The ADAS-Cog revisited: Novel composite scales based on ADAS-Cog to improve efficiency in MCI and early AD trials
Open accessAbstract
BACKGROUND: The Alzheimer's Disease Assessment Scale-Cognitive (ADAS-Cog) has been used widely as a cognitive end point in Alzheimer's Disease (AD) clinical trials. Efforts to treat AD pathology at earlier stages have also used ADAS-Cog, but failure in these trials can be difficult to interpret because the scale has well-known ceiling effects that limit its use in mild cognitive impairment (MCI) and early AD. A wealth of data exists in ADAS-Cog from both historical trials and contemporary longitudinal natural history studies that can provide insights about parts of the scale that may be better suited for MCI and early AD trials. METHODS: Using Alzheimer's Disease Neuroimaging Initiative study data, we identified the most informative cognitive measures from the ADAS-Cog and other available scales. We used cross-sectional analyses to characterize trajectories of ADAS-Cog and its individual subscales, as well as other cognitive, functional, or global measures across disease stages. Informative measures were identified based on standardized mean of 2-year change from baseline and were combined into novel composite endpoints. We assessed performance of the novel endpoints based on sample size requirements for a 2-year clinical trial. A bootstrap validation procedure was also undertaken to assess the reproducibility of the standardized mean changes of the selected measures and the corresponding composites. RESULTS: All proposed novel endpoints have improved standardized mean changes and thus improved statistical power compared with the ADAS-Cog 11. Further improvements were achieved by using cognitive-functional composites. Combining the novel composites with an enrichment strategy based on cerebral spinal fluid beta-amyloid (Aβ(1-42)) in a 2-year trial yielded gains in power of 20% to 40% over ADAS-Cog 11, regardless of the novel measure considered. CONCLUSION: An empirical, data-driven approach with existing instruments was used to derive novel composite scales based on ADAS-Cog 11 with improved performance characteristics for MCI and early AD clinical trials. Together with patient enrichment based on Aβ(1-42) pathology, these modified endpoints may allow more efficient clinical trials in these populations and can be assessed without modifying current test administration procedures in ongoing trials.
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- Authors
- Raghavan, N., Samtani, M. N., Farnum, M., Yang, E., Novak, G., Grundman, M., Narayan, V., DiBernardo, A., & Initiative, A. D. N.
- Affiliations
- Janssen Pharmaceutical Companies of Johnson & Johnson Raritan NJ
- Janssen Pharmaceutical Companies of Johnson & Johnson Springhouse PA
- Janssen Pharmaceutical Companies of Johnson & Johnson Titusville NJ
- Global R&D Partners San Diego CA
- Alzheimer’s Disease Neuroimaging Initiative (US)
- Corresponding author
- Raghavan, Nandini
- Venue
- Alzheimer's & Dementia
- Publisher
- Wiley
- Published
- 2012-11-05
- Volume
- 9
- Issue
- 1S
- Pages
- S21-31
- ISSN
- 1552-5260 (ISSN-L)
- 1552-5279
- PMC
- PMC3732822
- OpenAlex
- W2008405909
- Cited by
- 96
- References
- 36
- Citations by year
- 2026: 4 · 2025: 12 · 2024: 6 · 2023: 6 · 2022: 7 · 2021: 10 · 2020: 9 · 2019: 3 · 2018: 8 · 2017: 10 · 2016: 3 · 2015: 11 · 2014: 6 · 2013: 1
- FWCI
- 4.11
- Type
- journal article
- Language
- en
- Open access
- green
- europepmc.org
- Locations
- Alzheimer s & Dementia (publishedVersion)
- PubMed (publishedVersion)
- Europe PMC (PubMed Central) (acceptedVersion)
- PubMed Central (acceptedVersion)
- Funders
- National Institutes of Health (U01 AG024904)
- National Institute on Aging
- National Institute of Biomedical Imaging and Bioengineering
- Dana Foundation
- 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
- ADAS-Cog, Alzheimer's disease
- MeSH terms
- Aged, Alzheimer Disease, Clinical Trials as Topic, Female, Humans, Male, Neuropsychological Tests, Early Diagnosis, Cognitive Dysfunction
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