Editorial [Hot Topic:Alzheimer's Disease (Guest Editors: Shawn J. Stachel & Joseph P. Vacca)]

Alzheimer's disease (AD) is a fatal degenerative disease of the brain that is rapidly becoming one of the largest unmet medical needs in the developed world. It is estimated that 4.5 million Americans currently have Alzheimer's disease and that number is expected to rise dramatically due to the population bubble resulting from the baby boom and increased longevity from medical advances. Current national direct and indirect annual costs associated with treatment and care of Alzheimer's patients is upwards of 100 billion dollars. Researchers over the past 20 years have uncovered a variety of genetic mutations that result in early onset AD or familial AD (FAD). However, our current understanding of genetic predisposition accounts for < 10% of AD cases, the majority of cases are sporadic in nature and the risk factor increases in an age dependent manner. It is generally recognized that β-amyloid plaques and neurofibrillary tangles are the key pathological features of the disease, although the specific roles of these agents in disease progression remain debatable.

Currently there are no therapies available to treat the progression or onset of Alzheimer's disease. This issue of "Current Topic in Medicinal Chemistry" presents articles from six groups of researchers who are involved in various aspects of Alzheimer's disease with the shared focus of finding effective treatments. The first review by Al Robichaud focuses on approaches to palliative therapies for Alzheimer's disease. These agents are currently the 'front-line' treatment used to retard cognitive decline but are not directly disease-altering. Dr. Robichaud covers a diverse range of enzyme targets from muscarinic agonists to cannabinoid receptor ligands and summarizes their current developmental status.

The second review by Varghese John focuses on β-secretase (BACE). β-secretase is recognized as the rate limiting enzymatic event in the production of Aβ40-42. The Aβ42 peptide fragment is well documented as the major component of amyloid plaques. Dr. John describes the role of β-secretase in the amyloid cascade and the progress toward the development of BACE inhibitors. The next review by Ian Churcher describes the tau-related etiology of Alzheimer's disease as well as the therapeutic strategies to inhibit the hyperphosphorylation of tau. Hyperphosphorylation of the microtubule associated protein, tau, induces its aggregation to form neurofibrillar tangle (NFTs). Evidence suggests that these intracellular tangles are directly responsible for neuronal death. In the fourth review, Susan Catalano, Elizabeth Chen-Dodson, Darrel Henze, Joseph Joyce, Grant Krafft, and Gene Kinney discuss the role of amyloid-beta derived diffusible ligands (ADDLs) in Alzheimer's disease. ADDLs are composed of soluble oligomers of Aβ42 and have been implicated in neuronal cell death prior to plaque deposition. Vaccine and antibody-based therapeutic approaches aimed at lowering ADDL loads are covered.

The next two reviews focus on the development of biological and clinical methods for the assessment of promising therapeutic agents. Sethu Sankaranarayanan updates current views on amyloid and tau pathologies in mice models of AD. The development and limitations of these transgenic mice models and their effectiveness as human disease surrogates is described. Finally, Alexandre Coimbra, Donald Williams, and Eric Hostetler review the progress made in the fields of MRI and PET/SPECT imaging and their potential use as; a non-invasive tool to aid in early diagnosis, a method for assessing efficacy of disease-modifying agents, and a resource for monitoring progress in clinical evaluations.