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. 2015 May;2(5):534-47.
doi: 10.1002/acn3.192. Epub 2015 Mar 21.

Biomarkers and cognitive endpoints to optimize trials in Alzheimer's disease

Philip S Insel  1 , Niklas Mattsson  2 , R Scott Mackin  3 , John Kornak  4 , Rachel Nosheny  5 , Duygu Tosun-Turgut  1 , Michael C Donohue  6 , Paul S Aisen  7 , Michael W Weiner  1 ; Alzheimer's Disease Neuroimaging Initiative
Affiliations

Biomarkers and cognitive endpoints to optimize trials in Alzheimer's disease

Philip S Insel et al. Ann Clin Transl Neurol. 2015 May.

Abstract

Objective: To find the combination of candidate biomarkers and cognitive endpoints to maximize statistical power and minimize cost of clinical trials of healthy elders at risk for cognitive decline due to Alzheimer's disease.

Methods: Four-hundred and twelve cognitively normal participants were followed over 7 years. Nonlinear methods were used to estimate the longitudinal trajectories of several cognitive outcomes including delayed memory recall, executive function, processing speed, and several cognitive composites by subgroups selected on the basis of biomarkers, including APOE-ε4 allele carriers, cerebrospinal fluid biomarkers (Aβ 42, total tau, and phosphorylated tau), and those with small hippocampi.

Results: Derived cognitive composites combining Alzheimer's Disease Assessment Scale (ADAS)-cog scores with additional delayed memory recall and executive function components captured decline more robustly across biomarker groups than any measure of a single cognitive domain or ADAS-cog alone. Substantial increases in power resulted when including only participants positive for three or more biomarkers in simulations of clinical trials.

Interpretation: Clinical trial power may be improved by selecting participants on the basis of amyloid and neurodegeneration biomarkers and carefully tailoring primary cognitive endpoints to reflect the expected decline specific to these individuals.

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Figures

Figure 1
Figure 1
Plots of estimated curves for biomarker-positive (red) versus biomarker-negative (black) for all binary groups and all cognitive outcomes, over time. Estimation of curves included all participants regardless of length of follow-up time. Individual rows show the same cognitive outcome in its original scale, that is, the first row is all ADAS11. Individual columns show the same biomarker group, that is, the first column is all APOE+ versus APOE−. Composite #1 comprises ADAS11, Trails B, and Logical Memory II. Composite #2 comprises ADAS11, Trails B, and dAVLT. ADAS, Alzheimer's Disease Assessment Scale; dAVLT, delayed Rey Auditory Verbal Learning Test.
Figure 2
Figure 2
Comparison of cognitive outcomes plotted within each biomarker-positive group. All measures are standardized (centered and scaled) for comparability. Composite #1: ADAS11, Trails B, and Logical Memory II. Composite #2: ADAS11, Trails B, and dAVLT. ADAS, Alzheimer's Disease Assessment Scale; dAVLT, delayed Rey Auditory Verbal Learning Test.
Figure 3
Figure 3
Multiple pathology groups (0, 1, 2, 3+) plotted for each standardized cognitive measures with 7 years of follow up. Composite #1: ADAS11, Trails B, and Logical Memory II. Composite #2: ADAS11, Trails B, and dAVLT. ADAS, Alzheimer's Disease Assessment Scale; dAVLT, delayed Rey Auditory Verbal Learning Test.
See this image and copyright information in PMC

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