Pre‐amyloid stage of Alzheimer's disease in cognitively normal individuals

OBJECTIVE: To study risk factors for decreasing aβ (1–42) concentrations in cerebrospinal fluid (CSF) in cognitively unimpaired individuals with initially normal amyloid and tau markers, and to investigate whether such aβ1–42 decreases are associated with subsequent decline in cognition and other biomarkers of Alzheimer's disease. METHODS: Cognitively normal subjects (n = 83, 75 ± 5 years, 35(42%) female) with normal CSF aβ (1–42) and tau and repeated CSF sampling were selected from ADNI. Subject level slopes of aβ (1–42) decreases were estimated with mixed models. We tested associations of baseline APP processing markers (BACE1 activity, aβ (1–40), aβ (1–38) and sAPP β) and decreasing aβ (1–42) levels by including an interaction term between time and APP marker. Associations between decreasing aβ (1–42) levels and clinical decline (i.e., progression to mild cognitive impairment or dementia, MMSE, memory functioning) and biological decline (tau, hippocampal volume, glucose processing and amyloid PET) over a time period of 8–10 years were assessed. RESULTS: Aβ (1–42) levels decreased annually with −4.6 ± 1 pg/mL. Higher baseline BACE1 activity (β(se) = −0.06(0.03), P < 0.05), aβ (1–40) (β(se)= −0.11(.03), P < 0.001), and aβ (1–38) levels (β(se) = −0.11(0.03), P < 0.001) predicted faster decreasing aβ (1–42). The fastest tertile of decreasing aβ (1–42) rates was associated with subsequent pathophysiological processes: 11(14%) subjects developed abnormal amyloid levels after 3 ± 1.7 years, showed increased risk for clinical progression (Hazard Ratio[95CI] = 4.8[1.1–21.0]), decreases in MMSE, glucose metabolism and hippocampal volume, and increased CSF tau and amyloid aggregation on PET (all P < 0.05). INTERPRETATION: Higher APP processing and fast decreasing aβ (1–42) could be among the earliest, pre‐amyloid, pathological changes in Alzheimer's disease.