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. 2025 Mar;40(3):327-337.
doi: 10.1007/s10654-025-01220-1. Epub 2025 Mar 23.

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

Jacqueline J Claus  1   2 , Ilse Vom Hofe  1 , Annekee van Ijlzinga Veenstra  1 , Silvan Licher  1   3 , Harro Seelaar  4 , Frank J de Jong  4 , Julia Neitzel  1   2 , Meike W Vernooij  1   2 , M Arfan Ikram  1 , Frank J Wolters  5   6
Affiliations

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

Jacqueline J Claus et al. Eur J Epidemiol. 2025 Mar.

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.

Keywords: Alzheimer’s disease; Amyloid; Clinical trials; Generalisability; Monoclonal antibodies.

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Conflict of interest statement

Declarations. Ethical approval: 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. Consent to participate: All participants provided written informed consent to participate in the study and to obtain information from their treating physicians. Competing interests: The authors have no relevant financial or non-financial interests to disclose.

Figures

Fig. 1
Fig. 1
Prevalence of trial eligibility criteria among participants with mild cognitive impairment and early Alzheimer’s disease dementia in the population-based Rotterdam Study. Legend: Trial eligibility criteria among participants with mild cognitive impairment and early Alzheimer’s disease in aducanumab (EMERGE), lecanemab (CLARITY-AD) and donanemab (TRAILBLAZER-ALZ2) trials. Percentages reflect the percentage of participants with individual eligibility criterion, or any criterion
Fig. 2
Fig. 2
Title: Concurrence of eligibility criteria for aducanumab, lecanemab and donanemab. Legend: These intersection diagrams show the patterns of co-occurrence of different eligibility criteria. Rows represent the types of eligibility criteria and columns represent their combinations. All criteria that are part of a given combination are shown as black dots connected by a vertical black line. A single dot without a line implies the symptom occurred in isolation. The number of participants with a given combination of criteria is shown as a vertical bar on top of the matrix. The graph is truncated at a minimum of four participants per combination. BMI indicates body mass index
Fig. 3
Fig. 3
Prevalence of trial eligibility criteria among participants with positive predicted amyloid status and mild cognitive impairment or early Alzheimer’s disease dementia in the population-based Rotterdam Study. Trial eligibility criteria among participants with mild cognitive impairment and early Alzheimer’s disease in aducanumab (EMERGE), lecanemab (CLARITY-AD) and donanemab (TRAILBLAZER-ALZ2) trials. Percentages reflect the percentage of participants with individual eligibility criterion, or any criterion
Fig. 4
Fig. 4
Impact of MRI criteria on trial eligibility. Legend: Prevalence of trial eligibility criteria for brain magnetic resonance imaging (MRI) scan among participants with mild cognitive impairment and Alzheimer’s disease dementia in aducanumab (EMERGE), lecanemab (CLARITY-AD) and donanemab (TRAILBLAZER-ALZ2) trails. Percentages reflect the percentage of participants with individual eligibility criterion, and MRI abnormalities reflect the presence of any of the MRI criteria. MRI indicates magnetic resonance imaging, WMH indicates white matter hyperintensities
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References

    1. Gauthier SR-NP, Morais JA, Webster C. World Alzheimer Report 2021: Journey through the Diagnosis of Dementia 2021.
    1. Cummings J, Zhou Y, Lee G, Zhong K, Fonseca J, Cheng F. Alzheimer’s disease drug development pipeline: 2023. Alzheimers Dement (N Y). 2023;9(2):e12385. - PMC - PubMed
    1. Budd Haeberlein S, Aisen PS, Barkhof F, et al. Two randomized phase 3 studies of aducanumab in early Alzheimer’s disease. J Prev Alzheimers Dis. 2022;9(2):197–210. - PubMed
    1. van Dyck CH, Swanson CJ, Aisen P, et al. Lecanemab in early Alzheimer’s disease. N Engl J Med. 2023;388(1):9–21. - PubMed
    1. Sims JR, Zimmer JA, Evans CD, et al. Donanemab in early symptomatic alzheimer disease: the TRAILBLAZER-ALZ 2 randomized clinical trial. JAMA. 2023;330(6):512–27. - PMC - PubMed

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