Outreach, Screening, and Randomization of APOE ε4 Carriers into an Alzheimer's Prevention Trial: A global Perspective from the API Generation Program
Open accessAbstract
BACKGROUND: Alzheimer's disease (AD) prevention trials require a large outreach and screening funnel to identify cognitively unimpaired adults who meet the study's inclusion criteria, such as certain clinical or demographic criteria, genetic risk factors, and/or biomarker evidence of the disease. OBJECTIVES: Describe tactics and strategies to identify and enroll cognitively unimpaired adults with one (heterozygotes [HT]) or two (homozygotes [HM]) copies of the APOE ε4 allele, a genetic risk factor for dementia due to AD, into the Alzheimer's Prevention Initiative (API) Generation Program, the largest and only prevention trials for late onset AD using this enrichment technique. DESIGN AND SETTING: The Generation Program was comprised of two global, randomized, double-blind, placebo-controlled, parallel group adaptive design with variable treatment duration clinical trials. Generation Study 1 randomized participants into one of two cohorts: Cohort 1 which evaluated CAD106 vs. placebo or Cohort 2 which evaluated umibecestat vs placebo. Generation Study 2 randomized participants into two doses of umibecestat vs. placebo. The Generation Program was terminated early in 2019, while enrollment was still occurring. PARTICIPANTS: Both Generation Study 1 and Generation Study 2 enrolled cognitively unimpaired APOE ε4 HMs aged 60-75; Generation Study 2 also enrolled APOE ε4 HTs ages 60-75 with elevated brain amyloid. METHODS AND MEASUREMENTS: Describe results of the centralized and localized outreach, recruitment, screening strategies and tactics as well as characteristics of sites successful at enrolling genetically eligible participants, with a particular focus on APOE ε4 HMs given the 2-3% prevalence of this genotype. RESULTS: At the time the trial program was terminated, 35,333 individuals had consented to the optional prescreening ICF1a/ICFA and provided a sample of DNA for APOE genotyping, 1,138 APOE ε4 HMs consented to screening for Generation Study 1 (ICF1b), and 1,626 APOE ε4 carriers were randomized into either Generation Study 1 or Generation Study 2. Genetic testing registries, partnerships with genetic testing/counseling companies, and the optional prescreening ICF1a/ICFA were the most successful strategies for identifying genetically eligible participants for screening. CONCLUSIONS: It is feasible to recruit, screen and randomize cognitively unimpaired APOE ε4 carriers, particularly APOE ε4 HMs for a global AD prevention trial. The Generation Program was on track to complete enrollment by end of 2019. Factors that were key to this success included: working with sites to develop customizable outreach, recruitment, and screening programs specific to their site needs, providing forums for sites to exchange best practices, and developing partnerships between the sponsor team and trial sites.
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Two phase II/III trials of umibecestat in older APOE4 carriers without cognitive impairment were terminated prematurely due to observations of mild cognitive decline and brain atrophy.
“However, two phase II/III trials (NCT02565511 and NCT03131453), conducted on older individuals with high risk of AD (carriers of the APOE4 allele) but without cognitive impairment, were terminated prematurely. This decision was made due to observations of mild cognitive decline and brain atrophy in participants.446,447”
From Recent advances in Alzheimer's disease: Mechanisms, clinical trials and new drug development strategies. (2024) · cites this paper as [447]
The Methods (Study Design; page unavailable) identify the two trial numbers and describe cognitively healthy APOE ε4 carriers aged 60–75. The Introduction and Results (pages unavailable) say the program ended early after a signal of mild cognitive worsening with umibecestat. Our copy does not say brain atrophy contributed to the termination, nor does it identify the trials as phase II/III. (LLM, conf=0.88)
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Zhang, J., Zhang, Y., Wang, J., Xia, Y., Zhang, J., & Chen, L. (2024) · Signal Transduction and Targeted Therapy · doi:10.1038/s41392-024-01911-3 · Cited by 1,138 · see citing works
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- Authors
- Walsh, T., Duff, L., Riviere, M. E., Tariot, P. N., Doak, K., Smith, M., Borowsky, B., Lopez Lopez, C., Arratia, P. C., Liu, F., Scholten, I., Gordon, D., Arbuckle, J., Graf, A., Quinn, M., Ricart, J., & Langbaum, J.
- Affiliations
- Banner Alzheimer’s Institute (US)
- Novartis (Switzerland) (CH)
- Novartis (Spain) (ES)
- ORCID
- Borowsky, B.
- Venue
- The Journal of Prevention of Alzheimer's Disease
- Publisher
- Elsevier BV
- Published
- 2023-09
- Volume
- 10
- Issue
- 3
- Pages
- 453-463
- ISSN
- 2274-5807 (ISSN-L)
- PMC
- PMC10426731
- OpenAlex
- W4323906574
- Cited by
- 18
- References
- 2
- Citations by year
- 2026: 5 · 2025: 8 · 2024: 4 · 2023: 1
- FWCI
- 3.67
- Type
- journal article
- Language
- en
- Open access
- gold
- doi.org
- Licence
- Locations
- The Journal of Prevention of Alzheimer s Disease (publishedVersion, cc-by)
- PubMed (publishedVersion)
- PubMed Central (acceptedVersion, cc-by)
- Funders
- Alzheimer's Association
- Amgen
- Eli Lilly and Company
- Biogen
- GHR Foundation
- Eisai
- Novo Nordisk
- Foundation for Biomedical Research and Innovation
- National Institutes of Health
- Genentech
- Novartis Pharma
- National Institute on Aging (UF1AG046150, P30AG019610, P30AG072980)
- Topics
- Health Sciences › Medicine › Psychiatry and Mental health › Dementia and Cognitive Impairment Research
- Health Sciences › Medicine › Physiology › Alzheimer's disease research and treatments
- Health Sciences › Medicine › Public Health, Environmental and Occupational Health › Ethics in Clinical Research
- Keywords
- APOE ε4 carriers, genetic enrichment, amyloid PET, late-onset Alzheimer's disease, prescreening
- MeSH terms
- Adult, Alzheimer Disease, Genotype, Heterozygote, Humans, Random Allocation, Apolipoprotein E4
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