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Drug discovery has been directed, in the last 10 years, to develop \u2018disease modifying drugs\u2019 hopefully able to counteract the progression of AD. Because in a chronic, slow progressing pathological process, such as AD, an early start of treatment enhances the chance of success, it is crucial to have biomarkers for early detection of AD\u2010related brain dysfunction, usable before clinical onset. Reliable early biomarkers need therefore to be prospectively tested for predictive accuracy, with specific cut off values validated in clinical practice. Disease modifying drugs developed so far include drugs to reduce \u03b2 amyloid (A\u03b2) production, drugs to prevent A\u03b2 aggregation, drugs to promote A\u03b2 clearance, drugs targeting tau phosphorylation and assembly and other approaches. Unfortunately none of these drugs has demonstrated efficacy in phase 3 studies. The failure of clinical trials with disease modifying drugs raises a number of questions, spanning from methodological flaws to fundamental understanding of AD pathophysiology and biology. Recently, new diagnostic criteria applicable to presymptomatic stages of AD have been published. These new criteria may impact on drug development, such that future trials on disease modifying drugs will include populations susceptible to AD, before clinical onset. 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