From the Guidelines
Alzheimer's drugs have been largely ineffective, with most showing minimal effectiveness despite initial claims of promise, and their claimed effectiveness is typically limited to a small, statistically significant but clinically marginal improvement in measures of cognition and global assessment of dementia. The effectiveness of these drugs, such as cholinesterase inhibitors and memantine, has been evaluated in several studies, including a 2008 review of evidence for a clinical practice guideline, which found that treatment with these drugs can result in statistically significant but clinically marginal improvement in measures of cognition and global assessment of dementia 1.
Key Points
- The cholinesterase inhibitors, such as donepezil, galantamine, and rivastigmine, were claimed to improve memory and thinking by a small amount, typically 2-3 points on a 70-point cognitive scale—a statistically significant but clinically modest benefit.
- Memantine was later introduced with similar modest claims, and its effectiveness was also found to be limited to a small, statistically significant but clinically marginal improvement in measures of cognition and global assessment of dementia.
- More recent treatments, such as antibody treatments targeting amyloid plaques, have also been found to have limited effectiveness, with data suggesting they provide only marginal clinical benefits, while carrying risks of brain swelling and bleeding.
Limitations of Current Treatments
- The complex nature of Alzheimer's disease, which likely involves multiple pathological processes beyond just amyloid accumulation, makes single-target treatments inherently limited in their impact.
- The short duration of most studies, typically 6 months, limited their ability to detect delay in onset or progression of dementia.
- The inclusion of only patients with mild to moderate Alzheimer disease, poor reporting of adverse events, lack of clear definitions for statistical significance, limited evaluation of behavior and quality-of-life outcomes, and limited direct comparison of different treatments are also limitations of current studies 1.
From the FDA Drug Label
The effectiveness of donepezil hydrochloride in the treatment of patients with moderate to severe Alzheimer’s disease was established in studies employing doses of 10 mg/day and 23 mg/day Results of a controlled clinical trial in moderate to severe Alzheimer’s Disease that compared donepezil hydrochloride 23 mg once daily to 10 mg once daily suggest that a 23 mg dose of donepezil hydrochloride provided additional benefit The mean difference in the SIB change scores for donepezil hydrochloride treated patients compared to patients on placebo was 5. 9 points. The differences in mean scores for donepezil hydrochloride treated patients compared to the patients on placebo at Week 12 were 0.36 and 0. 38 points for the 5 mg/day and 10 mg/day treatment groups, respectively. The annualized rate of decline in the placebo patients participating in donepezil hydrochloride trials was approximately 2 to 4 points per year Experience based on longitudinal studies of ambulatory patients with mild to moderate Alzheimer's disease suggest that scores on the ADAS-cog increase (worsen) by 6 to 12 points per year
The effectiveness of donepezil hydrochloride was claimed to be around 5.9 points improvement in SIB scores and 0.36 and 0.38 points improvement in CIBIC-plus scores for the 5 mg/day and 10 mg/day treatment groups, respectively, compared to placebo. The annualized rate of decline in placebo patients was around 2 to 4 points per year, while the rate of decline in donepezil hydrochloride treated patients was not explicitly stated, but the treatment was shown to be statistically significantly superior to placebo 2.
From the Research
Effectiveness of Alzheimer's Drugs
The effectiveness of Alzheimer's drugs has been a topic of research and debate. According to various studies, these drugs have shown modest but statistically significant improvements in cognition and global functioning 3, 4, 5, 6, 7.
- The cholinesterase inhibitors (ChEIs) donepezil, rivastigmine, and galantamine, as well as the N-methyl D-aspartate receptor antagonist memantine, have been found to have modest effects on cognitive and functional decline in patients with Alzheimer's disease 4, 5, 7.
- A systematic review and meta-analysis of 33 articles on 26 studies found that these drugs have modest overall benefits for stabilizing or slowing decline in cognition, function, behavior, and clinical global change 7.
- However, the choice of pharmacological agent is based on the stage of Alzheimer's disease, tolerability, adverse effect profile, ease of use, and cost, and patients should be monitored for efficacy, side effects, and possible treatment discontinuation 3, 4.
Comparison of Different Drugs
Comparisons between different Alzheimer's drugs have yielded conflicting results.
- A study found that donepezil was more efficacious than galantamine, while another study found rivastigmine to be more efficacious than donepezil 7.
- An adjusted indirect comparison of placebo-controlled data did not find statistically significant differences among drugs with regard to cognition, but found the relative risk of global response to be better with donepezil and rivastigmine compared with galantamine 7.
- Indirect comparisons also favored donepezil over galantamine with regard to behavior 7.
Limitations and Future Directions
Despite the modest benefits of current Alzheimer's drugs, there is a need for more effective treatments that can modify the disease progression.
- Researchers are turning their efforts to tau-targeting therapies, as tau protein appears to be better correlated with the severity of cognitive decline than amyloid β 6.
- Several anti-tau agents are in clinical trials, including monoclonal antibodies and vaccines 6.
- Further research is needed to confirm the effectiveness of these new approaches and to develop more effective treatments for Alzheimer's disease 5, 6.