‘ALZHEIMER’S PROGRESSION SCORE’: DEVELOPMENT OF A BIOMARKER SUMMARY OUTCOME FOR AD PREVENTION TRIALS
J.-M. Leoutsakos, A.L. Gross, R.N. Jones, M.S. Albert, J.C.S. Breitner
J Prev Alz Dis 2016;3(4):229-235
Background: Alzheimer’s disease (AD) prevention research requires methods for measurement of disease progression not yet revealed by symptoms. Preferably, such measurement should encompass multiple disease markers.
Objectives: Evaluate an item response theory (IRT) model-based latent variable Alzheimer Progression Score (APS) that uses multi-modal disease markers to estimate pre-clinical disease progression.
Design: Estimate APS scores in the BIOCARD observational study, and in the parallel PREVENT-AD Cohort and its sister INTREPAD placebo-controlled prevention trial. Use BIOCARD data to evaluate whether baseline and early APS trajectory predict later progression to MCI/dementia. Similarly, use longitudinal PREVENT-AD data to assess test measurement invariance over time. Further, assess portability of the PREVENT-AD IRT model to baseline INTREPAD data, and explore model changes when CSF markers are added or withdrawn.
Setting: BIOCARD was established in 1995 and participants were followed up to 20 years in Baltimore, USA. The PREVENT-AD and INTREPAD trial cohorts were established between 2011-2015 in Montreal, Canada, using nearly identical entry criteria to enroll high-risk cognitively normal persons aged 60+ then followed for several years.
Participants: 349 cognitively normal, primarily middle-aged participants in BIOCARD, 125 high-risk participants aged 60+ in PREVENT-AD, and 217 similar subjects in INTREPAD. 106 INTREPAD participants donated up to four serial CSF samples.
Measurements: Global cognitive assessment and multiple structural, functional, and diffusion MRI metrics, sensori-neural tests, and CSF concentrations of tau, Aβ42 and their ratio.
Results: Both baseline values and early slope of APS scores in BIOCARD predicted later progression to MCI or AD. Presence of CSF variables strongly improved such prediction. A similarly derived APS in PREVENT-AD showed measurement invariance over time and portability to the parallel INTREPAD sample.
Conclusions: An IRT-based APS can summarize multi-modal information to provide a longitudinal measure of pre-clinical AD progression, and holds promise as an outcome for AD prevention trials.
J.-M. Leoutsakos ; A.L. Gross ; R.N. Jones ; M.S. Albert ; J.C.S. Breitner (2016): ‘Alzheimer’s Progression Score’: Development of a Biomarker Summary Outcome for AD Prevention Trials. The Journal of Prevention of Alzheimer’s Disease (JPAD). http://dx.doi.org/10.14283/jpad.2016.120