Advances in Alzheimer’s Disease Drug Development

Rafii and Aisen BMC Medicine Advances in Alzheimer's Disease Drug Development Michael S Rafii 0 Paul S Aisen 0 0 Department of Neurosciences, University of California , 9500 Gilman Dr., MC 0949, La Jolla, San Diego, CA 92093 , USA Alzheimer's disease (AD) is the foremost cause of dementia worldwide. Clinically, AD manifests as progressive memory impairment followed by a gradual decline in other cognitive abilities leading to complete functional dependency. Recent biomarker studies indicate that AD is characterized by a long asymptomatic phase, with the development of pathology occurring at least a decade prior to the onset of any symptoms. Current FDA-approved treatments target neurotransmitter abnormalities associated with the disease but do not affect what is believed to be the underlying etiology. In this review, we briefly discuss the most recent therapeutic strategies being employed in AD clinical trials, as well the scientific rationale with which they have been developed. Alzheimer's disease; Beta-amyloid; Clinical trials - Background Alzheimers disease (AD) currently affects over 36 million people worldwide with an estimated global economic impact of approximately $605 billion in 2010 [1] in addition to incalculable social and emotional costs. Initially, AD presents with memory impairment that progressively worsens with concomitant declines in other cognitive abilities and behaviors, which lead to the complete functional dependency that defines the dementia phase of the illness [2]. Converging data from longitudinal biomarker studies indicate that AD is characterized by a long asymptomatic phase, with the initial development of neuropathology beginning approximately 15 to 20 years prior to the onset of any symptoms [3]. Theories on AD pathogenesis AD is characterized by the accumulation of neuritic plaques consisting of the -amyloid (A) peptide and neurofibrillary tangles (NFT) comprised of hyperphosphorylated tau protein. This pathology is associated with disruption of synaptic function leading to neuronal degeneration and brain atrophy. One of the major deterrents to progress in this field is a lack of understanding as to what precisely causes AD. There have been a number of theories proposed to explain the etiology of AD, but to date, no one theory can adequately explain all aspects of this disease. The precise mechanisms in AD progression also remain unclear and there is some controversy regarding the timing of its molecular pathogenesis, including changes in brain amyloid and abnormalities in intracellular tau. Nonetheless, there are three major theories that are presently regarded as most likely to explain the molecular basis of AD and therefore serve as the bases for therapeutic development. The cholinergic hypothesis was the first theory proposed to explain AD and has since led to the development of the only drugs currently approved to treat mild to moderate dementia due to AD [4,5]. This theory is based on the finding that a loss of cholinergic neurons in the Nucleus Basalis of Meynert (NBM), and hence cholinergic activity, is commonly observed in AD brains [6]. Experimental studies in humans and non-human primates suggested a role for acetylcholine in learning and memory [7]. These studies reported that by blocking central cholinergic activity with scopolamine, young subjects would demonstrate memory deficits similar to those seen in aged individuals. These impairments could be reversed by treatment with the cholinergic agonist physostigmine. This theory led to early clinical studies utilizing another type of cholinergic agonist, acetylcholinesterase inhibitors, which showed promise in reversing the memory impairment in AD patients. What specifically leads to the demise of the cholinergic neurons in AD remains unclear and continues to be actively investigated. There are currently three acetylcholinesterase inhibitors (donepezil, rivastigmine, and galantamine) that have been approved by the Food and Drug Administration (FDA) for the treatment of mild to moderate AD. All of these drugs have been reported to have similar effectiveness; however, donepezil is the most widely prescribed. Clinical trials have reported modest but reproducible improvements in cognition and global functioning by treating patients with donepezil compared to placebo, but these effects were not permanent and patients still demonstrated a decline in cognitive functioning over time [8]. The second and most prevailing theory of AD is the amyloid hypothesis, which postulates the role of soluble A fragments as synaptotoxic and leading to plaque accumulation and subsequent development of intracellular NFTs. It has been supported by findings that amyloid precursor protein (APP) is located on chromosome 21, which may account for the increased prevalence of dementia in older people with Down syndrome, due to a triplication of this chromosome [9]. Additional support for this hypothesis comes from inherited forms of AD, where mutations have been found within APP leading to autosomal-dominant forms of this disease and from the recently discovered protective effects of an Icelandic mutation (A673T), which leads to a reduction in A formation [10]. Given the pivotal role suggested by the amyloid hypothesis for A, it is not surprising that many therapeutics have been designed to interfere with the production of A either through inhibition of enzymes, such as -secretase, or through strategies aimed at clearing existing plaques within the brain, such as anti-A immunotherapy. The third hypothesis is the tau hypothesis, which asserts that abnormalities in the intracellular protein tau are causative. In light of observations that tau oligomers are neurotoxic, clinical symptoms correlate most closely with tau pathology and the fact that anomalous tau hyperphosphorylations constitute a common final pathway for many other dementias, the tau theory is gaining greater acceptance. In this theory, anomalous signaling leads to tau hyperphosphorylation through, for instance, the fyn kinase pathway. Tau modifications lead to its oligomerization and the development of NFTs, resulting in abnormal intracellular trafficking, collapse of the microtubule-based cytoskeleton, and subsequent neuronal demise. As a result of neuronal death, oligomeric forms and tau filaments are released to the extracellular environment, contributing to activation of microglial cells and stimulating the deleterious cycle leading to progressive spread of neuronal degeneration. Increasing evidence indicates that the tau hypothesis provides close approximation to clinical observations in AD patients. These include the observation that severity of dementia correlates with increasing accumulation of NFTs and level of hyperphosphorylated tau species in the cerebrospinal fluid (CSF) of AD patients correlates with the extent of cognitive impairment [11]. Considering the evidence supporting a neurotoxic role of tau modifications and ag (...truncated)