Alzheimers Disease

The copious complex mechanisms involved in the pathogenesis and pathophysiology of Alzheimer’s Disease (AD) creates a challenge to innovate effective therapeutics to delay or halt the disease progression (Fig.1) (Anand, 2014). However, extensive scientific efforts have been devoted into pharmacotherapeutic research for the treatment of AD. The development of present therapeutics have been based upon the first theory proposed to explain the disease known as the cholinergic hypothesis (Francis, 1999). This study evidently reveals the selective loss of cholinergic neurons in the nucleus basalis, which results in reduction in cholinergic activity among patients with AD. (Whitehouse et al., 1981). Additional studies confirm that AD may be associated with diminution of cholinergic activity, further studies utilized rhesus monkeys to show the effects of anticholinergic scopolamine on memory deficits as seen in AD (Bartus, 1978). Therefore, the development of therapeutics to augment cholinergic activity such as cholinesterase inhibitors (CIs) have primarily been focused upon. The CI’s function to enhance the cholinergic transmission by reducing in the breakdown of acetylcholine (ACh). For this reason, elevated levels of ACh are presented between neuronal synaptic clefts, thereby, compensating for the attenuated levels of ACh due to cholinergic neuronal death (Stahl, 2000). Currently, four Cis for symptomatic treatment of the disease have been approved by the FDA – donepezil, rivastigmine, galantamine, tacrine (Lleo, 2007). Such therapies have been recognized as first-line of treatment for mild to moderate progression of AD, though, tacrine is no longer used in clinic due to its associated effects of tacrine-induced liver damage (Alfirevic, 2007). A systematic review and metanalysis conducted by Hansen et al. has shown that donepezil, galantamine, and rivastigmine have shown overall benefits for stabilizing or slowing decline in cognition, function, behavior and clinical global change (Hansen, 2008). Despite the benefits of CI for moderate AD, the elevation in the levels of ACh can result in cholinergic adverse effects among patients which include nausea, vomiting, diarrhea, bradycardia, muscle cramps, and insomnia (Ellis, 2005). Moreover, memantine – an N-methyl D-aspartate (NMDA) receptor antagonist provides a treatment option for moderate to severe cases of AD (Yiannopoulou, 2013). Such drug serves to preclude the excessive release of an excitatory neurotransmitter glutamate resulting in excitotoxicity (Aprahamian, 2013). Moreover, a study by McShane et al. shows the benefit of memantine in moderate to severe to severe AD, which includes improvement on cognition, activities of daily living, and behavior at six months (McShane, 2006). However, although memantine is shown to be well tolerated in clinical studies, it can commonly be associated with side effects such as dizziness, constipation, confusion, headaches, hypertension, comnolence and visual hallucinations (McShane, 2006; Gauthier, 2006 ). While CI’s have been used as a standard mode of treatment to offer palliative care, ongoing research has been conducted for treatments capable of halting or modifying the progression of AD (Yiannopoulou, 2013).