Report CSF Ab42 and tau in relation to amyloid in humans Cerebrospinal fluid tau and ptau increase 181 with cortical amyloid deposition in cognitively normal individuals: Implications for future clinical trials of Alzheimer ’s disease Anne M. Fagan1,2,3*, Mark A. Mintun2,4, Aarti R. Shah1,3, Patricia Aldea 4 , Catherine M. Roe1,2, Robert H. Mach2,4, Daniel Marcus4, John C. Morris1,2,5, David M. Holtzman1,2,3,6 Keywords: amyloid; biomarker; cerebrospinal fluid; Pittsburgh compound B; preclinical Alzheimer’s disease DOI 10.1002/emmm.200900048 Received June 16, 2009 Revised September 8, 2009 Accepted September 23, 2009 Alzheimer’s disease (AD) pathology is estimated to develop many years before detectable cognitive decline. Fluid and imaging biomarkers may identify people in early symptomatic and even preclinical stages, possibly when potential treatments can best preserve cognitive function. We previously reported that cerebrospinal ﬂuid (CSF) levels of amyloid-b42 (Ab42) serve as an excellent marker for brain amyloid as detected by the amyloid tracer, Pittsburgh compound B (PIB). Using data from 189 cognitively normal participants, we now report a positive linear relation- ship between CSF tau/ptau181 (primary constituents of neuroﬁbrillary tangles) with the amount of cortical amyloid. We observe a strong inverse relationship of cortical PIB binding with CSF Ab42 but not for plasma Ab species. Some individuals have low CSF Ab42 but no cortical PIB binding. Together, these data suggest that changes in brain Ab42 metabolism and amyloid formation are early pathogenic events in AD, and that signiﬁcant disruptions in CSF tau metabolism likely occur after Ab42 initially aggregates and increases as amyloid accumulates. These ﬁndings have important implications for preclinical AD diagnosis and treatment. INTRODUCTION Alzheimer’s disease (AD) is a progressive and fatal neurode- generative disorder that currently affects 10.6 million people (1) Department of Neurology, Washington University School of Medicine, St. Louis, MO, USA. (2) Alzheimer’s Disease Research Center, Washington University School of Medicine, St. Louis, MO, USA. (3) Hope Center for Neurological Disorders, Washington University School of Medicine, St. Louis, MO, USA. (4) Department of Radiology, Washington University School of Medicine, St. Louis, MO, USA. (5) Department of Pathology and Immunology, Washington University School of Medicine, St. Louis, MO, USA. (6) Department of Molecular Biology and Pharmacology, Washington University School of Medicine, St. Louis, MO, USA. *Corresponding author: Tel: +1 341 362 3453; Fax: +1 341 362 2244; E-mail: fagana@neuro.wustl.edu in the US and Europe, with projected estimates reaching 15.4 million by the year 2030 (Alzheimer’s Association). Clinicopathological studies support the notion of a long ‘preclinical’ stage of the disease, with brain pathology (amyloid plaques and neuroﬁbrillary tangles) estimated to begin 10–20 years prior to signiﬁcant neuronal cell death and the consequent appearance of any behavioural signs or symptoms (Braak & Braak, 1997; Gomez-Isla et al, 1996; Hulette et al, 1998; Markesbery et al, 2006; Morris & Price, 2001; Price et al, 2001). Fluid and imaging biomarkers of this pathology are currently being sought in order to conﬁrm early diagnoses and, importantly, to identify individuals in the preclinical stage so emerging therapies ultimately have a chance to preserve normal brain function (Craig-Schapiro et al, 2008). We recently reported an inverse relationship between cortical amyloid deposits, as viewed by positron emission tomography (PET) imaging with the amyloid binding agent, Pittsburgh compound B (PIB) and the amount of cerebrospinal ﬂuid (CSF) www.embomolmed.org EMBO Mol Med 1, 371–380 2009 EMBO Molecular Medicine 371