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J Prev Alzheimers Dis. 2016;3(4):229-235. doi: 10.14283/jpad.2016.120.

'Alzheimer's Progression Score': Development of a Biomarker Summary Outcome for AD Prevention Trials.

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Department of Psychiatry and Behavioral Sciences, Johns Hopkins School of Medicine, Baltimore, MD, USA.
Departments of Epidemiology and Mental Health, Johns Hopkins Center on Aging and Health, Johns Hopkins Bloomberg School of Public Health, Baltimore, MD, USA.
Department of Neurology and Psychiatry & Human Behavior, Warren Alpert Medical School, Brown University, Providence, RI, USA.
Department of Neurology, Johns Hopkins University School of Medicine, Baltimore, MD, USA.
Centre for Studies on Prevention of Alzheimer's Disease (StoP-AD), Douglas Mental Health University Institute Research Centre, McGill University Faculty of Medicine. Montreal, Canada.



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.


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.


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of the PREVENT-AD IRT model to baseline INTREPAD data, and explore model changes when CSF markers are added or withdrawn.


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.


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.


Global cognitive assessment and multiple structural, functional, and diffusion MRI metrics, sensori-neural tests, and CSF concentrations of tau, Aβ42 and their ratio.


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.


An IRT-based APS can summarize multimodal information to provide a longitudinal measure of pre-clinical AD progression, and holds promise as an outcome for AD prevention trials.


Alzheimer’s disease; Pre-clinical; disease progression; multiple outcome modalities; prevention trials; summary outcome measures

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