Abstract
BackgroundThere is growing interest in identifying sensitive composite cognitive tests to serve as primary endpoints in preclinical Alzheimer’s disease (AD) treatment trials. We reported previously a composite cognitive test score sensitive to tracking preclinical AD decline up to 5 years prior to clinical diagnosis. Here we expand upon and refine this work, empirically deriving a composite cognitive test score sensitive to tracking preclinical AD decline up to 11 years prior to diagnosis and suitable for use as a primary endpoint in a preclinical AD trial.MethodsThis study used a longitudinal approach to maximize sensitivity to tracking progressive cognitive decline in people who progressed to the clinical stages of AD (n = 868) compared to those who remained cognitively unimpaired during the same time period (n = 989), thereby correcting for normal aging and practice effects. Specifically, we developed the Alzheimer’s Prevention Initiative Preclinical Composite Cognitive test (APCC) to measure very early longitudinal cognitive decline in older adults with preclinical AD. Data from three cohorts from Rush University were analyzed using a partial least squares (PLS) regression model to identify optimal composites within different time periods prior to diagnosis, up to 11 years prior to diagnosis. The mean-to-standard deviation ratio (MSDRs) is an indicator of sensitivity to change and was used to inform the final calculation of the composite score.ResultsThe optimal composite, the APCC, is calculated: 0.26*Symbol Digit Modalities + 2.24*MMSE Orientation to Time + 2.14*MMSE Orientation to Place + 0.53*Logical Memory Delayed Recall + 1.36* Word List-Delayed Recall + 0.68*Judgment of Line Orientation + 1.39*Raven’s Progressive Matrices Matrices (subset of 9 items from A and B). The MSDR of the APCC in a population of preclinical AD individuals who eventually progress to cognitive impairment, compared to those who remained cognitively unimpaired during the same time period, was − 1.10 over 1 year.ConclusionsThe APCC is an empirically derived composite cognitive test score with high face validity that is sensitive to preclinical AD decline up to 11 years prior to diagnosis of the clinical stages of AD. The components of the APCC are supported by theoretical understanding of cognitive decline that occurs during preclinical AD. The APCC was used as a primary outcome in the API Generation Program trials.
Highlights
Alzheimer’s disease (AD) is the most common cause of dementia
Data were available for participants up to 5 years prior to the diagnosis of mild cognitive impairment (MCI) or dementia, as well as data from individuals who remained cognitively unimpaired during the same time period to control for aging and practice effects
989 were designated as non-progressors–cognitively unimpaired participants who were not diagnosed with MCI or AD dementia during the follow-up period
Summary
Alzheimer’s disease (AD) is the most common cause of dementia. Findings from numerous studies suggest that the pathophysiological process of AD begins years, if not decades, before clinical symptoms of AD are evident [1,2,3]. To have their greatest benefit, ADmodifying treatments may need to be started in the preclinical AD phase, before the onset of cognitive impairment or other clinical symptoms, to have their most profound effect [4] Several such preclinical AD trials are underway, with many more in various stages of planning [5]. Most existing cognitive assessment scales used as outcome measures in AD trials have been designed primarily for studies in individuals with mild cognitive impairment (MCI) or dementia These assessments are not suitable endpoints for use in preclinical AD trials due to their inability to detect or track subtle cognitive change during the preclinical stages of the disease [6, 7]. We expand upon and refine this work, empirically deriving a composite cognitive test score sensitive to tracking preclinical AD decline up to 11 years prior to diagnosis and suitable for use as a primary endpoint in a preclinical AD trial
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Free) 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a call
