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Editorial Alzheimer's Disease & Dementia Drug Development in Alzheimer’s Disease— The Role of Default Mode Network Assessment in Phase II Jeffrey Cummings, 1 Kate Zhong, 2 and Dietmar Cordes 1 1. Cleveland Clinic Lou Ruvo Center for Brain Health, Las Vegas, NV, US; 2. Global Alzheimer’s Platform, Washington, DC, US A lzheimer’s disease (AD) is rapidly becoming more common as the global population ages. New treatments are needed and new approaches to drug development are warranted. The phase II challenge for AD treatment development programs is how to provide proof-of-concept (POC) of the candidate agent without a large long trial equivalent to phase III. We propose that the available data support measures of the default mode network (DMN) using functional magnetic resonance imaging (fMRI) as demonstrating the effect of treatment on cognitive circuits critical to human cognition. Improved DMN function with symptomatic cognitive enhancing agents or decreased deterioration of DMN function compared to placebo in trials of disease-modifying agents would support POC and allow progression to phase III with greater confidence. Keywords Alzheimer’s disease, functional MRI, default mode network, disease-modifying therapy, cortical circuits Disclosure: Jeffrey Cummings has provided consultation to Abbvie, Acadia, Actinogen, Alzheon, Avanir, Axovant, Biogen, Boehinger-Ingelheim, Bracket, Dart, Eisai, Genentech, Kyowa, Lilly, Lundbeck, Medavante, Merck, Orion, Otsuka, Pfizer, QR, Roche, Suven, and Takeda pharmaceutical and assessment companies. Kate Zhong is employed by Global Alzheimer's Platform. Dietmar Cordes reports no disclosures. This article is a short opinion piece and has not been submitted to external peer reviewers. No funding was received in the publication of this article. Acknowledgment: Jeffrey Cummings acknowledges support of a COBRE grant from the NIH/MIGMS (P20GM109025) and Keep Memory Alive. Authorship: All named authors meet the International Committee of Medical Journal Editors (ICMJE) criteria for authorship of this manuscript, take responsibility for the integrity of the work as a whole, and have given final approval to the version to be published. Open Access: This article is published under the Creative Commons Attribution Noncommercial License, which permits any noncommercial use, distribution, adaptation, and reproduction provided the original author(s) and source are given appropriate credit. Received: May 9, 2017 Published Online: June 28, 2017 Citation: US Neurology, 2017;13(2):67–9 Corresponding Author: Jeffrey Cummings, Cleveland Clinic Lou Ruvo Center for Brain Health, 888 West Bonneville Ave, Las Vegas, NV 89106. E: cumminj@ccf.org TOU CH MED ICA L MEDIA Alzheimer’s disease (AD) is approaching epidemic proportions as the world’s population ages and the number of victims of this age-related disorder soars. 1 At the same time that this tsunami of affected individuals looms, there has been little progress in developing new therapies, either symptomatic drugs to relieve the symptoms of AD or disease-modifying therapies (DMTs) to prevent, delay onset, or slow progression. No new novel treatment of AD has been approved since 2003 and 100% of DMTs in development have failed. 2 Drug development progresses from preclinical studies in animals to phase I trials involving normal volunteers, to phase II “learning” trials in small populations of AD patients, to phase III confirmatory trials that demonstrate safety and efficacy prior to seeking marketing approval and making treatments widely available to patients. Phase II establishes proof-of-concept (POC) and determines the optimal doses to be included in phase III trials. 3 Phase III is the longest phase of drug development, includes the largest number of patients, and consumes the largest share of resources. Thus, only agents that have demonstrated POC efficacy in phase II should be advanced to phase III. Stopping development of ineffective drugs in phase II will save resources that can be devoted to other projects and will save exposing patients to drugs and side effects in futile trials. Many drugs that have failed and many in the current AD pipeline have not shown POC in phase II before proceeding to phase III. A high failure rate can be anticipated among these agents. A critical aspect of phase II POC is target engagement and proof of mechanism. Figure 1 shows how advances in understanding the biological underpinnings of human cognition can be applied to clinical trials to achieve POC in phase II. There is an ascending hierarchy of brain function from cells and cell processes, to circuit integration underlying cognitive function. In AD, amyloid-beta protein (Ab) and phosphorylated tau protein aggregate and form neuritic plaques and neurofibrillary tangles, respectively. Protein oligomerization and aggregation lead to cell death, inflammation, and apoptosis. 4 Several biomarkers have been identified that provide insight into these events in the basic biology of AD. Brain imaging relevant to this level of understanding includes amyloid positron emission tomography (PET), tau PET, and atrophy as measured by magnetic resonance imaging (MRI). Fluid biomarkers reflective of these events include cerebrospinal fluid (CSF) Ab, CSF total tau protein, CSF phosphorylated tau (p-tau) protein, visinin-like protein 1 (VILIP1), and neurofilament light chain protein. 5,6 CSF Ab production and clearance can be measured using stable isotope labeled kinetics (SILK) techniques. 7 67