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Alzheimer disease (AD) is a devastating neurodegenerative disorder, affecting almost 6 million people in the United States alone, characterized by abnormal accumulation of an aggregation-prone, variable-length peptide known as the amyloid-β protein (Aβ). Considerable progress has been made elucidating the molecular pathogenesis of rare forms of early-onset AD (EOAD) attributable to autosomal-dominant mutations, which in all cases have been found to affect the production of Aβ either by elevating the levels of all forms of Aβ or by increasing the relative proportion of longer, more amyloidogenic species (eg, Aβ42) to shorter, less aggregation-prone species (eg, Aβ40). Nevertheless, these familial forms of the disease account for< 2% of all AD diagnoses, and the precise mechanistic cause (s) of the remaining> 98% of late-onset AD (LOAD) cases remains poorly understood, apart from the identification of …