Figure 2. Comparison of Clinical, Cognitive, Structural, Metabolic, and Biochemical Changes as a Function of Estimated Years from Expected Symptom Onset.

The normalized differences between mutation carriers and noncarriers are shown versus estimated years from expected symptom onset and plotted with a fitted curve. The order of differences suggests decreasing Aβ₄₂ in the CSF (CSF Aβ₄₂), followed by fibrillar Aβ deposition, then increased tau in the CSF (CSF tau), followed by hippocampal atrophy and hypometabolism, with cognitive and clinical changes (as measured by the Clinical Dementia Rating–Sum of Boxes [CDR-SOB]) occurring later. Mild dementia (CDR 1) occurred an average of 3.3 years before expected symptom onset. 95% confidence interval bands are shown in Figure S2 in the Supplementary Appendix.