Pharmacotherapy of Alzheimer’s disease: current and future trends

Abstract

Alzheimer’s disease (AD) and its related dementia has shown an alarming rise in the global population. Although considerable efforts have been made to develop effective therapeutic agents for AD therapy, drug development has not met significant clinical success. Current pharmacotherapy of AD is limited to cholinesterase inhibitors and the N-methyl-D-aspartate antagonist memantine. Considerable research is underway to develop newer agents for the management of AD. Since amyloid-β (Aβ) has been implicated in AD pathogenesis, the use of β secretase inhibitors as well as immunotherapy against Aβ has been investigated. A considerable effort has been spent investigating the therapeutic potential of antioxidants and anti-inflammatory agents, several of natural products and dietary origin, in AD treatment. Numerous drug targets have also been investigated for AD treatment and a modest drug pipeline is available. Despite these efforts, drug development for AD has proved extremely difficult and most clinical trials have afforded disappointing results.

Keywords:

• Alzheimer’s disease
• anti-inflammatory agents
• antioxidants
• cholinesterase inhibitors
• dementia
• immunotherapy
• memantine
• multi-targeted drugs
• natural products
• pharmacotherapy

Alzheimer’s disease (AD) and its associated cognitive decline has shown an alarming rise due to an increasing aging global population. Current estimates demonstrate that there are over 40 million people suffering from AD dementia with the number expected to rise to over 100 million by the year 2050 [1]. In the past two decades there has been considerable effort, utilizing both pre-clinical and clinical paradigms, to understand the etiology and pathophysiology of AD, with the goal of producing effective therapeutic options. The key hallmark of AD pathogenesis is the accumulation of neuritic plaques formed of amyloid-β (Aβ) peptide, derived from amyloid precursor protein (APP) as well as neurofibrillary tangles made up of hyperphosphorylated protein [2]. Besides the aforementioned AD cascade hypothesis, various factors such as oxidative stress, inflammation, metal ion accumulation, protein misfolding, neurotransmitter dyshomeostasis and gene mutation have been implicated in AD pathophysiology [3]. Despite the tremendous development in our understanding of AD pathogenesis, drug development, especially in the clinical arena, has proven difficult and disappointing. In this article, we summarize the current status of AD pharmacotherapy and review the development of potential therapeutic agents for AD.

The cholinergic hypothesis states that AD patients show cognitive dysfunction due to extensive cholinergic cell loss and its associated inability to transmit neurologic impulses across cholinergic synapses [4]. This led to the development and approval of four cholinesterase inhibitors (tacrine, donepezil, rivastigmine, galantamine). Also approved is an N-methyl-D-aspartate antagonist (memantine). Although these drugs have been shown to slow the decline in disease progression they have not been shown to cure AD dementia [5,6]. Current research has focused on development of therapeutic agents targeting the causal pathological mechanisms of AD.

Due to the critical role of the amyloid hypothesis, interference of Aβ production as well as its clearance of existing amyloid plaques remain attractive targets in drug development. Also under development are therapies aimed at preventing binding and subsequent neurofibrillary tangles formation [7]. The enzyme β secretase, referred to as β-site APP cleaving enzyme 1 (BACE1) initiates Aβ production by cleaving the APP extracellular domain. Thus the therapeutic potential of BACE1 inhibitors, such as MK-8931, in lowering Aβ burden is being investigated. These class of agents are currently under clinical investigation although several questions regarding safety, side effects and the stage of disease at which these drugs should be administered remain [8]. The use of immunotherapy in targeting both Aβ and τ has been investigated for the development of therapeutic tools for AD. Active immunization using the full length 1–42 Aβ peptide has been under clinical investigation. Passive immunization utilizing monoclonal antibodies raised against Aβ, such as bapineuzumab, solanezumab, gantenerumab and crenezumab, are being investigated in Phase III clinical trials. TRx0237, a derivative of methylene blue, which has been reported to inhibit τ aggregation is also under clinical study. So far Aβ immunotherapy has not shown any clinical benefits in AD patients [7,9,10].

Both oxidative stress and inflammation have been implicated in AD pathogenesis and so consequently antioxidants as well as anti-inflammatory agents have been investigated for AD pharmacotherapy. Multiple markers of oxidative stress have been shown to be increased in AD with lowered antioxidant power in the brain, cerebrospinal fluid and blood of AD patients. The therapeutic potential of antioxidants such as vitamin C, vitamin E, coenzyme Q10, α-lipoic acid, omega-3 fatty acids and selenium have been evaluated in clinical trials with disappointing results. Neuroinflammation has been known for several decades to be involved in the pathogenesis of neurodegenerative diseases. Clinical studies evaluating the effects of NSAIDs, such as diclofenac, naproxen and rofecoxib, however, failed to produce any therapeutic benefit supposedly due to treatment timing, dosing and agent selection [11–13].

Natural products, several with potent antioxidant and anti-inflammatory properties, have been a subject of serious investigation for AD treatment [14]. Besides the aforementioned vitamins and other dietary antioxidants, a range of nutraceuticals have been evaluated. Dietary polyphenols, such as resveratrol, curcumin and tea catechins, have shown therapeutic promise in pre-clinical AD models [15]. Phytoestrogens have also shown considerable promise in improving cognitive decline in AD patients [16]. Ginkgo biloba has been a subject of intense investigation, both pre-clinical and clinical, to evaluate its therapeutic potential. A meta-analyses of clinical trials shows that Ginkgo may possibly slow the cognitive decline in AD patients, however, the overall results remain inconclusive [17].

Along with the aforementioned therapeutic agents mentioned, a multitude of targets have been investigated for their potential in AD therapy. Drugs interacting with receptors, enzymes, ion channels, nerve growth factors, re-uptake transporters, metal chelators have been proposed as agents to improve cognitive decline in AD patients. Some of the receptors for which drugs are investigated are muscarinic and nicotinic acetylcholine receptors, adenosine receptors, cannabinoid receptors, estrogen receptors, opioid receptors, receptor for advanced glycation end products, serotonin receptors (5-HT_1A, 5-HT₂, 5-HT₃, 5-HT₄, 5-HT₆) as well as sigma receptors. Besides drugs interacting with acetyl and butyryl cholinesterase enzymes, agents interacting with a wide variety of enzymes such as α-secretase, β-secretase, γ-secretase, caspases, cyclooxygenase, glycogen synthase kinase-3β, 3-hydroxy-3-methylglutaryl-coenzyme A reductase, phosphodiesterases, protein kinase C and transglutaminase besides several others. Froestl and colleagues have provided an extensive list of therapeutic targets for AD drug development [18,19].

Considering the multitude of therapeutic targets proposed for AD pharmacotherapy, a modern approach has been the development of multi-target-directed-ligands (MTDLs). It has been suggested that the multifactorial nature of AD pathogenesis requires the design of MTDLs with a wide spectrum of activity. Dual and multi-acting anti-AD drug candidates are obtained by linking structurally active moieties which interact with discreet targets. A major group of compounds designed as MTDLs are cholinesterase inhibitors with additional properties such as antioxidant activity, metal complexing property, calcium channel antagonistic activity, anti-glutamate-induced excitotoxicity as well as BACE1 inhibitory activity besides several others. A novel class of compounds combining BACE1 inhibition with metal chelating properties has also been developed. This strategy provides for a strong pipeline of novel compounds leading to potent and promising leads as potential AD therapeutic agents [3,20].

It becomes evident from the article that there is no dearth of targets for AD drug development. A significant amount of research effort has been taken to develop a significant number of compounds with potential for providing therapeutic benefits in AD. Nevertheless, drug development for AD has proven to be extremely difficult with clinical studies providing disappointing results. Thus besides the cholinesterase inhibitors and memantine there is no other approved treatment for AD. Although clinical investigation for the development of AD drugs is routinely carried out, the success rate to move from one phase to another is extremely low when compared to other therapeutic areas.

In summary, although AD drug development has met tremendous success in the pre-clinical arena it has failed to prove beneficial during its clinical investigations. Thus there exists a critical need to repair this anomaly. One key to bridging this translational gap is the development of better pre-clinical animal models which would be a more robust predictor of clinical success. Also critical is the development of well-designed clinical trials which include optimum dosing strategies, especially for compounds of natural origin, and the stage of the disease process during which the trial is conducted. Considering the fact that currently the pipeline for agents with potential use in AD treatment is relatively modest it is most important that efforts be made to enhance this pipeline. AD drug development remains dependent on a complex interplay of a multitude of organizations such as pharmaceutical companies, federal funding agencies, biotechnology ventures and clinical trial companies besides several others. Considerable effort and coordination would be required to significantly improve and enhance the results in AD clinical trials and the development of much needed therapeutic agents for AD. Also important is the need for development of better nutritional and dietary strategies, especially consumption of antioxidant rich food such as fruits, vegetables and fish, in the aging population which may lead to a lowered risk of AD along with providing a better therapeutic outcome of currently used drugs in AD patients.

Financial & competing interests disclosure

The authors have no relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties.

No writing assistance was utilized in the production of this manuscript.