Review of the next generation of Alzheimer's disease therapeutics: Challenges for drug development

1. AD is believed to stem from dysfunctional cholinergic signaling in the r egions of the brain associated with memory and cognition. 2. The occurrence of AD in afflicted individuals correlates with an increas e in the accumulation of A beta -rich senile plaques and neurofibrillary ta ngles in the brain. 3. Currently, the only FDA-approved AD therapies are a group of acetylcholi nesterase inhibitors which slow the turnover of the neurotransmitter acetyl choline in the synapse. 4. Many other compounds which target other aspects of the disease, such as reducing neuronal damage and limiting oxidation, are in clinical trials. Th ese include monoamine oxidase (MAOB) inhibitors, NSAIDs, antioxidants and e strogen, among others. 5. Recent research discoveries have more completely defined the molecular n ature of AD, and are generating new approaches for treatment. One idea is t o limit the ability of the protein tau to become phosphorylated in hopes th at this will limit the formation of neurofibrillary tangles in the brain. 6. A separate approach that is being pursued is to prevent formation and ac cumulation of A beta plaques. This may be accomplished by either regulating gamma -secretase activity, or using anti-beta-amyloid antibodies to reduce the size of existing plaques. 7. Employing improved procedural and technological approaches during clinic al trials, such as bridging studies, dynabridge studies and PET analysis, p romises to streamline the drug development process. 8. The use of biomarkers and MRI analysis may be an effective means by whic h to identify the disease early. Consequently, early intervention treatment therapies may be an effective way of delaying onset of the disease. 9. Long term AD studies, particularly those focusing on the MCI population, are likely to provide statistically valid results using a smaller study po pulation.