Figure 6. Hypothetical and data-driven models of LOAD progression.
Hypothetical (a) and data-driven (b) models of LOAD progression. (a) Adapted from Jack et al.10, (with permission from Elsevier). (b) On the basis of our statistical analysis (Results section, Figs 2, 3, 4, 5, Supplementary Tables 2 and 3). Confidence intervals were omitted for visual clarity. Crucial inter-model differences are: (1) the absence of a vascular component in a and the subsequent assumption that Aβ measurements are the earliest biomarkers, whereas in b the vascular dysfunction is the earliest/stronger altered event, followed by Aβ deposition; (2) CSF Aβ42 and tau are proposed in a as the two major proteinopathies underlying LOAD, with higher sensitivity to disease progression than the metabolic/structural and memory biomarkers, however our results suggest that these proteins were not the strongest altered CSF proteins during disease progression (for example, plasma IP-10, PAPP-A and total proinsulin, and CSF hFABP, cortisol and Apo A, showed higher sensitivity) while imaging and memory biomarkers appeared consistently as earlier biomarkers (see Results section, and Supplementary Tables 2 and 3); (3) in a, abnormalities in cognitive decline are only detectable at advanced abnormality levels for the considered biological biomarkers. In contrast, in b, alterations in cognition are observable in parallel with changes in the primary disease factors (for example, vascular/metabolic dysfunction and Aβ deposition) and exceed in magnitude alterations observed for CSF Aβ1−42, tau and ptau.