Estimating sample sizes for predementia Alzheimer's trials based on the Alzheimer's Disease Neuroimaging Initiative
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This study modeled predementia Alzheimer's disease clinical trials. Longitudinal data from cognitively normal (CN) and mild cognitive impairment (MCI) participants in the Alzheimer's Disease Neuroimaging Initiative were used to calculate sample size requirements for trials using outcome measures, including the Clinical Dementia Rating scale sum of boxes, Mini-Mental State Examination, Alzheimer's Disease Assessment Scale-cognitive subscale with and without delayed recall, and the Rey Auditory Verbal Learning Task. We examined the impact on sample sizes of enrichment for genetic and biomarker criteria, including cerebrospinal fluid protein and neuroimaging analyses. We observed little cognitive decline in the CN population at 36 months, regardless of the enrichment strategy. Nonetheless, in CN subjects, using Rey Auditory Verbal Learning Task total as an outcome at 36 months required the fewest subjects across enrichment strategies, with apolipoprotein E genotype ε4 carrier status requiring the fewest (n = 499 per arm to demonstrate a 25% reduction in disease progression). In MCI, enrichment reduced the required sample sizes for trials, relative to estimates based on all subjects. For MCI, the Clinical Dementia Rating scale sum of boxes consistently required the smallest sample sizes. We conclude that predementia clinical trial conduct in Alzheimer's disease is enhanced by the use of biomarker inclusion criteria.
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The improvements in both clinical outcomes are interpreted as evidence of practice effects.
“we interpret this finding as evidence of practice effects, which are increasingly recognized in AMCI[90], are inversely related with conversion to AD, and can be examined as an outcome in clinical trials [91].”
From Metformin in Amnestic Mild Cognitive Impairment: Results of a Pilot Randomized Placebo Controlled Clinical Trial (2016) · cites this paper as [90]
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- Authors
- Grill, J. D., Di, L., Lu, P. H., Lee, C., Ringman, J., Apostolova, L. G., Chow, N., Kohannim, O., Cummings, J. L., Thompson, P. M., & Elashoff, D.
- Affiliations
- University of California, Los Angeles (US)
- Cleveland Clinic (US)
- Corresponding author
- Grill, Joshua D.
- ORCID
- Venue
- Neurobiology of Aging
- Publisher
- Elsevier BV
- Published
- 2013-01
- Volume
- 34
- Issue
- 1
- Pages
- 62-72
- ISSN
- 0197-4580 (ISSN-L)
- PMC
- PMC3412892
- OpenAlex
- W2047170994
- Cited by
- 58
- References
- 74
- Citations by year
- 2026: 1 · 2025: 6 · 2024: 1 · 2023: 3 · 2022: 5 · 2021: 3 · 2020: 1 · 2019: 3 · 2018: 7 · 2017: 2 · 2016: 4 · 2015: 9 · 2014: 5 · 2013: 5 · 2012: 3
- FWCI
- 5.01
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Locations
- Neurobiology of Aging (publishedVersion)
- PubMed (publishedVersion)
- PubMed Central (acceptedVersion)
- eScholarship (California Digital Library) (submittedVersion, cc-by)
- Funders
- NIA (AG016570)
- National Institutes of Health (U01 AG024904, P30 AG010129, K01 AG030514)
- Topics
- Health Sciences › Medicine › Psychiatry and Mental health › Dementia and Cognitive Impairment Research
- Health Sciences › Medicine › Physiology › Alzheimer's disease research and treatments
- Physical Sciences › Mathematics › Statistics and Probability › Statistical Methods in Clinical Trials
- Keywords
- sample size determination, clinical trial design, mild cognitive impairment, cognitively normal older adults, biomarker enrichment, APOE ε4, cerebrospinal fluid biomarkers, neuroimaging biomarkers, Clinical Dementia Rating, Mini-Mental State Examination, Alzheimer's Disease Assessment Scale, cognitive decline, disease progression
- MeSH terms
- Aged, Aged, 80 and over, Alzheimer Disease, Brain, Clinical Trials as Topic, Female, Humans, Longitudinal Studies, Male, Mental Status Schedule, Multicenter Studies as Topic, Biomarkers, Sample Size, Disease Progression, Apolipoprotein E4, Neuroimaging, Cognitive Dysfunction
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