Review article
A review on Alzheimer's disease pathophysiology and its management: an update

https://doi.org/10.1016/j.pharep.2014.09.004Get rights and content

Abstract

Alzheimer's disease acknowledged as progressive multifarious neurodegenerative disorder, is the leading cause of dementia in late adult life. Pathologically it is characterized by intracellular neurofibrillary tangles and extracellular amyloidal protein deposits contributing to senile plaques. Over the last two decades, advances in the field of pathogenesis have inspired the researchers for the investigation of novel pharmacological therapeutics centered more towards the pathophysiological events of the disease. Currently available treatments i.e. acetylcholinesterase inhibitors (rivastigmine, galantamine, donepezil) and N-methyl d-aspartate receptor antagonist (memantine) contribute minimal impact on the disease and target late aspects of the disease. These drugs decelerate the progression of the disease, provide symptomatic relief but fail to achieve a definite cure. While the neuropathological features of Alzheimer's disease are recognized but the intricacies of the mechanism have not been clearly defined. This lack of understanding regarding the pathogenic process may be the likely reason for the non-availability of effective treatment which can prevent onset and progression of the disease. Owing to the important progress in the field of pathophysiology in the last couple of years, new therapeutic targets are available that should render the underlying disease process to be tackled directly. In this review, authors will discusses the different aspects of pathophysiological mechanisms behind Alzheimer's disease and its management through conventional drug therapy, including modern investigational therapeutic strategies, recently completed and ongoing.

Introduction

Alzheimer's disease (AD) is one of the most common neurodegenerative disease and accounts for more than 80% of dementia cases worldwide in elderly people. It leads to the progressive loss of mental, behavioral, functional decline and ability to learn [1].

Approximately 200,000 people younger than 65 years with AD comprise the younger onset AD population; 5 million are age 65 years or older. It is expected that by 2050, one new case of AD is expected to develop every 33 seconds, or nearly a million new cases per year, and the total estimated prevalence is expected to be 13.8 million [2].

Since the time of Dr. Alois Alzheimer, neuropathologists have identified amyloid plaques and NFTs in the autopsied brains of people with AD, suggesting that these pathologies cause the disease [3]. Amyloid plaques are extracellular deposits of Aβ in the brain parenchyma and in the cerebral blood vessels where it is known as congophilic angiopathy also known as cerebral amyloid angiopathy (CAA). NFTs composed largely of paired helical filaments with hyperphosphorylated tau proteins, neuronal and synaptic loss [1].

Currently and/or “only” approved treatments by US Food and Drug Administration (FDA), includes five drugs that are used to treat the cognitive manifestations of AD AChEIs–rivastigmine (Exelon), galantamine (Razadyne, Reminyl), tacrine (Cognex), and donepezil (Aricept) and NMDA receptor antagonist–memantine (Namenda) that target symptoms at its best [4]. Each drug acts in a different way to delay the breakdown of Ach (a chemical in the brain important for memory). AD is associated with inadequate levels of this important neurotransmitter. Tacrine (Cognex) is rarely prescribed due to its serious side effects (liver damage). In general, Reminyl, Exelon and Aricept are most effective when treatment is begun in the early stages. Memantine (Namenda) is the only drug shown to be effective for the later stages of the disease. They have all been shown to modestly slow the progression of cognitive symptoms and reduce problematic behaviors in some people, but at least half of the people who take these drugs do not respond to them. These present treatment strategies only delay the progression of symptoms associated with AD [5]. Much effort is being directed towards the discovery of disease-modifying therapies which can block the progression of the disease (i.e. clinical symptoms) and drugs targeting various molecular pathways. For development of disease modifying therapies complete knowledge about the various metabolic pathways is essential which includes production of Aβ from APP, in vivo clearance and pathophysiological events that leads to fibril formation and deposition into plaques [6]. The present article reviews the advance achieved recently in the field of pathogenesis of AD and also revealing possible new drug candidate targets. The most likely expected treatment strategies includes γ- and β-secretase inhibitors, Aβ vaccination, Cu–Zn chelators, cholesterol lowering drugs, statins and non-steroidal anti-inflammatory drugs (NSAIDs) [3].

In this review, we discuss the supporting mechanisms of AD pathogenesis and progression. We also summarize the existing therapeutic strategies till date in correlation with the pathophysiological mechanisms for AD.

Section snippets

Pathophysiology of AD

With pathophysiology of AD, debate goes back to the Alzheimer's time 1907 when he observed the neuropathological features of the disease i.e. amyloidal plaques and hyperphosphorylated NFTs. Several hypotheses have been put forward on the basis of the various causative factors in order to explain this multifactorial disorder [7] such as the cholinergic hypothesis, Aβ hypothesis, tau hypothesis and inflammation hypothesis [6]. Recently it has been shown that the most commonly used Aβ hypotheses,

Management of AD

The currently available treatment strategies include AChEIs and NMDA receptor antagonists [23]. In order to modify the disease process novel strategies have been developed. In this regard major developing is targeted to the Aβ and tau based therapeutics, which is a major key to unlock this disease in the near future [1], [6]. In this paper we highlight the currently approved treatment along with some disease modifying therapeutic drug targets.

Targeting Aβ protein (anti-amyloid approach)

The anti-amyloid therapeutics targets several aspects of APP metabolism [24].

Conclusion

In this paper we learn more detail about the pathophysiology and disease progression of AD and an insight into the potential therapeutic targets. Despite of the bulk of knowledge regarding this complex disease, only a fistful options are available for its management. Currently available drugs (AChEIs and memantine) for the treatment unfortunately target symptoms only and not the cause of the disease. So, the hope is now raised for the novel therapies that act at the root of the disease process

Conflict of interest

None declared.

Funding

Financial support from Rajiv Gandhi National Fellowship (RGNF) is gratefully acknowledged.

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