Not all drugs are the same (even if their mechanism of action is similar)
- Prof. Yehudit Aharon Peretz
- No comments
A letter in response to a Cochrane systematic review that sparked heated debate
What did the Cochrane systematic review say?
A systematic review was published on April 16, 2026.[1] In Cochrane[2] (Cochrane), which combines data from 17 randomized trials (involving more than 20,000 subjects), of all preparations that examined the effect of treatment in a research setting In monoclonal antibodies against amyloid[3].
The authors of the scan claim that monoclonal antibodies targeting the clearance of amyloid deposits from the brain in patients with early-stage Alzheimer's disease yield statistically significant but minimal clinical benefits (i.e. minimal cognitive and functional efficacy) and significantly increase the risk of ARIA (especially cerebral edema).
The review authors question both the clinical significance of the cognitive-functional outcomes and the research methods used by the researchers in the various studies reviewed. They also wonder whether the results of the studies prove that the relatively modest effect of the treatment has a significant advantage on the course of the disease and the functional status of the patient, especially when considering the risks of the treatment (edema and cerebral hemorrhage).
The authors also cast doubt on the view that amyloid protein plays a central role in the pathological processes leading to brain damage in Alzheimer's disease and claim that "successful removal of amyloid from the brain does not lead to a significant clinical effect in patients with mild cognitive impairment or mild dementia due to Alzheimer's disease."
-----
[1] The full systematic review appears here , and here is its location:
Nonino, F., Minozzi, S., Sambati, L., Del Giovane, C., Baldin, E., Bassi, MC, De Santis, C., Gonzalez-Lorenzo, M., Vignatelli, L., Filippini, G., & Richard, E. (2026). Amyloid-beta-targeting monoclonal antibodies for people with mild cognitive impairment or mild dementia due to Alzheimer's disease. Cochrane Database of Systematic Reviews. https://doi.org/10.1002/14651858.CD016297
[2] The Cochrane Library is a collection of databases in medicine and other health professions, provided by the Cochrane Foundation and other organizations. At its core is the Cochrane Reviews collection , a repository of systematic reviews and meta-analyses that summarize and interpret the results of medical research.
[3] Antibodies are produced by the body as a defense against disease. They can also be made in a laboratory for use as a medical treatment. Anti-amyloid antibodies are designed to target the amyloid proteins that cause the plaques in Alzheimer's disease and remove them from the brain. They are called "monoclonal " because they target only amyloid proteins. Removing amyloid proteins from the brain may slow the progression of Alzheimer's disease.
Are there any anti-amyloid antibodies that have proven effective?
To Kanmab (Lecanemab) Andonanmav (Donanemab) are monoclonal antibodies against the amyloid protein approved by the FDA, the European authorities (EMA), the Japanese authorities (JMA) and the Israeli Ministry of Health, for the treatment of patients diagnosed with Alzheimer's disease with mild cognitive impairment or mild dementia. That is, symptomatic disease in the early stages. The treatments are given by intravenous infusion.
These are the only two drugs , so far, that have proven effective in slowing cognitive and functional decline when given in the early stages of the disease. This is a modest, but statistically significant, slowdown.
The Lecanemab study demonstrated a 27% slowdown in cognitive and functional decline after 18 months of treatment. This slowdown was estimated to be equivalent to a delay of approximately 4–5 months in disease progression over an 18-month period. Follow-up data (36 months) demonstrated that the benefit was sustained.
The Donanemab study demonstrated a 36% slowdown in cognitive and functional decline in the population with low to moderate tau levels (a subgroup in the study). The slowdown in decline was sustained in treated participants (over 3 years), compared to an untreated age- and diagnosis-matched comparison group.
And what about the safety of these antibodies?
Treatment with both drugs is fraught with Risks of damage to brain tissue (side effects). These changes are usually mild, can be detected on imaging tests (Amyloid related imaging abnormalities-ARIA), and when diagnosed early, are reversible With appropriate treatment, And do not Permanent brain damage is left. Follow-up is performed with repeated brain MRI scans, mainly in the first six months of treatment.
Sensitivity to the infusion (with the antibodies) is another side effect, which usually occurs in response to the first infusions.
So what does the Cochrane review miss?
After examining the methods in the Cochrane review, we believe that its conclusions are not based on a proper processing of existing research data.
The research/therapeutic premise that clearing amyloid-beta will alter the course of the disease has driven the development of numerous monoclonal antibody drugs over the past two decades. Although all of these drugs target amyloid-beta, they differ in how they are processed in the body, the doses required for effective treatment, the site of action on the amyloid protein, the extent of amyloid clearance from the brain, and the clinical impact.
Of the clinical trials to date, only the drugs lancome and dunamb have reduced amyloid burden in patients below the threshold defined as “amyloid positive” on PET scans, and have demonstrated efficacy in slowing clinical deterioration compared to placebo. Therefore, including the results of all studies in one group, those that demonstrated effective amyloid clearance and those that did not, those that led to clinical improvement and those that did not, is, in our opinion, prejudicial and hinders the drawing of meaningful conclusions.
This is also true when looking at the rate of side effects. Although the authors report a small increase in the risk of ARIA rates, the data in the review combine low rates observed with drugs that have little or no effect on amyloid burden with high rates observed in trials of lekenamab and dunenamab, the only drugs to date that have demonstrated clinical efficacy. It is obvious that interpreting the efficacy and safety of all drugs acting against the amyloid protein as a group, without addressing the differences between the different drugs, obscures the differences between the different treatments.
In conclusion
When examining whether a preparation is clinically effective, it is necessary to determine whether the treatment Significantly beneficial to the patient. A sustained slowdown in the rate of deterioration, even if moderate, may delay Deterioration into stages of Loss of independence, increased support requirements, and the need for institutional care. For patients and their caregivers, slowing the pace of the disease is usually significant.
We join the opinion of doctors and researchers treating patients suffering from Alzheimer's disease from all over the world and argue that we should not agree with the conclusions of the Cochrane review - both in relation to the role of amyloid protein in Alzheimer's disease, and in relation to the clinical efficacy of monoclonal antibody treatment. The obvious conclusions are that the efficacy and side effect profile of each drug should be examined separately , and conclusions should not be drawn from grouping the findings of different preparations whose mechanism of action and efficacy are fundamentally different.
The Cochrane review does not conclude that amyloid protein does not play a role in the pathology of Alzheimer's disease. However, it can be concluded that the mechanism of action differs between drugs. So far, only drugs that have led to significant removal of amyloid from the brain have demonstrated clinical efficacy. Of course, it is always necessary to determine whether the treatment is effective and beneficial, consider the side effects and try to avoid them and/or treat them in the most effective way.
What else is important to know?
- It is recommended to consult a physician who specializes in diseases that cause dementia before deciding on specific treatment with monoclonal antibodies.
- Specialized clinics for the diagnosis and pharmacological and non-pharmacological treatment of cognitive decline, dementia, and Alzheimer's disease operate in the major public hospitals in Israel.
Prof. Yehudit Aharon-Peretz She is the chair of the Scientific Advisory Committee of EMDA Association and a senior physician at the Institute for Stroke and Cognition, Rambam Medical Center. Previously, director of the Institute for Cognitive Neurology.