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

ObjectiveTo study risk factors for decreasing a(1-42) concentrations in cerebrospinal fluid (CSF) in cognitively unimpaired individuals with initially normal amyloid and tau markers, and to investigate whether such a1-42 decreases are associated with subsequent decline in cognition and other biomarkers of Alzheimer's disease. MethodsCognitively normal subjects (n = 83, 75 5 years, 35(42%) female) with normal CSF a(1-42) and tau and repeated CSF sampling were selected from ADNI. Subject level slopes of a(1-42) decreases were estimated with mixed models. We tested associations of baseline APP processing markers (BACE1 activity, a(1-40), a(1-38) and sAPP) and decreasing a(1-42) levels by including an interaction term between time and APP marker. Associations between decreasing a(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. ResultsA(1-42) levels decreased annually with -4.6 +/- 1 pg/mL. Higher baseline BACE1 activity ((se) = -0.06(0.03), P < 0.05), a(1-40) ((se)= -0.11(.03), P < 0.001), and a(1-38) levels ((se) = -0.11(0.03), P < 0.001) predicted faster decreasing a(1-42). The fastest tertile of decreasing a(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). InterpretationHigher APP processing and fast decreasing a(1-42) could be among the earliest, pre-amyloid, pathological changes in Alzheimer's disease.