Rafii_2013_Rev.Recent.Clin.Trials_8_110

Alzheimer's disease (AD) is the leading cause of dementia worldwide. Clinically, it is characterized by progressive cognitive impairment and neuropsychiatric disturbances. Pathologically, it is characterized by the accumulation of extracellular amyloid plaques and intraneuronal neurofibrillary tangles, accompanied by widespread neurodegeneration, including loss of cholinergic neurons in the basal forebrain, leading to decreased cholinergic transmission and impaired memory (Bartus et al, 1982; Whitehouse et al, 1982). Currently, the symptoms of AD dementia are treated with acetylcholinesterase inhibitors (AChEI) which target this deficiency (Birks J, 2006). However, such treatments merely afford palliative relief and do not slow or reverse the underlying progression of the disease. Approved AChEIs include donepezil, rivastigmine, and galantamine. An excess of glutamatergic neurotransmission, manifested as neuronal excitotoxicity, is also hypothesized to be involved in the pathology of Alzheimer's disease. Memantine is a low-affinity voltage-dependent uncompetitive antagonist at glutamatergic NMDA receptors (Chen HV, 1992). Memantine is approved for treatment of moderate-to-severe Alzheimer's disease. The Food and Drug Administration (FDA) has not approved any new drugs for the treatment of AD since memantine in 2003. In 2011, the FDA approved a new formulation of donepezil hydrochloride, a 23mg continuous release pill and in 2012, the FDA approved a 13.3 mg formulation of the rivastigmine transdermal patch. In recent years many drug candidates aimed at disease modification have advanced into large, randomized controlled trials but have not demonstrated efficacy in treating AD. While the exact cause of AD is still being fervently investigated, the field is moving toward earlier identification and treatment of the disease as it is believed this may be the main reason for so many clinical trial failures. There are currently four main mechanisms of action that are being actively developed in AD therapeutics: Drugs aimed at reducing Abeta production, notably secretase inhibitors; Drugs aimed at reducing Abeta plaque burden via inhibition of aggregation or disruption of aggregates; Drugs aimed at promoting Abeta clearance via active or passive immunotherapy; and Drugs aimed at preventing tau protein phosphorylation or fibrillarization. In this review, recent findings from clinical and preclinical studies in each of these categories will be discussed, as well as a category entitled 'other therapies,' that includes treatments that do not fit under a single mechanism of action, but represent rational interventions for the underlying pathology of Alzheimer's disease.