A major challenge in developing therapies for Alzheimer disease (AD) as well as most neurodegenerative diseases is that by the time even the earliest clinically detectable signs and symptoms of the disease are apparent, there is already substantial brain injury.1- 3 Most therapeutic trials in AD that are intended to address fundamental molecules and mechanisms underlying the disease have been performed in individuals who have mild to moderate dementia. A few trials have targeted people with very mild dementia/mild cognitive impairment believed to be due to AD. However, recent studies suggest that the use of cerebrospinal fluid (CSF) and amyloid imaging can detect the presence of amyloid-β (Aβ) deposition beginning as early as 10 to 15 years prior to the onset of any clinically detectable cognitive decline owing to AD.1,2,4- 9 In addition, evidence of neurodegeneration and tauopathy appear to begin approximately 5 years prior to the cognitive decline that characterizes early AD.1,2,4- 9 If both academic groups and the pharmaceutical industry are going to move toward prevention trials to delay the onset of cognitive impairment and dementia, biomarkers will need to be used to select people who are clinically normal but at high risk for near-term cognitive decline. Without such an approach, trial size will be enormous and cost prohibitive, and individuals may be subjected to treatments that have the potential for toxicity with no clear benefit.
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