Reacción a "Anti-amyloid drugs for Alzheimer's disease have not been shown to have clinically significant effects, according to a Cochrane review"

Abstract

This review evaluates the clinical benefits and risks associated with the use of anti-Aβ monoclonal antibodies (anti-Aβ mAbs) in individuals with mild cognitive impairment (MCI) or mild Alzheimer’s-type dementia, an early stage of the disease.

Alzheimer’s disease is an incurable cognitive disorder typically associated with aging that arises from neuronal death in various brain regions. Initially, it affects the hippocampus and associated regions, leading to memory problems; however, over time, the disease progresses and affects different areas of the brain. Neuronal death, which only produces clinical symptoms once a significant number of neurons in these areas have already been lost, is linked to the formation of extracellular Aβ deposits and intracellular tau protein deposits, in both cases accompanied by other molecules.

This is a disease for which only symptomatic treatment is available—a treatment that is very ineffective and, in some individuals, manages to delay the progression of the disease by a few weeks or months.

Recently, a new class of treatments based on monoclonal antibodies against Aβ has been approved. The idea behind this treatment is that the antibodies can “tag” Aβ deposits and thereby activate the cellular machinery responsible for removing that peptide from the brain.

This review has analyzed the effect of the various anti-Aβ mAbs currently on the market, as they all act similarly and focus their mechanism of action on the same process: binding to the Aβ peptide and its removal from the brain environment. It is worth noting that the approval processes for these treatments, particularly in the case of the first ones—aducanumab and donanemab—were not without some academic controversy, as several members of the FDA and EMA approval committees assessed that the clinical effect was very limited. Ultimately, following a review of the treatments’ efficacy criteria and their effects, the first two were approved, followed by the rest. In this regard, this review is timely as it addresses an issue of great clinical relevance.

Using a methodology common in meta-analysis studies, they conclude that, 18 months into treatment, they observe little or no difference in cognitive function between treated individuals and those treated with placebo. Using improvement on the ADAS-Cog SMD test as a criterion, they observe that treated individuals show a very slight improvement (of less than 1 point, when a change of at least 2–4 points is considered necessary). If the effect is analyzed at 24 months, the result is even more uncertain. This minimal or no effect is also observed with other measures of cognitive function. The authors conclude that these slight improvements on various tests were unlikely to translate into significant improvements in daily functioning or the ability to maintain a certain degree of independence.

On the other hand, these treatments also have side effects, such as amyloid-related imaging abnormalities (ARIA), which occur more frequently in treated individuals, while other adverse side effects did not occur more frequently than in individuals treated with a placebo.

Finally, carriers of the e4 allele in the APOE gene have a higher probability of developing ARIA. This allele is the primary known genetic risk factor for Alzheimer’s disease, and a relatively high number of people with the disease carry this allele. This review was unable to analyze the role of this gene in treatment effectiveness in sufficient detail because, despite this evidence, many studies did not perform genotyping of participants due to the family implications involved.

Quality of the study

The “Cochrane,” as it is commonly known, is an international nonprofit organization dedicated to producing high-quality evidence to support health decision-making. Its most renowned output is the Cochrane Systematic Reviews, regarded as the gold standard for summarizing health evidence. These reviews are conducted using a specific structure and focus on evaluating existing evidence and assessing the risk of bias in published studies. Their reviews are routinely used by international organizations (WHO, EMA, FDA) and various national committees. Furthermore, the reviews are periodically updated as new evidence emerges, reinforcing their clinical relevance.

This study follows the organization’s rigorous review process.

Implications, fit with existing evidence

The implications of this study are clear from a public health management perspective. The annual cost of these treatments is around €25,000. If there is no evidence that they have a significant clinical effect, does it make sense to continue using them? During the approval processes for these treatments, pressure from companies and patients played an important role in bringing them to market, but there were many experts who recommended against their approval. As evidence accumulates regarding their use, it is becoming quite clear that the benefits are extraordinarily limited. And we do not yet know if they are sustained over time. The only remaining question is what happens if patients are stratified based on the presence of certain genetic risk factors.

Limitations

The study itself has no greater limitations than those of the studies on which it is based. Thus, the authors note that the results cannot be generalized to the entire patient population, since the average age at onset is around 80 years, while the groups studied in the review have an age at onset ranging from 69.5 to 73.9 years. Furthermore, the follow-up period is relatively short. The authors also identify some limitations related to the studies analyzed, such as the fact that many of them are funded by the pharmaceutical industry that produces these treatments.

Regarding the study itself, the authors do not identify any limitations concerning the analysis performed.

General comments

This study represents an effort to demonstrate, based on the publications emerging regarding the efficacy of these treatments, to what extent this therapy is effective. It is to be hoped that in the coming months we will see an update to this review that includes follow-up over longer periods, with more diverse populations—not just predominantly of Caucasian origin—with greater detail on the genetic profile of the participants, and with ages closer to those of the general patient population.