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Evaluation of: Bateman RJ, Xiong C, Benzinger TLSet al.Clinical and biomarker changes in dominantly inherited Alzheimer's disease.N. Engl. J. Med.367, 795–804 (2012). The prevailing model of neurodegeneration leading to Alzheimer's disease (AD) is thought to begin with amyloid-β (Aβ) protein accumulation, followed by tau-mediated neuronal injury, metabolic and structural brain changes, and culminating with cognitive and functional impairments. The findings reported by Bateman et al. support this ordered progression, although a number of other recent studies have begun to show that change in sensitive memory measures precede change in biomarkers, including hippocampal volumes, imaging measures of brain metabolism or amyloid burden, and cerebrospinal fluid markers of Aβ and tau. Bateman et al. also incidentally found Aβ deposition to be particularly dense in the neostriatum. One of the most important goals of the coming decade will be to identify the earliest and most reliable markers of this neurodegenerative cascade, prior to widespread neuronal loss. Targeting those individuals most at risk for AD dementia represents one of the most promising windows for therapeutic interventions in AD. The combination of sensitive neuropsychological measures and other biomarker assays, such as neostriatal amyloid levels in the detection of preclinical AD, merits further investigation.