Blood-based diagnostics of Alzheimer's disease.

: This review is focused on the methods used for biomarker discovery for Alzheimer's disease (AD) in blood rather than on the nature of the biomarkers themselves. : All biomarker discovery programs explicitly rely on contrasts in phenotype as a basis for defining differences. In this review, we explore the basis of contrasting choices as a function of the type of biomarker (genetic, protein, metabolite, non-coding RNA, or pathogenic epitope). We also provide an overview of the capacity to identify pathogenic epitopes with our new platform called Aptamarkers. It is suggested that a pre-existing hypothesis regarding the pathophysiology of the disease can act as a constraint to the development of biomarkers. : Limiting putative biomarkers to those that have a postulated role in the pathophysiology of disease imposes an unrealistic constraint on biomarker development. The understanding of Alzheimer's disease would be accelerated by agnostic, non-hypothesis-based biomarker discovery methods. There is a need for more complex contrasts and more complex mathematical models.