Although the pathological features of AD have been extensively investigated, the relationship between known pathological features and disease progression remains unclear. In APP-transgenic mice, specific spatial learning impairment is evident in young mice and becomes severe with age without the formation of plaques [8]. Moreover, it is reported that neuronal loss, but not the plaque and tangle, in AD patients’ brain is closely associated with the cognitive decline [9]. Indeed, it is reported that pathological and biochemical changes of AD in cerebrospinal fluid, brain metabolism, brain amyloid deposition, as well as cognitive impairment may have existed for more than 20 years before the recognized symptom onset in FAD [10]. Therefore, it is urgently needed to identify the early events of AD pathogenesis and to develop effective strategies for disease-modifying therapy at the early stage of AD.
