Introduction
Alzheimer disease (AD) is the most common cause of neuro degeneration and the consequent intellectual decline in the elderly population worldwide. It is characterized by memory impairment, deficit in other cognitive domains as well as non-cognitive neurological deficits. The disease is also characterized by oxidative stress, mitochondrial impairment, neuron inflammation, synaptic dysfunction, and blood-brain barrier disruption, which may be caused in part by abnormal extracellular accumulation of amyloid-β peptide (Aβ) in amyloid plaques and tau protein aggregation in intracellular neuro fibrillary tangles (NFTs), which are the hallmarks of Alzheimer’s disease, causing synaptic and neuronal loss and enhancing cognitive dysfunction. Acetylcholine neurotransmitter is also implicated in AD in that its level are decreased due to its rapid hydrolysis by acetyl cholinesterase (AChE).
Classes of Alzheimer Disease
Alzheimer Disease can be classified into two types according to the age of onset and pathological factors:
- The first type, Early-Onset Alzheimer Disease (EOAD) or familial AD (<60 years of age) occurs in 5% of all cases of AD in individuals with a family history of at least three generations.
- The other type is Late Onset Alzheimer Disease (LOAD) or sporadic AD(> 65 years of age), which usually have sporadic occurrence and is multifactorial.
Risk factors that occurs with greater incidence in patients with LOADS are diabetes, hypertension, hypercholesterolemia, obesity, and metabolic syndrome, which are related to lipid metabolism. LOAD has been linked to oxidative stress phenomena, mitochondrial damage, and ApoE polymorphism in the vascular endothelium , which involves an increase in Aβ42 fragment level leading to an elevation in amyloid plaque formation and excitotoxic processes.
Pharmacological Intervention
The discovery of the loss of the cholinergic neurons and acetylcholine in the brain of Alzheimer’s disease patients led to the use of drugs that would enhance the actions of acetylcholine in the brain. The drug that is mainly used in the management of Alzheimer Disease is cholinesterase inhibitors.
Cholinesterase Inhibitors:
These are therapeutic agents approved for the treatment of Alzheimer’s disease . They block the break-down of acetylcholine and increase the availability of the neurotransmitter in synapse. These drugs are palliative only and do not cure or prevent neurodegeneration.
Examples of Cholinesterase inhibitors include:
- Tacrine (Cognex),
- Donepezil(Aricept)
- Rivastigmine (Exelon), and
- Galanthamine(Reminyl).
They have significant but modest effect on the cognitive status of patients, possibly because the drugs do not correct for changes that occur in other neuronal systems.
Side Effects of Cholinesterase Inhibitors
- Nausea
- Diarrhea
- Vomiting, and
- Insomnia.
These symptoms are most frequent and severe with tacrine. Hepatotoxicity is also associated with tacrine therapy and because of these significant side effects, tacrine is not widely used.