1. Jason Hassenstab, Ph.D.
Assistant Professor of Neurology and Psychology
Knight Alzheimer’s Disease Research Center
Washington University in St. Louis
hassenstabj@wustl.edu

2. Test Selection
 DIAN Pharma Consortium Cognitive Endpoint
Working Group
Cognitive Core, incorporate neuropsychological
measures from DIAN Observational Study
Focus on 6 domains of cognitive functioning
1. Verbal Episodic Memory
2. Spatial Memory
3. Visual Memory
4. Executive Functioning
5. Visuomotor Speed and Immediate Memory
6. Global Measures of Cognitive Functioning

3. Outcome Variables
 Select a measure that optimizes sensitivity to
change in autosomal dominant AD
DIAN participants are mostly younger, few
comorbidities, relatively “pure” disease population
Clinical Dementia Rating (CDR) Sum of Boxes score
provided best sensitivity to change in cognitive, clinical,
and ADLs
Ceiling effects? Probably not relevant
○ Sensitive to any noticeable change by the informant or by
the clinician
○ Test performance more sensitive to range of performance
levels, but may be subject to false negatives
Verified by comparing longitudinal DIAN and AIBL
study results with published findings from ADNI and
ADCS

4. Additional Outcome Variables
 Neuropsychological Tests
 Episodic Memory
○ Delayed Recall Tests
 Composite Cognitive Measure
○ Why composite?
 Avoid leveraging results on single measures
 Better reliability + reduced variance = more statistical power
 Other tests
 Computerized batteries, ELSMEM, CogState
 Other Metrics
 Coefficient of Variation (Mean:SD)
 Reaction Time Distributional Analysis
 Attentional Control Measures
 Switching Stroop, others?
 Ex-Gaussian function
 See work by David Balota, Ph.D.

5. Final Thoughts for Discussion
 Can we develop tests that capture the pathological
course of AD?
 Detecting treatment vs detecting impairment
 Possible Criteria to Evaluate Tasks:
 Construct validity
 Clarity of link to neural circuits
 Clarity of link to cognitive mechanisms
 Avoid tasks that involve combinations of cog processes?
 Availability of Animal Model
 Link to neural systems through neuropsychopharmacology
 Amenable for use in human neuroimaging studies
 Evidence of impairment specific to AD
 Linked to functional outcome in AD
 Good psychometric characteristics

6. Final Thoughts for Discussion
 Can we develop tests that capture the pathological
course of AD?
 Detecting treatment vs detecting impairment
 Possible Criteria to Evaluate Tasks:
 Construct validity
 Clarity of link to neural circuits
 Clarity of link to cognitive mechanisms
 Avoid tasks that involve combinations of cog processes?
 Availability of Animal Model
 Link to neural systems through neuropsychopharmacology
 Amenable for use in human neuroimaging studies
 Evidence of impairment specific to AD
 Linked to functional outcome in AD
 Good psychometric characteristics