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

Abstract

AbstractBackgroundTreatment with monoclonal antibodies against amyloid-β slowed cognitive decline in recent randomized clinical trials in patients with mild cognitive impairment (MCI) and early dementia due to Alzheimer’s disease (AD). However, stringent trial eligibility criteria may affect generalizability of these findings to clinical practice.MethodsWe extracted eligibility criteria for trials of aducanumab, lecanemab and donanemab from published reports, and applied these to participants with MCI or early clinical AD dementia from the population-based Rotterdam Study. Participants underwent questionnaires, genotyping, brain MRI, cognitive testing, and cardiovascular assessment. We had continuous linkage with medical records and pharmacy dispensary data. We determined amyloid status using an established and validated prediction model based on age andAPOEgenotype. We assessed progression to dementia within 5 years among participants with MCI, stratified for eligibility.ResultsOf 968 participants (mean age: 75 years, 56% women), 779 had MCI and 189 early clinical AD dementia. Across the three drug trials, around 40% of participants would be ineligible because of predicted amyloid negativity. At least one clinical exclusion criterion was present in 76.3% (95% CI; 73.3-79.3) of participants for aducanumab, 75.8% (73.0-78.7) for lecanemab, and 59.8% (56.4–63.3) for donanemab. Criteria that most often led to exclusion were a history of cardiovascular disease (35.2%), use of anticoagulant (31.2%), use of psychotropic or immunological medications (20.4%), history of anxiety or depression (15.9%), or lack of social support (15.6%). One-third of participants were ineligible based on brain MRI findings alone, which was similar across trials and due predominantly to various manifestations of cerebral small-vessel disease. Combining amyloid, clinical, and imaging criteria, eligibility ranged from 9% (7.0-11.1) for aducanumab, 8% (6.2-9.9) lecanemab to 15% (12.4-17.5) for donanemab. Risk of progression to dementia tended to be higher for ineligible than for eligible participants for lecanemab (hazard ratio [95%CI]: 1.64 [0.92-2.91]), aducanumab (HR: 1.17 [0.65-2.12]), and only marginally for donanemab (HR: 1.03 [0.67-1.59]).ConclusionsFindings 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.