Disease progression model in subjects with mild cognitive impairment from the Alzheimer's disease neuroimaging initiative: CSF biomarkers predict population subtypes

Abstract

WHAT IS ALREADY KNOWN ABOUT THIS SUBJECT• Amnestic mild cognitive impairment MCI) represents the prodromal stage of Alzheimer's dementia and this disease progresses in a non-linear fashion.• Disease progression depends on a variety of demographic, biochemical, genetic and cognitive factors. WHAT THIS STUDY ADDS• Baseline CSF biomarkers carry information about disease pathology and critical thresholds for these markers (Ab and p-tau181P) have been identified that allow segregation of the population into MCI progressers and non-progressers. AIMThe objective is to develop a semi-mechanistic disease progression model for mild cognitive impairment (MCI) subjects. The model aims to describe the longitudinal progression of ADAS-cog scores from the Alzheimer's disease neuroimaging initiative trial that had data from 198 MCI subjects with cerebrospinal fluid (CSF) information who were followed for 3 years. METHODVarious covariates were tested on disease progression parameters and these variables fell into six categories: imaging volumetrics, biochemical, genetic, demographic, cognitive tests and CSF biomarkers. RESULTSCSF biomarkers were associated with both baseline disease score and disease progression rate in subjects with MCI. Baseline disease score was also correlated with atrophy measured using hippocampal volume. Progression rate was also predicted by executive functioning as measured by the Trail B-test. CONCLUSIONCSF biomarkers have the ability to discriminate MCI subjects into sub-populations that exhibit markedly different rates of disease progression on the ADAS-cog scale. These biomarkers can therefore be utilized for designing clinical trials enriched with subjects that carry the underlying disease pathology.

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“…One such example is the apolipoprotein E locus-the strongest and best established genetic susceptibility factor for late-onset Alzheimer's disease (24). The apolipoprotein E ε4 variant associated with susceptibility to late-onset Alzheimer's disease has little, if any, effect on disease progression when individuals fulfill the clinical criteria of dementia or mild cognitive impairment (25,26). In such instances, trials to prevent progression as early as possible, or even delay initial clinical manifestation, will likely be required to demonstrate efficacy of compounds acting on disease-causing mechanisms (27,28).…”

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