Reference: Ann Fam Med. 2024 Jan-Feb;22(1):50-62
Practice Point: Even if monoclonal antibody therapy for Alzheimer dementia was risk-free and cost-free (it is risky and expensive), exercise and cholinesterase inhibitors have more cognitive benefit.
EBM Pearl: Statistical significance ≠ clinical value.
Leprechauns and their famous pots of fool’s gold were making their yearly rounds last week with St. Patrick’s Day. This week, we are making the case that although monoclonal antibody treatment for Alzheimer dementia has the glittery sheen of high tech, the currently available options are no better than the imaginary gold found under a rainbow. The authors of a recent meta-analysis on amyloid-plaque-targeting-antibody treatment in Alzheimer dementia certainly seem to think so anyway.
The authors gathered 19 RCTs comparing eight different monoclonal antibodies directed against cerebral amyloid with placebo treatments looking at benefits and harms over a period of at least one year. They found data from 23,202 patients and gathered information on numerous metrics of benefit including improvement in the mini-mental status exam (MMSE) as well as other dementia-specific metrics of cognition, affect, and function. They also evaluated harms such as amyloid-related imaging abnormalities (ARIA) with and without edema, hemorrhage, or clinical response. It is notable that only three of the studies were found to be at low risk of bias, with four more considered at unclear risk and the remaining 12 considered at high risk because more than 10% of outcome data was missing.
For our purposes, we will focus on the MMSE outcome, mostly because it is ubiquitous and simple to understand (scale 0-30, with higher scores indicating better cognition), and because it’s likely to be the most recognized and used tool for assessing cognition. MMSE is also used frequently in studies of other therapies for Alzheimer dementia. For now, we will ignore other outcomes, such as the risk of harm and cost of therapy (estimated at > $26,000 annually), to focus on the MMSE results. The MMSE may not be a perfect patient-oriented outcome, but it is certainly more clinically relevant than asymptomatic ARIAs.
Let’s consider other therapies for Alzheimer dementia. We know that lifestyle differences like exercise and diet might impact cognition, and indeed, a meta-analysis from 2018 found that enrolling people with Alzheimer dementia in exercise programs increased performance on the MMSE by 2.53 points (95% CI 0.84-4.22 points). A difference of at least 1 point on the MMSE test is generally accepted as the minimal clinically important difference (MCID), defined as a difference that is noticeable by either the patient or caregiver. In other words, the small benefit from exercise is probably noticeable compared to not exercising. What about cholinesterase inhibitors? Depending on which one you pick, they improve the MMSE by between 1.39 and 2.5 points. Again, not a big difference, but not chopped liver! Lastly, how about monoclonal antibody therapy? According to this meta analysis, the improvement in MMSE score was a mean of 0.32 points (95% CI 0.13 points to 0.5 points).
For this particular study, statistical significance is achieved because the 0.13 on the lower end of the confidence interval is greater than zero. But notice that the upper limit of possible benefit is not even close to 1 point, which is the MCID, whereas the lower limit of the 95% CI for both exercise and cholinesterase inhibitors was higher than 1 point. To be explicit: if this study was repeated 100 times, monoclonal antibodies would be better than placebo 95% of the time, and are therefore statistically impactful. However, also 95% of the time, no one taking monoclonal antibody therapy would ever even notice an improvement, so they are therefore clinically worthless. This is worth repeating because this isn’t guesswork: we are more than 95% certain that there will not be a meaningful benefit in any given patient, at least in these circumstances.
What do we think? We think Alzheimer dementia is a terrible disease and there should be many studies looking at whatever we can do to slow its progression or onset. We also think that maybe the FDA jumped the gun in approving any of these monoclonal therapies, not following their own rule requiring an MCID for approvals. Perhaps the case can be made that the terrifying nature of Alzheimer dementia in an aging baby-boom population justifies treating it like a public health emergency. However, outside of research protocols, there does not seem to be an ethical or EBM justification for using any of these drugs at this time.
For more information, see the topic Alzheimer Dementia in DynaMed.
DynaMed EBM Focus Editorial Team
This EBM Focus was written by Dan Randall, MD, MPH, FACP, Deputy Editor at DynaMed. Edited by Alan Ehrlich, MD, FAAFP, Executive Editor at DynaMed and Associate Professor in Family Medicine at the University of Massachusetts Medical School; Katharine DeGeorge, MD, MS, Senior Deputy Editor at DynaMed and Associate Professor of Family Medicine at the University of Virginia; Nicole Jensen, MD, Family Physician at WholeHealth Medical; Vincent Lemaitre, PhD, Medical Editor at DynaMed; Hannah Ekeh, MA, Senior Associate Editor at DynaMed; and Jennifer Wallace, BA, Senior Associate Editor at DynaMed.