«Compounded Interest» in Alzheimer’s Disease: Do New Amyloid-Targeting Treatments Justify Their Use

Al z h e i m e r ’ s d i s e a s e i s a p ro g re s s i v e neurodegenerative disorder that affects millions of people worldwide, causing a significant burden on patients, caregivers, and healthcare systems. The recent licensing in the USA of amyloidtargeted drugs, which have shown a modest positive effect in delaying cognitive deterioration, has generated a debate on whether these treatments have a clinically meaningful impact on disease progression. The central issue under discussion is whether the measurable effect of amyloid-targeting antibody therapy is worth the financial cost and patients’ burden associated with its administration. The issue of clinical meaningfulness regarding small effect sizes in Alzheimer ’s disease treatments is not new. Over two decades ago, when Anticholinesterease inhibitors (ACHEI) were first licensed worldwide, there were intense debates about their therapeutic value, considering the minor improvement detected after six months of treatment in ADAS-Cog now established as around 2.7 points (95%CI -3.0 to -2.3) (1). At that time, most countries agreed to reimburse the treatment, but several constraints were implemented, such as prescription restrictions and guidelines for efficacy monitoring using what would today be called real-world data (2). Over time, most of these restrictions were lifted, and now there is a general consensus that ACHEIs and Memantine provided incremental value to Alzheimer’s disease therapeutics, impacting not just cognition but also functional and global outcomes. In retrospect, payers took a risk amid the lack of alternatives and immense societal pressure. However, it can now be argued that this risk paid off, as it brought value that was initially doubted. Determining what constitutes a clinically meaningful effect size is more an art than a science, and it still falls under the category of concepts that are recognized only when they are seen, similar to the term’s origin in discussions about «pornography». There is no doubt about the clinically meaningful effects of nusinersen or zolgensma in Spinal Muscular Atrophy types 1 and 2 (3); however, controversy arises with borderline effect sizes. This controversy may be fueled by a genuinely small effect that is not inherently doubtful, as with lecanemab (4), or by small to moderate effect sizes established in small sample size clinical trials, which might not be real. The latter is the case surrounding AMX0035 for ALS (5). There are straightforward definitions of clinical meaningfulness and methodologies to rigorously establish the value for a clinically meaningful change (6). Clinically meaningful change, also known as a minimum clinical important difference (MCID), is a threshold value for which any change as large or larger is considered meaningful to patients, clinicians, or both, with patients’ perspectives taking precedence. Several methods exist to establish this: 1. Anchor-based methods: Compare the change in an outcome measure to an external criterion or «anchor» that is considered clinically meaningful, reflecting patients’ perspectives, usually through a global measure or patient-reported outcome (PRO). 2. Distribution-based methods: Estimate the magnitude of change in an outcome measure using statistical approaches based on data distribution. 3. Delphi technique: Assemble a panel of experts to reach consensus on what constitutes a clinically meaningful difference for a specific outcome measure. 4. Patient-reported outcomes (PROs): Identify the minimal change in the outcome that patients perceive as important or beneficial. 5. Clinical trials and responder analyses: Compare the proportion of patients achieving a predefined level of improvement or lower deterioration between treatment groups.