Expanding knowledge on genetic and epigenetic risk factors is rapidly enhancing our understanding of the complex molecular interactions and systems involved in the pathogenesis of Alzheimer’s disease. In this publication, leading experts discuss emerging novel conceptual models of the disease along with advances in the development of surrogate markers that will not only improve the accuracy of diagnostic technologies but also improve the prospects of developing disease-modifying interventions. The novel framework of the disease presented here highlights research on biological markers as well as efforts to validate technologies for early and accurate detection. It also introduces notion of a complex systems dysfunction that extends beyond prevailing ideas derived from the ‘amyloid’ or ‘tau’ hypotheses. This outstanding publication provides researchers, clinicians, students and other professionals interested in neurodegenerative disorders with a comprehensive update on current trends and future directions in therapy development, with special focus on advances in clinical trial designs.