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

Background Treatment with monoclonal antibodies against amyloid-beta; slowed cognitive decline in recent randomized clinical trials in patients with mild cognitive impairment (MCI) and early dementia due to Alzheimers disease (AD). However, stringent trial eligibility criteria may affect generalizability of these findings to clinical practice. Methods We 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 and APOE genotype. We assessed progression to dementia within 5 years among participants with MCI, stratified for eligibility. Results Of 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]). Conclusions Findings from recent RCTs reporting protective effects of monoclonal antibodies against amyloid-beta 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. ### Competing Interest Statement The authors have declared no competing interest. ### Funding Statement The Rotterdam Study is supported by the Erasmus MC and Erasmus University Rotterdam, The Netherlands Organization for Scientific Research (NWO), The Netherlands Organization for Health Research and Development (ZonMw), the Research Institute for Diseases in the Elderly (RIDE), the Netherlands Genomics Initiative, the Ministry of Education, Culture and Science, the Ministry of Health, Welfare and Sports, the European Commission (DG XII), and the Municipality of Rotterdam. FJW was supported by the Netherlands Organisation for Health Research and Development (ZonMw) (Veni grant number 09150162010108). None of the funding organizations or sponsors were involved in study design, in collection, analysis, and interpretation of data, in writing of the report, or in the decision to submit the article for publication. ### Author Declarations I confirm all relevant ethical guidelines have been followed, and any necessary IRB and/or ethics committee approvals have been obtained. Yes The details of the IRB/oversight body that provided approval or exemption for the research described are given below: The Rotterdam Study has been approved by the Medical Ethics Committee of the Erasmus MC and by the Ministry of Health, Welfare and Sport of the Netherlands, implementing the Population Screening Act: Rotterdam Study. All participants provided written informed consent to participate in the study and to obtain information from their treating physicians. I confirm that all necessary patient/participant consent has been obtained and the appropriate institutional forms have been archived, and that any patient/participant/sample identifiers included were not known to anyone (e.g., hospital staff, patients or participants themselves) outside the research group so cannot be used to identify individuals. Yes I understand that all clinical trials and any other prospective interventional studies must be registered with an ICMJE-approved registry, such as ClinicalTrials.gov. I confirm that any such study reported in the manuscript has been registered and the trial registration ID is provided (note: if posting a prospective study registered retrospectively, please provide a statement in the trial ID field explaining why the study was not registered in advance). Yes I have followed all appropriate research reporting guidelines, such as any relevant EQUATOR Network research reporting checklist(s) and other pertinent material, if applicable. Yes Data can be obtained upon request. Requests should be directed towards the management team of the Rotterdam Study (secretariat.epi@erasmusmc.nl), which has a protocol for approving data requests. Because of restrictions based on privacy regulations and informed consent of the participants, data cannot be made freely available in a public repository. FJW had full access to the data in the study and takes responsibility for data integrity and accuracy of data analysis.