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   PRIORITY RESEARCH PAPER   
   AGING, Vol 6, No 9 , pp 707-717   
   PDF version     |    Abstract   
      
   Reversal of cognitive decline: A novel therapeutic program   
      
   Dale E. Bredesen1, 2   
   1 Mary S. Easton Center for Alzheimer's Disease Research, Department of   
   Neurology, University of California, Los Angeles, CA 90095;   
   2 Buck Institute for Research on Aging, Novato, CA 94945.   
   Key words:   
   Alzheimer's, dementia, mild cognitive impairment, neurobehavioral disorders,   
   neuroinflammation, neurodegeneration, systems biology   
   Received:   
   9/15/14; Accepted: 9/26/14; Published: 9/27/14   
   Correspondence:   
   Dale E. Bredesen, MD; E-mail: dbredesen@mednet.ucla.edu; dbredes   
   n@buckinstitute.org   
   Abstract   
   This report describes a novel, comprehensive, and personalized therapeutic   
   program that is based on the underlying pathogenesis of Alzheimer's disease,   
   and which involves multiple modalities designed to achieve metabolic   
   enhancement for neurodegeneration    
   (MEND). The first 10 patients who have utilized this program include patients   
   with memory loss associated with Alzheimer's disease (AD), amnestic mild   
   cognitive impairment (aMCI), or subjective cognitive impairment (SCI). Nine of   
   the 10 displayed    
   subjective or objective improvement in cognition beginning within 3-6 months,   
   with the one failure being a patient with very late stage AD. Six of the   
   patients had had to discontinue working or were struggling with their jobs at   
   the time of presentation,    
   and all were able to return to work or continue working with improved   
   performance. Improvements have been sustained, and at this time the longest   
   patient follow-up is two and one-half years from initial treatment, with   
   sustained and marked improvement.    
   These results suggest that a larger, more extensive trial of this therapeutic   
   program is warranted. The results also suggest that, at least early in the   
   course, cognitive decline may be driven in large part by metabolic processes.   
   Furthermore, given the    
   failure of monotherapeutics in AD to date, the results raise the possibility   
   that such a therapeutic system may be useful as a platform on which drugs that   
   would fail as monotherapeutics may succeed as key components of a therapeutic   
   system.   
   INTRODUCTION   
   Magnitude of the problem   
   Cognitive decline is a major concern of the aging population, and Alzheimer's   
   disease is the major cause of age-related cognitive decline, with   
   approximately 5.4 million American patients and 30 million affected globally   
   [1]. In the absence of effective    
   prevention and treatment, the prospects for the future are of great concern,   
   with 13 million Americans and 160 million globally projected for 2050, leading   
   to potential bankruptcy of the Medicare system. Unlike several other chronic   
   illnesses, Alzheimer'   
   s disease prevalence is on the rise, which makes the need to develop effective   
   prevention and treatment increasingly pressing. Recent estimates suggest that   
   AD has become the third leading cause of death in the United States [2],   
   behind cardiovascular    
   disease and cancer. Furthermore, it has been pointed out recently that women   
   are at the epicenter of the Alzheimer's epidemic, with 65% of patients and 60%   
   of caregivers being women [3]. Indeed, a woman's chance of developing AD is   
   now greater than her    
   chance of developing breast cancer [4].   
   Failure of monotherapeutics   
   Neurodegenerative disease therapeutics has been, arguably, the field of   
   greatest failure of biomedical therapeutics development. Patients with acute   
   illnesses such as infectious diseases, or with other chronic illnesses, such   
   as cardiovascular disease,    
   osteoporosis, human immunodeficiency virus infection, and even cancer, have   
   access to more effective therapeutic options than do patients with AD or other   
   neurodegenerative diseases such as Lewy body dementia, frontotemporal lobar   
   degeneration, and    
   amyotrophic lateral sclerosis. In the case of Alzheimer's disease, there is   
   not a single therapeutic that exerts anything beyond a marginal, unsustained   
   symptomatic effect, with little or no effect on disease progression.   
   Furthermore, in the past decade    
   alone, hundreds of clinical trials have been conducted for AD, at an aggregate   
   cost of billions of dollars, without success. This has led some to question   
   whether the approach taken to drug development for AD is an optimal one.   
   Therapeutic success for other chronic illnesses such as cardiovascular   
   disease, cancer, and HIV, has been improved through the use of combination   
   therapies [5]. In the case of AD and its predecessors, mild cognitive   
   impairment (MCI) and subjective    
   cognitive impairment (SCI), comprehensive combination therapies have not been   
   explored. However, the past few decades of genetic and biochemical research   
   have revealed an extensive network of molecular interactions involved in AD   
   pathogenesis, suggesting    
   that a network-based therapeutics approach, rather than a single target-based   
   approach, may be feasible and potentially more effective for the treatment of   
   cognitive decline due to Alzheimer's disease.   
   Preclinical studies   
      
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