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The preclinical Alzheimer cognitive composite: Measuring amyloid-related decline


Donohue, Michael C., Sperling, Reisa A., Salmon, David P., Rentz, Dorene M., Raman, Rema, Thomas, Ronald G., Weiner, Michael, Aisen, Paul S


JAMA Neurology, Volume: 71, No.: 8, Pages.: 961-970

Year of Publication



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. (PsycINFO Database Record (c) 2015 APA, all rights reserved). (journal abstract)

Bibtex Citation

@article{Donohue_2014, doi = {10.1001/jamaneurol.2014.803}, url = {}, year = 2014, month = {aug}, publisher = {American Medical Association ({AMA})}, volume = {71}, number = {8}, pages = {961}, author = {Michael C. Donohue and Reisa A. Sperling and David P. Salmon and Dorene M. Rentz and Rema Raman and Ronald G. Thomas and Michael Weiner and Paul S. Aisen}, title = {The Preclinical Alzheimer Cognitive Composite}, journal = {{JAMA} Neurology} }


alzheimer’s disease, amyloidrelated decline, beta amyloid, clinical trials, diagnosis, preclinical alzheimer cognitive composite

Countries of Study


Types of Dementia

Alzheimer’s Disease

Types of Study

Cohort Study

Type of Outcomes


Type of Interventions

Diagnostic Target Identification

Diagnostic Targets

Cognition testing (inc. task driven tests such as clock drawing)