Commentary on “A roadmap for the prevention of dementia II. Leon Thal Symposium 2008.” Facilitating Alzheimer's disease drug development in the United States

Therapeutic research of Alzheimer’s disease (AD) is on the brink of a major advance. The field is poised to add effective disease-modifying treatments to our current symptomatic agents. The basic scientific understanding of AD pathophysiology has yielded a number of exceedingly promising targets for intervention, with many drugs now in various phases of clinical testing. Whether we reach a breakthrough within 5 or 15 years will be determined by the national will. In addition to financial support (specifically, funding by the National Institutes of Health for AD translational research), several concrete steps will facilitate progress toward bringing the next generation of therapeutics to the market. These steps are related to some important issues specific to the development of disease-modifying AD treatments, as well as some broader clinical research issues. 2. Change the diagnostic criteria for AD A diagnosis of AD should indicate the presence of neurobiological abnormalities that, if unchecked, will eventually lead to dementia. At present, diagnostic criteria require the presence of dementia [1]. But we now have tools that allow the documentation of reduction in cerebral metabolic rate [2], amyloid and tau dysregulation [3], amyloid deposition in the brain [4], and regional brain atrophy [5], many years before the appearance of the functional impairments of dementia. Further, we can measure subtle cognitive decline many years before clinically important impairment occurs [6]. Based on observations regarding the prevalence of brain amyloid deposition and mild cognitive decline in the nondemented elderly, we can estimate that the number of cases of ‘‘neurobiological AD’’ is at least 2–3 times larger than the number of cases of clinical AD according to current criteria. In other words, there are now at least 10–15 million people in the United States with AD pathology, though only about 5 million are demented. Appreciation of the ‘‘true’’ prevalence of AD will encourage a more reasonable allocation of resources. But more importantly, the millions of people with early AD neurobiology represent the proper target population for effective disease-modifying interventions. The recently proposed research criteria for AD serve as an excellent start in the process of adjusting diagnoses based on our growing understanding of the neurobiology of AD [7].