Biomarkers in Alzheimer’s disease drug development Jeffrey L. Cummings* Cleveland Clinic Lou Ruvo Center for Brain Health, Cleveland Clinic Neurological Institute, Las Vegas, NV and Cleveland, OH, USA Abstract Developing new therapies for Alzheimer’s disease (AD) is critically important to avoid the impend- ing public health disaster imposed by this common disorder. Means must be found to prevent, delay the onset, or slow the progression of AD. These goals will be achieved by identifying disease-modifying therapies and testing them in clinical trials. Biomarkers play an increasingly important role in AD drug development. In preclinical testing, they assist in decisions to develop an agent. Biomarkers in phase I provide insights into toxic responses and drug metabolism and in Phase II proof-of-concept trials they facilitate go/no-go decisions and dose finding. Biomarkers can play a role in identifying presymptom- atic patients or specific patient subgroups. They can provide evidence of target engagement before clinical changes can be expected. Brain imaging can serve as a primary outcome in Phase II trials and as a key secondary outcome in Phase III trials. Magnetic resonance imaging is currently best po- sitioned for use in large multicenter clinical trials. Cerebrospinal fluid (CSF) measures of amyloid beta protein (Ab), tau protein, and hyperphosphorylated tau (p-tau) protein are sensitive and specific to the diagnosis of AD and may serve as inclusion criteria and possibly as outcomes in clinical trials targeting relevant pathways. Plasma measures of Ab are of limited diagnostic value but may provide important information as a measure of treatment response. A wide variety of measures of detectable products of cellular processes are being developed as possible biomarkers accessible in the cerebrospinal fluid and plasma or serum. Surrogate markers that can function as outcomes in pivotal trials and reliably predict clinical outcomes are needed to facilitate primary prevention trials of asymptomatic persons where clinical measures may be of limited value. Fit-for-purpose biomarkers are increasingly available to guide AD drug development decisions. Ó 2011 The Alzheimer’s Association. All rights reserved. Keywords: Alzheimer’s disease; Drug development; Biomarkers; Amyloid imaging; FDG PET; FDDNP; MRI; Proteomics; Clinical Dementia Rat- ing; ADAS-cog; MMSE 1. Introduction Alzheimer’s disease (AD) is a progressive brain disorder that becomes increasingly common with aging. As the global population ages, AD is rapidly becoming an urgent public health challenge; it now affects 35 million individuals world- wide and is projected to affect 115 million by 2050 if effec- tive therapeutics are not developed [1]. Current therapies for AD provide symptomatic relief either by improving symp- toms above baseline or by delaying decline [2,3]. Increasing insight into the molecular mechanisms of AD has provided multiple potential targets for disease- modifying therapeutic intervention. The study of the molec- ular neurobiology of beta-amyloid (Ab) protein, tau protein, and hyperphosphorylated tau (p-tau), and intracellular signal- ing pathways, mitochondrial dysfunction, synaptic abnor- malities, and cell death have identified multiple exploitable steps potentially vulnerable to pharmacologic manipulation [2,4]. Agents with putative disease-modifying properties have been identified and have entered preclinical and clinical testing [2,4]. Over 80 compounds—most of them being assessed for disease-modification—are currently in clinical trials for the treatment of AD [5]. Proof of efficacy of AD treatment depends on demonstrat- ing benefits on the clinical measures in patients. However, biomarkers may provide faster, more convenient answers to some questions and are playing increasingly diverse roles in drug development (Fig. 1). Biomarkers may provide new insights into the neurobiology of AD and generate new and *Corresponding author. Tel.: 310-794-3665; Fax: 310-794-3148. E-mail address: jcummings@mednet.ucla.edu Dr. Cummings has no disclosures specific to the contents of this article. 1552-5260/$ - see front matter Ó 2011 The Alzheimer’s Association. All rights reserved. doi:10.1016/j.jalz.2010.06.004 Alzheimer’s & Dementia 7 (2011) e13–e44