 years) suggest some patients do better over time than might be expected without treatment, but these studies are open-label or observational — meaning they lack placebo control and are subject to selection bias (i.e., patients who tolerate and stay on meds may differ systematically). (8)

 

 

Safety profile:

Side effects are most likely when first starting or increasing the dose, and may improve over time.

 

 

Common side effects:

Nausea, vomiting, diarrhea, appetite loss, weight loss (studies show ~1 in 20 patients may lose 10 or more pounds in a year), muscle cramps, insomnia, and vivid dreams

 

 

Serious but less common:

Slow heart rate, fainting and increased risk of falls in frail elders 

 

 

 

Practical Points 

 

Acetylcholinesterase inhibitors are first-line treatments for mild to moderate Alzheimer’s disease. They offer modest, temporary benefits in memory, daily function, and behavior. While not a cure, they can make day-to-day life a little easier for some patients and caregivers.

 

Not all patients respond equally; some show noticeable benefit, others minimal. Long-term benefit seems more likely when therapy is started early and maintained, but there’s wide individual variation.

 

You may notice only subtle changes within 4-6 weeks. Benefits are usually small—a bit more alertness, easier conversations, steadier daily tasks—but for some, the difference is meaningful.

 

If the medicine is going to help, you’ll often see signs in the first 1–3 months. Most clinical trials measure benefit at 3 months—this is when doctors usually reassess if the medication is helping.

 

The benefit usually lasts 6–12 months clearly, and sometimes longer, but it slows the decline rather than stopping the disease.

 

Beyond 1 year: many patients slowly return to their pre-treatment rate of decline, but they may still be functioning at a higher level than they would have without treatment. Some patients continue to show modest benefit into the moderate or even severe stages, which is why guidelines often recommend continuing treatment if tolerated.

 

Monitor weight, heart rate, and falls regularly. Report to your doctor any significant changes. 

 

Don’t stop taking the medication without your doctor's supervision. Some guidelines recommend continuing even into moderate-to-severe stages if the patient still benefits and tolerates the medication.

 

Though not proven yet, it mays logical sense that combining lifestyle interventions with therapies like AChEIs may lead to more significant improvements in mental health and cognitive function, potentially reducing depression and anxiety symptoms associated with dementia.

References:

1. Birks, J. S. (2006). Cholinesterase inhibitors for Alzheimer’s disease. Cochrane Database of Systematic Reviews, 2006(1), Article CD005593. https://doi.org/10.1002/14651858.CD005593 

2. Birks, J. S., & Grimley Evans, J. (2015). Rivastigmine for Alzheimer’s disease. Cochrane Database of Systematic Reviews, 2015(4), Article CD001191. https://doi.org/10.1002/14651858.CD001191.

3.Clegg, A., Bryant, J., Nicholson, T., McIntyre, L., De Broe, S., Gerard, K., & Waugh, N. (2001). Clinical and cost-effectiveness of donepezil, rivastigmine and galantamine for Alzheimer's disease. Health Technology Assessment, 5(1), 1–137. In Efficacy and safety of donepezil, galantamine, and rivastigmine for the treatment of Alzheimer's disease: a systematic review and meta-analysis. NCBI Bookshelf. NCBI

4. Persistent use of antidementia drugs slows clinical progression of Alzheimer disease. (2010). Alzheimer’s Research & Therapy, 2, 7. https://doi.org/10.1186/alzrt7 SpringerLink

5. AAFP Clinical Summary. (2006, September 1). Cholinesterase Inhibitors for Alzheimer’s Disease: Practice pointers for family physicians. American Family Physician, 74(5), 747–754.

6. Agnoli, T., Visser, M., Cooper, C., et al. (2024). Advances in Clinical and Experimental Medicine, 33(11), 1179–1190.

Carbone, M., Caroppo, P., & Romagnoli, S. (2023). Effect of long-term pharmacological treatments on Alzheimer disease: A systematic review and network meta-analysis. Journal of Alzheimer’s Disease, (published July 2023). 

7. Holmes, C., Wilkinson, D., Dean, M., et al. (2015). The comparative efficacy and safety of cholinesterase inhibitors in patients with mild-to-moderate Alzheimer's disease: A Bayesian network meta-analysis. International Journal of Geriatric Psychiatry, 30(5), 445–456. (Note: this study is often cited as 2015 — combining data across many RCTs to compare AChEIs).

8. Farlow, M., et al. (2013). Persistent treatment with cholinesterase inhibitors and/or memantine slows clinical progression of Alzheimer disease. Alzheimer’s Research & Therapy, 5, Article 7.

9. Rogers, S. L., Farlow, M. R., Doody, R. S., Mohs, R., & Friedhoff, L. T. (1998). A 24-week, double-blind, placebo-controlled trial of donepezil in patients with Alzheimer’s disease. Neurology, 50(1), 136-145.

10. Lanctôt, K. L., Herrmann, N., Yau, K. K., Khan, L. R., Liu, B. A., LouLou, M. M., & Einarson, T. R. (2003). Efficacy and safety of cholinesterase inhibitors in Alzheimer’s disease: A meta-analysis. Canadian Medical Association Journal, 169(6), 557-564.