Assessing risk for preclinical β-amyloid pathology with APOE, cognitive, and demographic information

Abstract

Introduction: Clinical trials in Alzheimer's disease are aimed at early stages of disease, including preclinical Alzheimer's disease. The high cost and time required to screen large numbers of participants for Aβ pathology impede the development of novel drugs. This study's objective was to evaluate the extent to which inexpensive and easily obtainable information can reduce the number of screen failures by increasing the proportion of Aβ+ participants identified for screening.

Methods: We used random forest models to evaluate the positive predictive value of demographics, APOE, and longitudinal cognitive rates in the prediction of amyloid pathology, measured by florbetapir PET or cerebrospinal fluid.

Results: Predicting Aβ positivity with demographic, APOE, and cognitive information yielded a positive predictive value estimate of 0.65 (95% CI, 0.50-0.96), nearly a 60% increase over the reference Aβ+ prevalence in the cohort of 0.41.

Conclusions: By incorporating this procedure, clinical trial screening costs of 7500 USD per participant may be reduced by nearly 7 million USD total.

Keywords: APOE; Amyloid; Clinical trials; Cognition; Preclinical Alzheimer's.

Fig. 1

Positive predictive value (PPV) plots: age and education. Estimates of PPV (proportion of Aβ+) are plotted against continuous predictors, age and education. For age, the thresholds on the x-axis are more exclusive, with fewer participants included moving from right to left, that is, at age = 70 years, the estimate of the proportion of Aβ+'s is shown for individuals ≥70 years. For education, the thresholds are also more exclusive from right to left, that is, at education = 17 years, the estimate of the proportion of Aβ+'s is shown in individuals with ≤17 years of education. The gray shaded areas are 95% confidence intervals for the PPV estimates. The dashed black line is the reference PPV for the full cohort.

Fig. 2

Individual predictor positive predicted value (PPV) curves: baseline cognition and 24-month rates. PPV curves are plotted against baseline cognitive thresholds in the left column and 24-month rate thresholds in the right column. Thresholds become more exclusive moving from the right to left, i.e. PPV estimates are shown for individuals with worse scores than the threshold given on the x-axis. The gray shaded areas are 95% confidence intervals for the PPV estimates. The dashed black line is the reference PPV for the full cohort. Abbreviations: dMemory, delayed memory recall; dAVLT, delayed AVLT.

Fig. 3

Full model PPV estimates and 95% confidence intervals. PPV estimates and 95% confidence intervals are shown for seven different groups of predictors. When the 24-month rates are included, baseline (BL) cognition is also included. The vertical dashed black line in the reference PPV for the full cohort.