Effect of age, ethnicity, sex, cognitive status and APOE genotype on amyloid load and the threshold for amyloid positivity

Abstract

The threshold for amyloid positivity by visual assessment on PET has been validated by comparison to amyloid load measured histopathologically and biochemically at post mortem. As such, it is now feasible to use qualitative visual assessment of amyloid positivity as an in-vivo gold standard to determine those factors which can modify the quantitative threshold for amyloid positivity. We calculated quantitative amyloid load, measured as Standardized Uptake Value Ratios (SUVRs) using [18-F]florbetaben PET scans, for 159 Hispanic and non-Hispanic participants, who had been classified clinically as Cognitively Normal (CN), Mild Cognitive Impairment (MCI) or Dementia (DEM). PET scans were visually rated as amyloid positive (A+) or negative (A-), and these judgments were used as the gold standard with which to determine (using ROC analyses) the SUVR threshold for amyloid positivity considering factors such as age, ethnicity (Hispanic versus non-Hispanic), gender, cognitive status, and apolipoprotein E ε4 carrier status. Visually rated scans were A+ for 11% of CN, 39.0% of MCI and 70% of DEM participants. The optimal SUVR threshold for A+ among all participants was 1.42 (sensitivity = 94%; specificity = 92.5%), but this quantitative threshold was higher among E4 carriers (SUVR = 1.52) than non-carriers (SUVR = 1.31). While mean SUVRs did not differ between Hispanic and non-Hispanic participants;, a statistically significant interaction term indicated that the effect of E4 carrier status on amyloid load was greater among non-Hispanics than Hispanics. Visual assessment, as the gold standard for A+, facilitates determination of the effects of various factors on quantitative thresholds for amyloid positivity. A continuous relationship was found between amyloid load and global cognitive scores, suggesting that any calculated threshold for the whole group, or a subgroup, is artefactual and that the lowest calculated threshold may be optimal for the purposes of early diagnosis and intervention.

Keywords: APOE; Amyloid; Cognition; Hispanic; SUVR; Threshold.

Fig. 1

Composite cortical SUVR shown for Hispanic (H) and Non-Hispanic (NH) participants who are APOE ε4- and APOE ε4+. The box and whisker plots are overlaid with data values (open circles). The boxes show the median (a line in the middle), the upper and lower interquartiles (Q3 and Q1), the upper fence (Q3 + 1.5 x Inter quartile range [IQR]) and the lower fence (Q1 – 1.5xIQR). There was a significant interaction between Hispanic ethnicity and APOEε4 carrier status (F_1,132 = 4.79; p = .03).

Fig. 2

The figure show the distribution of composite SUVR scores by APOEε4 carrier status and binary visual read status. Optimal SUVR thresholds (shown as dashed lines) to discriminate amyloid positive and amyloid negative, as determined by visual reads, were computed using Youden's criterion for ApoE ε4 positive and negative subjects (Youden, 1950). The 95% confidence intervals for the Youden's index (shown as shaded regions) were generated by 1000 bootstrap samples using a bias-corrected and accelerated method. Optimal thresholds and confidence intervals are superimposed.

Fig. 3

Correlation of composite SUVR with MMSE Score. Composite SUVR was calculated as the ratio of the mean SUV of 5 cortical regions (frontal, temporal, parietal, anterior and posterior cingulate cortex regions, each region summed from left and right hemispheres) to the cerebellar gray matter SUV. The regression model fit and 95% confidence limits are plotted and model statistics are shown. The correlation of composite SUVR to MMSE was r = −0.46, p < .0001.