Figure 1. Cross-Sectional Analyses of Clinical, Cognitive, Structural, Metabolic, and Biochemical Changes in Autosomal Dominant Alzheimer’s Disease Mutation Carriers versus Noncarriers, According to Estimated Years from Expected Symptom Onset.

The clinical and cognitive measures of the Clinical Dementia Rating–Sum of Boxes (scores range from 0 [cognitive normality] to 18 [maximal cognitive impairment]) (Panel A), the Mini–Mental State Examination (scores range from 0 [severe impairment] to 30 [no impairment]) (Panel B), and the Logical Memory subtest of the Wechsler Memory Scale–Revised (scores range from 0 [no recall] to 25 [complete recall]) (Panel C) showed impaired ratings beginning approximately 5 to 10 years before expected symptom onset. MRI measures of hippocampal volume (Panel D) showed increased brain atrophy approximately 15 years before expected symptom onset. Decreases in cerebral glucose metabolism, as measured by positron-emission tomography (PET) with the use of fluorodeoxyglucose (Panel E), occurred approximately 10 years before expected symptom onset, and deposition of amyloid-beta (Aβ) in the precuneus, as measured by PET with the use of Pittsburgh compound B (Panel F), began approximately 15 to 20 years before expected symptom onset. In the cerebrospinal fluid (CSF), levels of tau protein (Panel G) increased beginning 10 to 15 years before expected symptom onset, and levels of Aβ₄₂ (Panel H) decreased at least 15 years before expected symptom onset. Plasma Aβ₄₂ levels were elevated throughout the range of estimated years from expected symptom onset (Panel I). Dashed lines represent 95% confidence intervals of the fitted curves. SUVR denotes standardized uptake value ratio.