Shapes of the Trajectories of 5 Major Biomarkers of Alzheimer Disease

Figure 1. Prototypical linear mixed-effects models based on different baseline shapes and longitudinal change. The dashed line in each panel characterizes the mean value of the biomarker at baseline as a function of disease severity while the solid lines characterize the mean within-subject rate of change. The dashed lines show either no baseline effect (flat line) (A, B, and C), a linear baseline effect (D, E, and F), or a nonlinear baseline effect, which in this case is reaching an asymptote or saturation point (G, H, and I). The solid lines show either no within-subject changes with increasing disease severity (flat lines) (A, D, and G), constant within-subject changes over time (parallel increasing lines) (B, E, and H), or nonconstant within-subject changes, which in this case are greater early in the disease and less when the disease becomes more severe (C, F, and I).

Figure 2. Cerebrospinal fluid (CSF)/magnetic resonance imaging (MRI) cohort. Individual trajectory plots by Mini-Mental State Examination (MMSE) score for hippocampal volume, CSF Aβ42 level, and CSF total tau (t-tau) level are plotted in the left column. Because of the large number of subjects, the left column illustrates a random subset of the CSF/MRI cohort. Plots in the middle and right columns are based on modeling the entire cohort. Cognitively normal (CN) participants are represented with red squares; participants with mild cognitive impairment (MCI), with blue circles; and participants with Alzheimer disease (AD), with green triangles. Arrows indicate trajectories that extend beyond the plotting region. The center and right columns are model summary plots in the CSF/MRI cohort for APOE ϵ4 noncarriers (center) and APOE ϵ4 carriers (right). The dashed lines represent the baseline relationship with biomarker and MMSE score estimated from the linear mixed-effects models. The solid lines represent the within-subject rate of change in biomarker with a decrease in MMSE score of 3 points. Light orange (APOE ϵ4 noncarriers) and light blue (APOE ϵ4 carriers) lines represent the effects for a subject with a baseline age of 75 years and dark orange (APOE ϵ4 noncarriers) and dark blue (APOE ϵ4 carriers) lines represent the effects for a subject with a baseline age of 85 years. P values are shown for all effects in the model, with a P value <.10 being significant. BL indicates baseline biomarker and MMSE score effects. These may be nonzero, nonlinear, or interact with baseline age. WSR indicates within-subject rates of change in biomarker with worsening MMSE score. These may be nonzero, interact with baseline age, or be nonconstant such that the rate of change differs by baseline MMSE score. * P values reported when the change in age and the change in MMSE score are zero.

Figure 3. Positron emission tomography/magnetic resonance imaging cohort. Individual trajectory plots by Mini-Mental State Examination (MMSE) score for hippocampal volume, Pittsburgh Compound B (PiB) ratio, and fluorodeoxyglucose (FDG) ratio in a random subset of the positron emission tomography/magnetic resonance imaging cohort. Model summary plots by MMSE score for hippocampal volume, PiB ratio, and FDG ratio by APOE ϵ4 genotype. The organization of Figure 3 is analogous to that of Figure 2. AD indicates Alzheimer disease; BL, baseline biomarker and MMSE score effects; CN, cognitively normal; MCI, mild cognitive impairment; and WSR, within-subject rates of change in biomarker with worsening MMSE score.

Figure 4. Amyloid-positive cohorts. Individual trajectory plots by Mini-Mental State Examination (MMSE) score of hippocampal volume and cerebrospinal fluid (CSF) tau level for the amyloid-positive CSF/magnetic resonance imaging (MRI) cohort and of hippocampal volume and fluorodeoxyglucose (FDG) ratio for the amyloid-positive positron emission tomography (PET)/MRI cohort. The organization of Figure 4 is analogous to that of Figure 2 and Figure 3. AD indicates Alzheimer disease; BL, baseline biomarker and MMSE score effects; CN, cognitively normal; MCI, mild cognitive impairment; t-tau, total tau; and WSR, within-subject rates of change in biomarker with worsening MMSE score. * P values reported when the change in age and the change in MMSE score are zero.