Misfolded proteins are at the core of many neurodegenerative diseases, nearly all of them associated with cognitive impairment. For example Creutzfeldt-Jacob disease is associated with aggregation of prion protein, Lewy body dementia and Parkinson disease with α-synuclein and forms of frontotemporal dementia with tau, TDP 43 and host of other proteins, Alzheimer disease (AD), the most common cause of dementia, and its prodromal syndrome mild cognitive impairment (MCI) are an increasing public health problem and a diagnostic challenge to may clinicians. AD is characterized pathologically by the accumulation of amyloid β protein (Aβ) as senile plaques and in the walls of blood vessels as amyloid angiopathy. Additionally, there are accumulations of tau-protein as neurofibrillary tangles and dystrophic neurites. Biological markers of AD and MCI can serve as in vivo diagnostic indicators of underlying pathology, particularly when clinical symptoms are mild and are likely present years before the onset of clinical symptoms. Research to discover and refine fluid and imaging biomarkers of protein aggregation has undergone a rapid evolution and combined analysis of different modalities may further increase diagnostic sensitivity and specificity. Multi-center trials are now investigating whether imaging and/or cerebrospinal fluid (CSF) biomarker candidates can be used as outcome measures for use in phase III clinical trials for AD.