In 1906, the German physician Alois Alzheimer provided the first description of the “serious and peculiar disease” of mental deterioration that would later on take his name. Alzheimer described the classic pathology of neuritic plaques and neurofibrillary tangles in an affected patient. Since that time, understanding of Alzheimer's disease (AD) has progressed substantially, although the ability to influence disease progression has not progressed as rapidly. It is likely that over the next decade these advances will lead to earlier diagnosis and development of disease-modifying treatments for AD.

It is known that two variants of AD exist: a rare hereditary form and a more prevalent sporadic form. As with many neurodegenerative diseases, early clues to the pathology of AD came from the inherited form of the disease. Hereditary links include mutations of the amyloid precursor protein (APP) and the presenilins, both of which are integrally involved in the cascade of events that leads to the deposition of the 42-amino-acid amyloid β protein and the eventual cell death responsible for AD.

Alzheimer's disease (AD) is a progressive neurodegenerative disease characterized by cognitive decline, functional disability, and neuropsychiatric symptoms. Initial diagnosis is often delayed to a point when there is significant neurodegenerative pathology and secondary downstream pathogenic sequelae. The disease should be diagnosed during its earliest stage, as this would likely represent an ideal therapeutic window for disease-modifying therapies. Despite recent research that has focused on defining the clinically identifiable at-risk phase that precedes AD, reliable criteria for identifying patients in the prodromal to incipient stages of AD remain elusive.

In addressing the prodrome of AD, it has been clearly recognized that there are age-inappropriate cognitive declines that fall short of meeting the criteria for dementia. Most broadly, patients in this category have been classified as cognitively impaired not demented (CIND). In epidemiological studies, it has been estimated that 19% to 37% of patients ≥65 years of age are CIND. Conditions within the taxonomy of CIND include age-associated memory impairment (AAMI), age-associated cognitive decline (AACD), and mild cognitive impairment (MCI) (Slide 1).

AAMI is defined psychometrically by memory test scores that are ≥1 standard deviation below scores of young healthy control patients. AACD is characterized by scores in any cognitive domain that are ≥1 standard deviation below age- and education-adjusted normal measures. MCI is identified by memory function at a level ≥1.5 standard deviations below age- and education-adjusted means. Of these three conditions, MCI has been investigated most thoroughly and is defined by a clinical phenotype.

Alzheimer's disease (AD) is a progressive disorder in which neurodegeneration begins decades before clinical symptoms appear. Detecting AD during this preclinical phase presents both the enormous challenge of identifying at-risk patients prior to symptom onset and the potential reward of treating patients early enough to prevent or slow disease progression. Given that a 5-year delay in the onset of the clinical manifestations of AD could result in almost a 50% reduction in disease prevalence, early detection of AD is a major focus of clinical research. Several objective, measurable indicators of preclinical and clinical characteristics of AD are currently available or in development. These biomarkers are promising because they promote identification of individuals at risk for AD onset and disease progression; diagnostic accuracy and treatment during the early stages of AD; and the development of disease-modifying therapies that may potentially slow or prevent disease progression during the preclinical phase of AD.

Alzheimer's disease (AD) is the most prevalent neurodegenerative disorder in the United States and the number of AD patients is increasing at an alarming rate. There is no cure for AD and the currently available treatments are symptomatic, providing only limited effects on disease pathophysiology and progression. An overwhelming need exists for therapies that can slow or halt this debilitating disease process. Disease modification in AD has been defined from patient-focused, regulatory, and neurobiological perspectives. The latter two of these perspectives rely largely on an interruption of the disease process and a clear demonstration of this interruption. As defined by Cummings, a disease-modifying treatment is a “pharmacologic treatment that retards the underlying process of AD by intervening in the neurobiological processes that constitute the pathology and pathophysiology of the disease and lead to cell death or dysfunction.” By this definition, the burden of confirmatory study is placed on any new treatment for which the claim of “disease modification” is to be made (Slide 1).