Past and Present Drug Development for Alzheimer's Disease
Pp. 214-253 (40)
Pratap Kumar Sahu, Prashant Tiwari, Shakti Ketan Prusty and Bharat Bhusan Subudhi
Alzheimer’s disease (AD) is a progressive and an irreversible chronic
neurodegenerative disorder causing dementia. Worldwide, the prevalence of AD is
estimated to be 30 million and likely to quadruple in the next 40 years. Thus, the global
cost of dementia is estimated to be 1.09% of global GDP (US$ 818 billion). Several
factors including age and family history are involved in its etiology and considered as
the predisposing factors for AD. The neurochemical basis of AD can be explained by
the ‘Cholinergic’, ‘Amyloid plaque’ and ‘Tauopathy’ hypotheses. The ‘Cholinergic’
hypothesis put forth a relationship between Acetyl choline (ACh) levels to cognitive
memory and the other two hypotheses propose an excessive deposition of amyloid
plaques extracellularly and accumulation of tau protein intracellularly, eventually
causing neuronal death. The cholinergic system is mainly targeted for therapeutic
management of AD symptoms. In view of that, acetylcholinesterase inhibitors (AChEI)
such as tacrine, donepezil, rivastigmine and galantamine have been used. Memantine,
an N –methyl – D - aspartate (NMDA) receptor antagonist inhibiting glutamate
mediated exocitotoxicity, is also used to improve dementia symptoms. However, the
degree of improvement with this approach has been minimal as no one of these drugs
can reverse the course of AD, nor prevent destruction of neurons. Accordingly,
amyloid based strategies including ‘secretive enzymes modulation’, ‘amyloid
aggregation prevention’ and ‘amyloid clearance promotion’ have been adopted.
Inhibition of tau phosphorylation/oligomerization, microtubule stabilization, reduction
of stress/inflammation, modulation of neurotransmitters and cellular calcium
homeostasis has also been used as strategy to manage AD with varying degree of
A high rate of attrition combined with huge cost of new drug development has
encouraged drug repurposing strategies. This approach ensures minimal developmental
cost and shorter approval time to launch a drug. Moreover, the risk associated with
conventional drug discovery is reduced due to existing pharmacokinetic and safety
data. Thus, drug repurposing is considered to be a preferred strategy against AD.
Modern advances in disease biology of AD have substantially assembled data from pre-clinical, clinical, in-vitro, epidemiological, toxicological, and computational
sources. Thus, an implementation of systematic approaches using this on hand
information with a clear understanding of the network pharmacology can give way the
next therapeutic alternative for successful management of AD.
The current chapter describes the scope and limitations of some currently marketed
drugs like cholinergic drugs, cyclooxygenase (COX) and lipoxygenase (LOX)
inhibitors, renin angiotensin system (RAS) inhibitors, lipid lowering drugs (statins),
NMDA receptor antagonists, anti-diabetics, anti-oxidants, vitamin D etc in
management of AD. Many of them have the potential against AD and some of them are
validated pre-clinically and clinically. But none of them has reached the market yet.
Drugs targeting neuroinflammation including COX inhibitors, LOX inhibitors and
RAS inhibitors can potentially arrest the disease progression in AD. However, their
repurposing potential needs to be clinically validated.
School of Pharmaceutical Sciences, Siksha O Anusandhan Deemed University, Bhubaneswar, Odisha, India-751029.