Commentary on “A roadmap for the prevention of dementia II: Leon Thal Symposium 2008.” Establishing a national biomarker database: Utility and incentives

Alzheimer’s disease (AD) represents an increasing threat to public health. AD becomes more common with increasing age, and the entry of the baby boomer population into the advanced years of life will greatly increase the number of AD victims. It is critically important to develop new therapies for AD that prevent, delay the onset, slow the progression, or improve symptoms. Disease-modifying therapies are particularly important and are being sought by many academic investigators and biotechnology and pharmaceutical companies. These compounds exploit our emerging understanding of the molecular neurobiology of AD. A variety of targets have emerged in amyloid beta (As) protein pathways including As production, degradation, oligomerization, and deposition. Each of these mechanisms has a variety of targets that are potentially exploitable as therapeutic opportunities for AD. In addition, As appears to lead to hyperphosphorylation of tau protein and the formation of neurofibrillary tangles as well as to excitotoxicity, oxidative brain injury, inflammation, and apoptosis. As effects on mitochondria appear to have an important role in the cascade of events leading to cell dysfunction and death. All of these pathways present potential targets for therapeutic intervention that would prevent the occurrence of AD if initiated in asymptomatic individuals, defer the onset of AD in persons with no or minimal symptoms, or slow the progression of AD in persons identified at symptomatic stages of the disease. Substantial progress has been made in identifying possible therapeutic candidates, and clinical trials are being pursued that include inhibition of s-secretase; inhibition of g-secretase; augmentation of a-secretase; enhancement of As degradation through insulin-degrading enzyme (IDE), neprilysin and plasmin-related pathways; reduction of oligomerization