Pathogenic Agents of Alzheimer’s Disease and Their Corresponding Pharmacotherapeutic Treatment Hypotheses

by | Apr 16, 2021 | Alzheimer's Disease, I. Issues, II. Roles, Medical Officers, Physical Therapy / Medicine and Rehabilitation, Prescribers | 0 comments

Alzheimer’s Disease (AD), the most common cause of dementia, is a progressive and fatal neurodegenerative disorder that primarily affects older adults. Though the definitive etiology of the disease is still to be uncovered, several characteristic features of the disease have been investigated. AD is characterized by the selective damage of brain regions responsible for cognition and memory. Clinically, patients with AD most commonly exhibit  insidiously progressive memory loss, to which other spheres of cognition are impaired over several years [1]. In addition to memory loss, patients may also experience language difficulties and loss of executive skills, symptoms that epitomize the generalized term “dementia”. In essence, AD interferes with memory, thinking, and behavior severely enough to affect a person’s work, hobbies, and social life; it is inexorably progressive and fatal within 5 to 10 years. In the damaged regions of an AD brain, the dysfunction and death of neurons is associated with cytoskeletal abnormalities and results in a reduction in the levels of synaptic proteins (proteins necessary for neuron function) in the regions of the brain in which these neurons terminate (the location at which the neural signal is transmitted) [2]. 

These pathological hallmarks are abnormal intraneuronal cytoskeletal changes, known as neurofibrillary tangles (NFTs), and extracellular protein deposits called amyloid plaques. NFTs are clusters of tau proteins that are commonly found in the brains of AD patients; this contributes to the symptoms of neurodegeneration by causing neuronal death when they interfere with intracellular transport through the microtubule transport system in the cells [3]. NFTs form when the tau protein is misfolded due to electrostatic interactions between the functionally significant domains of the protein and a negatively charged phosphate group that exists in AD individuals with genetic mutations [4]. Amyloid plaques are aggregated misfolded proteins that accumulate in the regions between nerve cells. This beta amyloid is a protein fragment cleaved post-translationally from a larger amyloid precursor protein (APP); these fragments are usually broken down and eliminated from nerve cells. In AD patients, amyloid plaques are hard, insoluble accumulations of beta amyloid proteins that clump together between the nerve cells. The presence of plaques around a neuron causes it to die by triggering inflammation via an immune response, using the immune system’s macrophages to ingest the neuron via phagocytosis or engulfment [5]. 

Other risk factors of AD are hypercholesterolemia, hypertension, and disturbances in glucose metabolism via signal transduction using the insulin receptor. Hypercholesterolemia accelerates intraneuronal accumulation beta amyloid composites (and subsequent synapse loss, resulting in memory impairment) seeing as cholesterol acts as a modulator for the cleavage and clearance process of APP; excess cholesterol has been implicated in the aberrant cleavage and aggregation of the beta amyloid plaques [6]. Moreover, hypertension can worsen the brain’s ability to cope with increased beta amyloid deposits and NFTs; a lack of proper blood flow to the brain can result in the brain being less fit to work around the damaged tissue, lessening its adaptability to the accumulation of AD damages. AD symptom progression is also mediated by glucose metabolism. The brain is the organ with the highest basal rate of glucose consumption; most of the energy generated by the oxidation of glucose is used for the work necessary to maintain the ionic balances associated with synaptic transmission between neurons [7]. Patients with AD suffer from significantly reduced glucose metabolism in fronto-temporo-parietal and cingulate cortices (part of the limbic system involved with memory) as  a result of genetic variation in the DNA that is responsible for bioenergetics [8]. 

These pathological causes of AD are an important avenue of research when examining the potential drug treatments. Many current options focus on the palliative treatment of AD, where the symptoms of the underlying disease are treated, rather than the causes of the diseases itself. This in the past has been difficult due to limited knowledge and understanding of the etiological nature of AD. Recently, advances in our knowledge of the pathogenesis of disease and an increase in the disease burden in the population have prompted investigation into innovative therapeutics over the last two decades, most of which attempt to tackle the source of AD as opposed to its symptomatic manifestations [9]. However, as of today there has been no clinical success in this avenue.

Despite the significant public health issue that it poses, only four medical treatments have been approved for Alzheimer’s disease (AD), and these act to control symptoms rather than alter the course of the disease. Currently available treatments for AD (donepezil, rivastigmine, galantamine and memantine) are symptomatic and do not decelerate or prevent the progression of the disease [10]. Several overlapping mechanisms have been proposed to explain the underlying pathology of AD, and both current and potential future treatments are based on modification of these pathways. These proposed pathways that pharmaceutical companies are most actively investigating for therapeutic targets include: the “Amyloid Cascade” hypothesis, the “Tau” hypothesis, the “Cholinergic” hypothesis, and the “Excitotoxicity” hypothesis [11,12].

The amyloid hypothesis of AD began to gain traction in the 1990s, and centers on abnormal processing of the amyloid precursor protein (APP) that leads to production of beta amyloid deposits [13]. Proteolytic (protein-cleaving) secretase enzymes that cleave APP and the aberrancy of this process can lead to the abnormal aggregation into amyloid plaques. This can then trigger a cascade leading to synaptic damage and neuron loss [14]. Several clinical trials of pharmacological agents targeted at modifying this amyloid cascade have been undertaken; these agents generally had three different target sites: directly targeting the beta amyloid fragments, the gamma-secretase enzyme, or beta-secretase enzyme (both of which are involved in APP cleavage) [15]. Small molecule beta-secretase inhibitors, that enter cells easily and bind to the enzyme and inhibit its activity, have demonstrated reduced beta-amyloid compared to controls. Phase II/III clinical trials of two agents, AZD3293 and MK-8931, are underway as of now [16]. Phase III clinical trials of semagacestat, a small molecule gamma-secretase inhibitor, were discontinued in 2010 because of no improvement in cognition in the study group and worsening cognition at higher doses compared to controls; it was also associated with skin cancer in high incidence of the study group [17]. Tarenflurbil, which is related to the NSAID flurbiprofen, had been shown to reduce levels of beta amyloid deposits by modulating the gamma-secretase enzyme, but demonstrated no improvement in cognition or function compared with placebo in phase III trials [18]. An attempt was made to immunize AD patients against beta amyloid, which would allow the cell to expel fragments and reduce deposit severity. However, the initial human clinical trial of active immunisation against Aβ with the agent AN 1792 was stopped because of cases of meningoencephalitis in 6% of subjects [19]. This effort was made again with Bapineuzumab, using monoclonal antibodies (lab-made antibody mimic proteins) in 2007 to 2012 to reduce the rate of amyloid accumulation. However, Bapineuzumab did not demonstrate any treatment effect on either cognitive or functional outcomes despite engaging its target [20].

Tau is a protein expressed in neurons that normally functions in the stabilisation of microtubules in the cell cytoskeleton. Hyperphosphorylation (adding extra phosphate groups to the protein after it is translated from mRNA) causes it to accumulate into these NFT masses inside nerve cell bodies [21]. Both lithium and valproic acid may act to inhibit tau phosphorylation (and thus the misfolding of the tau protein), but randomised controlled trials of these agents were negative. More recently, a phase II clinical trial of methylthioninium, a tau aggregation inhibitor, has demonstrated minor benefits in cognition in patients with both mild and moderate AD after 50 weeks therapy, but there are plans to proceed to phase III trials [22].

An initial breakthrough in AD came in the 1970s with the demonstration of a cholinergic (acetylcholine neurotransmitter) deficit in the brains of patients with AD, mediated by deficits in the enzyme choline acetyltransferase [23]. This, along with the recognition of the role of acetylcholine in memory and learning, led to the cholinergic hypothesis of AD and stimulated attempts to therapeutically increase cholinergic activity. Cholinesterase inhibitors block the cholinesterase enzyme, which breaks down acetylcholine at the synaptic cleft (the space between the two neurons-the one transmitting the signal and the one receiving the signal). This inhibition allows the acetylcholine to remain at the cleft instead of being prematurely and excessively broken down. Tacrine was the first-generation cholinesterase inhibitor but was limited by hepatotoxic (liver toxicity) side effects [23]; Donepezil, rivastigmine and galantamine then followed. These all passed FDA clinical trials and gained approval as a common treatment for AD patients.

Excitotoxicity, defined as overexposure to the neurotransmitter glutamate, or overstimulation of its N-methyl-D-aspartate (NMDA) receptor, plays an important role in the progressive neuronal loss of AD [24]. Memantine uncompetitively blocks the NMDA receptor and, thus, may be neuroprotective by preventing neuron loss, as well as improving symptoms by helping to restore function of damaged neurons. Memantine has been shown to have modest benefits in moderate to severe AD, with little evidence supporting its use in milder AD. Additionally, the addition of memantine to donepezil monotherapy may be beneficial in those with mid-stage AD or who are deteriorating cognitively [25].

Given the rising prevalence of dementia, and the relative inadequacy of current available pharmacological treatments, the need to develop and implement new therapies is pressing. Recent results from trials of agents in AD with potential disease-modifying effects are encouraging but must also be interpreted with caution. Such medicines could potentially delay the onset of dementia and would therefore markedly reduce its prevalence and impact; however, currently we remain a good distance away from clinically available disease-modifying therapy. In addition, while focus on the development of new therapies is on the rise, we must also be mindful that dementia is a multifaceted, complex disease, which by its nature directs a need for a multidisciplinary approach to care [1]. Our focus in managing patients with dementia must remain well rounded and holistic, concentrating not just on pharmacological therapy but also on the complex biopsychosocial aspects of caring for this group of patients.

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