The Human Alzheimer Disease Project: A New Call to Arms.

The message of this Editorial is simple and straightforward. For the past decade or more, billions of dollars have been invested by the pharmaceutical industry and the National Institutes ofHealth (NIH) to develop effective therapies for Alzheimerdisease.Despite thesevast sumsofmoney, aneffective therapy todelayorpreventAlzheimerdiseasehasnotbeendeveloped. Seeing the lack of progress, several major pharmaceutical companies have reduced or eliminated their Alzheimerdiseaseefforts. The resultmeans thatwithout aneffective therapy, the number of individuals in the United States who will develop Alzheimer disease in the next 25 years will increase from about 5.5 million to 12 million or more. In a recent analysis of the state of UShealth from 1990 to 2010,Murray and colleagues1 reported that Alzheimer disease had increased more in rank (from 32 to 9) of years lost to life because of prematuremortality comparedwith any othermajor disease during this 20-year period. On a worldwide basis, approximately 50 million persons will develop Alzheimer disease by 2050. Further, as we all know, it is not just the individual with Alzheimer disease who is affected but entire families, including spouses, children, and significant others who are mobilized to help the affected individual. Thebiologyof thisdisease is clearly formidable.Thepathogenesis of Alzheimer disease involves amajor segment of the human genome. It interacts with the aging process and other comorbidities, including cerebrovascular disease, hypertension, diabetes mellitus, and themetabolic syndrome. Loss of synapsesandbrainatrophyareconsequencesand theseevents are irreversible, making early intervention essential. Currently, 3monoclonal antibody therapies arebeingused in clinical trials of individualswhoare cognitively asymptomatic but at risk for Alzheimer disease by virtue of accumulating β-amyloid as shown by positron emission tomography. It is thehope thatveryearly intervention toblockβ-amyloidstoragewill prevent thesecondarypathologies frombeginningand progressing independently.2-5The resultsof theseclinical trials are eagerly awaited. The concern is that β-amyloidmaynot be the earliest pathology and thatmore antecedent neurodegenerative changes, such as the accumulation of tau, may already be in place andwill function to render loss of synapses, induce atrophy, and more diffusely reduce glucose level uptake and metabolism. In addition, the interaction of various pathological processes is unknown. Substantial progress has beenmade through thedevelopment of the Alzheimer Disease Centers Programs established by theNational Institute onAging (NIA). A network of 27NIAfundedcentersatmedical schoolsacross thecountryarehighly effective indeveloping research, clinical, andeducational programs.Hundredsof first-rate researchpapersarepublishedannually and are funded by the NIA through the Alzheimer Disease Centers Programs. Advances in understanding the etiology, differential diagnosis, andprogression of Alzheimer diseaseandrelateddisordershaveclearly resulted.Great credit goes toCreightonH.Phelps,PhD,directorof theAlzheimerDiseaseCenters Programsat theNIA, andhis staff, includingNina Silverberg, PhD, who developed this network during the past 22 years. His remarkable efforts follow the pioneering efforts of ZavenKhachaturian, PhD, andTerryRadebaugh, PhD,who founded the program 30 years ago. Federal investment in othermajor health issues has been successful. Support for cancer research through the National Cancer Institute is approximately $5 billion per year. Support for heart disease research through the National Heart, Lung, andBlood Institute is approximately$3billionperyear andhuman immunodeficiencyvirus/AIDS receives$3billionperyear. Through the NIA and other institutes, the NIH is able to provideonlyabout 10%of those levelsof supportby fundingabout $600millionperyear forAlzheimerdisease research.The rates of several major cancers, heart disease, and stroke have decreased in recent years as a consequence of these appropriately generous levels of NIH support. What is now needed is equivalent support ofAlzheimerdisease andother relateddiseases, including frontotemporal degeneration and dementia with Lewy bodies. Anewemphasis is necessary to capture theurgencyof the problemand tomotivate thepublic and theUSCongress to act decisively. Alzheimer disease is as horrific a disease as cancer, heart disease, and stroke. It deserves tobe singledout and receive a level of attention and research dedication comparable to the other major causes of death and disability in the United States. A focused exemplary research group dedicated to complex biological issues or diseases has precedence for achieving scientific success. The great clinical and scientific successes of the Neurological Institute of Columbia University Medical Center and the Montreal Neurological Institute of McGill University are exampleswhere talent coming together for a specific set of neurological causes produced exponential growth in science. Themembers of TheLaboratory of BiochemicalGenetics at theNIHdirectedbyNobel LaureateMarshall Nirenberg in the 1960s deciphered the genetic code, the universality of the genetic code for all life forms. This research enterprise was concentrated, intense, and highly focused to achieve a single scientific purpose of deciphering the Opinion