CSF Ab1-42 combined with neuroimaging biomarkers in the early detection, diagnosis and prediction of Alzheimer’s disease Simone Lista a, *, Francesco G. Garaci b,c , Michael Ewers d , Stefan Teipel e , Henrik Zetterberg f,g , Kaj Blennow f , Harald Hampel a a Department of Psychiatry, Goethe-University, Frankfurt am Main, Germany b Department of Diagnostic Imaging, Molecular Imaging, Interventional Radiology, and Radiotherapy, University of Rome “Tor Vergata,” Rome, Italy c IRCCS San Raffaele Pisana, Rome, Italy d Department of Radiology, University of California at San Francisco, San Francisco, CA, USA e Department of Psychiatry, University of Rostock, Rostock, Germany DZNE, German Center for Neurodegenerative Diseases, Rostock, Germany f Institute of Neuroscience and Physiology, Department of Psychiatry and Neurochemistry, The Sahlgrenska Academy at the University of Gothenburg, M€ olndal, Sweden g University College London Institute of Neurology, Queen Square, London, UK Abstract The development of validated, qualified, and standardized biomarkers for Alzheimer’s disease (AD) that allow for an early presymptomatic diagnosis and discrimination (classification) from other types of dementia and neurodegenerative diseases is warranted to accelerate the successful develop- ment of novel disease-modifying therapies. Here, we focus on the value of the 42-residue-long am- yloid b isoform (Ab1-42) peptide in the cerebrospinal fluid as the core, feasible neurobiochemical marker for the amyloidogenic mechanisms in early-onset familial and late-onset sporadic AD. We discuss the role and use of Ab1-42 in combination with evolving neuroimaging biomarkers in AD detection and diagnosis. Multimodal neuroimaging techniques, directly providing structural- functional-metabolic aspects of brain pathophysiology, are supportive to predict and monitor the progression of the disease. Advances in multimodal neuroimaging provide new insights into brain organization and enable the detection of specific proteins and/or protein aggregates associated with AD. The combination of biomarkers from different methodologies is believed to be of incremen- tally added risk-value to accurately identify asymptomatic and prodromal individuals who will likely progress to dementia and represent rational biomarker candidates for preventive and symptomatic pharmacological intervention trials. Ó 2013 The Alzheimer’s Association. All rights reserved. Keywords: Alzheimer’s disease; Mild cognitive impairment; Cerebrospinal fluid; Prodromal; Asymptomatic; Preclinical; am- yloid b peptides; Ab1-42; Neurochemical biomarkers; Imaging biomarkers; Combination of biomarkers; Positron emission tomography; Magnetic resonance imaging; Early diagnosis; Early detection 1. Introduction Alzheimer’s disease (AD) is a genetically complex, slowly progressive, and irreversible neurodegenerative disease of the brain. During decades of asymptomatic pro- gression, multiple interactive systems, pathways, and molec- ular mechanisms contribute to the development of the early clinical prodromal stage with episodic memory deficits and to further decline and loss of general cognitive functioning during the final syndromal dementia stage [1]. The patho- physiology of AD involves the aggregation of amyloid b (Ab) peptides with amyloid plaque formation and hyper- phosphorylation of tau protein with deposition of neurofi- brillary tangles (NFTs). The “amyloid cascade hypothesis” [2] or “amyloid deposition cycle” [3] remains the best accepted model for explaining AD. It states that the patho- logical cleavage of the amyloid precursor protein (APP), the excessive formation and aggregation of toxic soluble *Corresponding author. Tel.: 149-15251904006; Fax: 139-0382-525097. E-mail address: slista@libero.it 1552-5260/$ - see front matter Ó 2013 The Alzheimer’s Association. All rights reserved. http://dx.doi.org/10.1016/j.jalz.2013.04.506 Alzheimer’s & Dementia - (2013) 1–12