Therapeutics of Alzheimer's disease: Past, present and future

Highlights

• The pathophysiology of Alzheimer's disease is complex.

• Only symptomatic management is currently offered.

• Numerous disease modifying approaches are currently being tried.

• The various novel therapeutic strategies have been reviewed here.

Abstract

Alzheimer's disease (AD) is the most common cause of dementia worldwide. The etiology is multifactorial, and pathophysiology of the disease is complex. Data indicate an exponential rise in the number of cases of AD, emphasizing the need for developing an effective treatment. AD also imposes tremendous emotional and financial burden to the patient's family and community. The disease has been studied over a century, but acetylcholinesterase inhibitors and memantine are the only drugs currently approved for its management. These drugs provide symptomatic improvement alone but do less to modify the disease process. The extensive insight into the molecular and cellular pathomechanism in AD over the past few decades has provided us significant progress in the understanding of the disease. A number of novel strategies that seek to modify the disease process have been developed. The major developments in this direction are the amyloid and tau based therapeutics, which could hold the key to treatment of AD in the near future. Several putative drugs have been thoroughly investigated in preclinical studies, but many of them have failed to produce results in the clinical scenario; therefore it is only prudent that lessons be learnt from the past mistakes. The current rationales and targets evaluated for therapeutic benefit in AD are reviewed in this article.

This article is part of the Special Issue entitled ‘The Synaptic Basis of Neurodegenerative Disorders’.

Introduction

Alzheimer's disease (AD) is the most common cause of dementia, and with a new case occurring every seven seconds globally, the disease itself is becoming a slow pandemic (Ferri et al., 2005). One person for every 85 individuals can be expected to suffer from AD by the year 2050 (Brookmeyer et al., 2007). AD also imposes tremendous emotional and financial burden to the patient's family and community through the provision of care and loss of wages. The disease maybe classified based on the age of onset into early-onset AD and late-onset AD. Early onset AD accounts for approximately 1%–6% of all cases and manifests roughly between 30 and 60 years. Late onset form accounting for around 90% of cases has an age at onset later than 60 years. Etiology of AD is multifactorial with genetic, environmental, behavioral and developmental components playing a role. The greatest risk factor is advancing age; others being a positive family history, head trauma, female gender, previous depression, diabetes mellitus, hyperlipidemia and vascular factors (Kivipelto et al., 2001). The understanding of the pathophysiology of AD is constantly changing; for instance the tangles, a well known pathological hallmark of AD, earlier thought to be responsible for the disease now rather seem to reflect the damage which the neurons have endured over a long time. The notion that amyloid beta peptide (Aβ) and phosphorylated tau are pathologic molecules is slowly changing, and it seems that they represent a cellular adaptive strategy to oxidative stress. Apart from them, various deranged mechanisms such as chronic oxidative stress, mitochondrial dysfunction, Aβ production, neurofibrillary tangles accumulation, hormone imbalance, inflammation, mitotic dysfunction, calcium mishandling, and genetic components play a role in the disease process. Although the mechanisms are diverse, neuronal death, the inevitable event occurs resulting in AD.