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Cited by 860Dementia and Cognitive Impairment ResearchAlzheimer's disease research and treatmentsCancer-related cognitive impairment studies

The Preclinical Alzheimer Cognitive Composite: Measuring Amyloid-Related Decline

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Donohue, Michael C., Sperling, Reisa A., Salmon, David P., Rentz, Dorene M., Raman, Rema, Thomas, Ronald G., Weiner, Michael, Aisen, Paul S.·2014·JAMA Neurology
DOI 10.1001/jamaneurol.2014.803PMC PMC4439182
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Abstract

IMPORTANCE: As Alzheimer disease (AD) research moves to intervene in presymptomatic phases of the disease, we must develop outcome measures sensitive to the earliest disease-related changes. OBJECTIVE: To demonstrate the feasibility of a cognitive composite outcome for clinically normal elderly participants with evidence of AD pathology using the ADCS Preclinical Alzheimer Cognitive Composite (ADCS-PACC). The ADCS-PACC combines tests that assess episodic memory, timed executive function, and global cognition. The ADCS-PACC is the primary outcome measure for the first clinical trial in preclinical AD (ie, the Anti-Amyloid Treatment in Asymptomatic Alzheimer's study). DESIGN, SETTING, AND PARTICIPANTS: With the ADCS-PACC, we derive pilot estimates of amyloid-related decline using data from 2 observational studies conducted in North America and another conducted in Australia. The participants analyzed had normal cognition and mean ages of 75.81, 71.37, and 79.42 years across the 3 studies. MAIN OUTCOMES AND MEASURES: For the 2 studies that collected data on Aβ levels (ADNI and AIBL), we estimate decline in a preclinical AD "Aβ-positive" placebo group and compare them with an "Aβ-negative" group. For the study that did not include data on Aβ levels (the ADCS Prevention Instrument [ADCS-PI] study), we grouped participants by the presence of APOE-ε4 and by clinical progression. RESULTS: In ADNI, Aβ-positive participants showed more decline than did Aβ-negative participants with regard to the ADCS-PACC score at 24 months (mean [SE] difference, -1.239 [0.522] [95% CI, -2.263 to -0.215]; P = .02). In AIBL, the mean (SE) difference is significant at both 18 months (-1.009 [0.406] [95% CI, -1.805 to -0.213]; P = .01) and 36 months (-1.404 [0.452] [95% CI, -2.290 to -0.519]; P = .002). In the ADCS-PI study, APOE-ε4 allele carriers performed significantly worse on the ADCS-PACC at 24 months (mean [SE] score, -0.742 [0.294] [95% CI, -1.318 to -0.165]; P = .01) and 36 months (-1.531 [0.469] [95% CI, -2.450 to -0.612]; P = .001). In the ADCS-PI study, cognitively normal participants who progress from a global Clinical Dementia Rating score of 0 are significantly worse on the ADCS-PACC than cognitively normal participants who are stable with a global Clinical Dementia Rating score of 0 at months 12, 24, and 36 (mean [SE] ADCS-PACC score, -4.471 [0.702] [95% CI, -5.848 to -3.094]; P < .001). Using pilot estimates of variance and assuming 500 participants per group with 30% attrition and a 5% α level, we project 80% power to detect effects in the range of Δ = 0.467 to 0.733 on the ADCS-PACC. CONCLUSIONS AND RELEVANCE: Analyses of at-risk cognitively normal populations suggest that we can reliably measure the first signs of cognitive decline with the ADCS-PACC. These analyses also suggest the feasibility of secondary prevention trials.

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  • Insel and colleagues found that a trial with 2,000 participants per group over 4 years would have 80% power to detect a 25% treatment effect in cognitively unimpaired amyloid-positive individuals.

    “This study revealed that a study with 2,000 participants per group in a trial lasting 4 years would provide 80% power to reveal a 25% treatment effect -a huge undertaking.”

    From The amyloid hypothesis in Alzheimer disease: new insights from new therapeutics (2022) · cites this paper as [95]

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Authors
Donohue, M. C., Sperling, R. A., Salmon, D. P., Rentz, D. M., Raman, R., Thomas, R. G., Weiner, M., & Aisen, P. S.
Affiliations
  • University of California San Diego (US)
  • Brigham and Women's Hospital (US)
  • San Francisco VA Medical Center (US)
Corresponding author
Donohue, Michael C.
ORCID
Venue
JAMA Neurology
Publisher
American Medical Association (AMA)
Published
2014-08-01
Volume
71
Issue
8
Pages
961
ISSN
2168-6149 (ISSN-L)
DOI
10.1001/jamaneurol.2014.803
PMC
PMC4439182
OpenAlex
W2051737015
Cited by
860
References
47
Citations by year
2026: 116 · 2025: 112 · 2024: 95 · 2023: 75 · 2022: 99 · 2021: 80 · 2020: 67 · 2019: 49 · 2018: 48 · 2017: 41 · 2016: 35 · 2015: 37 · 2014: 6
FWCI
30.26
Type
journal article
Language
en
Open access
Locations
  • JAMA Neurology (publishedVersion)
  • PubMed (publishedVersion)
  • PubMed Central (acceptedVersion)
  • eScholarship (California Digital Library) (submittedVersion)
Funders
  • National Institute on Aging (U01‐AG10483, P50AG005131, U01AG010483, U19AG010483)
  • National Center for Research Resources (KL2RR031978)
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 › Pulmonary and Respiratory Medicine › Cancer-related cognitive impairment studies
Keywords
preclinical Alzheimer's disease, amyloid-beta, APOE ε4, episodic memory decline, executive function, global cognition, clinical trial outcome measures, ADNI, AIBL
MeSH terms
Aged, Aged, 80 and over, Alzheimer Disease, Clinical Trials as Topic, Cognition Disorders, Feasibility Studies, Female, Heterozygote, Humans, Male, Middle Aged, Neuropsychological Tests, Prospective Studies, Amyloid beta-Peptides, Disease Progression, Early Diagnosis, Positron-Emission Tomography, Apolipoprotein E4, Executive Function, Antibodies, Monoclonal, Humanized, Memory, Episodic, Prodromal Symptoms

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