Generalizability of trial criteria on amyloid-lowering therapy against Alzheimer’s disease to individuals with mild cognitive impairment or early Alzheimer’s disease in the general population

Abstract

Treatment with anti-amyloid-β monoclonal antibodies slowed cognitive decline in recent RCTs in patients with mild cognitive impairment (MCI) and early dementia due to Alzheimer’s disease (AD). However, stringent trial eligibility criteria may affect generalisability to clinical practice. We extracted eligibility criteria for trials of aducanumab, lecanemab and donanemab, and applied these to participants with MCI and early clinical AD dementia from the population-based Rotterdam Study. Participants underwent questionnaires, genotyping, brain-MRI, cognitive testing, and cardiovascular assessment. We determined amyloid status using a validated prediction model based on age and APOE-genotype. Of 968 participants (mean age: 75 years, 56% women), 779 had MCI and 189 dementia. Across trials, around 40% of participants would be ineligible because of predicted amyloid negativity. At least one clinical exclusion criterion was present in 76.3% of participants for aducanumab, 75.8% for lecanemab, and 59.8% for donanemab. Common criteria were cardiovascular disease (35.2%), anticoagulant (31.2%), psychotropic or immunological medication use (20.4%), anxiety or depression (15.9%), or lack of social support (15.6%). One-third were ineligible based on brain-MRI findings alone, similar across trials and predominantly due to cerebral small-vessel disease. Combining amyloid, clinical, and imaging criteria, eligibility ranged from 9% (95% CI:7.0-11.1) for aducanumab, 8% (6.2–9.9) lecanemab to 15% (12.4–17.5) for donanemab. Findings from recent RCTs reporting protective effects of monoclonal antibodies against amyloid-β are applicable to less than 15% of community-dwelling individuals with MCI or early AD. These findings underline that evidence for drug efficacy and safety is lacking for the vast majority of patients with MCI/AD in routine clinical practice.