The Alzheimer’s disease (AD) has become one of the most critical social and medical problems facing older people around the world. There is no cure for the condition and sufferers have to rely on symptomatic treatments, which are designed to counterbalance the neurotransmitter disorder.
Medical practitioners currently rely on three cholinesterase inhibitors (CIs), which have been approved to treat either mild or moderate Alzheimer’s symptoms. People with severe conditions are often treated using a therapeutic drug known as memantine. This option is essentially an N-methyl-D-aspartate receptor noncompetitive antagonist.
Extensive research is still being conducted to develop disease-modifying drugs. These types of medications have the capacity to modify or halt the course of the disease. They achieve this purpose by interfering with the pathogenic steps, which trigger the clinical symptoms. Some of the steps include:
– The disposition of extracellular amyloid ß plaques
– Cholesterol metabolism
– Iron deregulation
– Intracellular neurofibrillary tangle formation
– Oxidative damage
Research studies have shown that the prevalence rate of dementia rises from 1 percent at the age of 60 to 35 percent by the age of 90. Alzheimer’s has been identified as the most prevalent subtype within the spectrum of dementias. The disease accounts for up to 60 percent of all dementia cases.
Clinically, Alzheimer’s is characterized by the progressive deterioration of cognitive abilities. This results in orientation and memory loss as well as language disturbances, apraxia and impaired judgment. These symptoms are usually accompanied by neuropsychiatric problems, such as depression, hallucinations, apathy, agitation and more.
The improvement in life expectancy is contributing to an increase in the number of patients with dementia, especially Alzheimer’s. This trend has led to the advancements in research studies aimed at the discovery of effective treatments for AD. Researchers are hoping to discover drugs for primary, secondary or tertiary prevention.
The early stages of AD affect the cholinergic system in the basal forebrain. As a result, patients experience memory loss due to the deterioration of enzymatic function and acetylcholine neurons. Researchers have proposed a specialized strategy aimed at enhancing the cholinergic transmission using cholinesterase inhibitors (CIs). This helps delay the deterioration of acetylcholine between the synaptic cleft.
Some of the cholinesterase inhibitors (CIs) that are currently approved by regulators include Galantamine by Janssen (Europe), Donepezil by Pfizer (North America) and Rivastigmine by Novartis (Europe). These medications are widely regarded as the first-line treatment for Alzheimer’s.
A number of clinical trials involving these drugs have been conducted with the aim to establish their effectiveness. All three cholinesterase inhibitors (CIs) showed significant benefits when it comes to global function, activities of daily living (ADL) and cognitive functions. The participants in the placebo-controlled trials had mild to moderate symptoms of Alzheimer’s disease.
Researchers did not observe a significant difference in the levels of efficacy between the three drugs. In addition, there were low incidences of gastrointestinal side effects with Donepezil when compared to Rivastigmine and Galantamine. Examples of the adverse effects, which were reportedly caused by higher therapeutic doses include diarrhea, nausea, abdominal cramp and vomiting.
The dermal form of Rivastigmine has been shown to provide comparable efficacy at a lower dose. The medication triggers fewer adverse effects.
On the downside, CIs have been linked to increased rates of pacemaker insertion, bradycardia and syncope. For this reason, patients are advised to carefully consider the risks against the benefits.
Healthcare practitioners prefer administering treatment in the early stages of Alzheimer’s. The preference is based on research findings that revealed that patients starting treatment late achieve lower cognitive performance outcomes when compared to those starting immediately after the diagnosis.
Patients who undergo 12 months of therapeutic treatment with Rivastigmine show preserved cognitive function. This is not the case with untreated patients whose condition deteriorated significantly in the same period.
Memantine is a moderate-affinity and uncompetitive N-methyl-D-aspartate (NMDA) antagonist used to treat mild to severe cases of Alzheimer’s. It has the capacity to protect neurons from excitotoxicity. Clinical studies have shown that patients improve in cognition, active daily life, global state and behaviors. The improvements were observed after 6 months of use.
Another system review also revealed that memantine is capable of reducing psychological and behavioral symptoms of dementia. Some of the side effects associated with the drug include confusion, dizziness and headaches. Some patients may show signs of agitation.
Combination therapy for Alzheimer’s Disease
The combined use of memantine and donepezil also showed considerable benefits during an RCT study involving a parallel group of participants. The benefits were observed in patients with moderate to severe Alzheimer’s but not in participants with mild to moderate AD.
Treatment of psychological and behavioral symptoms
The prevalence of psychological and behavioral symptoms of dementia or noncognitive neuropsychiatric symptoms is significantly high in clinical stages. These symptoms have been shown to increase caregiver burden and often lead to the institutionalization of patients. Behavioral and psychological symptoms of dementia (BPSD) can be categorized into four key clusters based on prevalence. These include:
– Apathy (65%)
– Hyperactivity (64%) disinhibition and aggression
– Affective symptoms (59%) depression and anxiety
– Psychosis (38%) delusions
Although memantine and cholinesterase inhibitors (CIs) provide an effective therapeutic treatment option for behavioral symptoms, they are not as effective when dealing with severe BPSD cases. As a result, additional drugs are required. When it comes to treating comorbid depression in AD dementia, serotonin reuptake inhibitors are more effective. These antidepressants include citalopram, fluvoxamine, sertraline, fluoxetine and paroxetine.
In addition, they may be considered for dealing with cases of agitation and psychosis in AD dementia. On the other hand, aggression or agitation and psychotic symptoms are generally treated using antipsychotics in patients with AD dementia. A number of atypical agents are used owing to their mild parkinsonian effects. The agents include aripiprazole, ziprasidone, quetiapine, olanzapine and risperidone.
However, the use of antipsychotics in patients with dementia is rather a controversial subject due to higher mortality and cerebrovascular morbidity. In some cases, the drugs have been linked to pneumonia and hip fracture in addition to the deterioration of cognitive impairment. Researchers have discovered that mortality can be prevented by reducing the length of time patients take the antipsychotics.
Healthcare practitioners use benzodiazepines to counteract anxiety and agitation. However, the medications are known to cause further agitation when prescribed to older patients. Studies discovered that there is a link between increased use of benzodiazepines and rapid functional and cognitive decline. The adverse effect has been observed in Alzheimer’s sufferers and older patients.
Anticonvulsant drugs, such as carvamazepine have the capacity to reduce behavioral and psychological symptoms of dementia (BPSD) in AD. Overall, it is widely accepted that drugs currently available to patients provide moderate benefits on both cognitive function and BPSD. For this reason, it is important to ensure early intervention as delays can lead to irreversible symptom progression.
The amyloid hypothesis
Amyloid plaques, neuronal loss and NFTs are the main histopathologic lesions associated with Alzheimer’s pathology. Mature plaques usually consist of a central amyloid core, which is surrounded by deteriorating neurons. The degeneration is exacerbated by the toxic effect of Aß. Meanwhile, NFTs come with a hyperphosphorylated tau protein that is characterized by a double helical filament conformation.
Amyloidogenic processing is the most preferred pathway of APP metabolism in neurons. This is largely due to the abundance of BACE1. On the other hand, the nonamyloidogenic pathway predominates in other cells.
The production of Aß in the brain triggers a number of events that contribute to the clinical syndrome of Alzheimer’s dementia. Aß is essentially a protein that comes in two forms: Aß40 and Aß42. The later is considerably more soluble and tends to aggregate into fibrils, which later form the major composite of amyloid plaques.
Aß42 is the major form in the brain parenchyma of people with Alzheimer’s whereas Aß40 is mainly found in the cerebral vasculature. Aß is known to cluster into oligomers that have the capacity to form Aß-fibrils as well as protofibrils. The formation of these fibrils leads to the appearance of amyloid plaques, which are widely regarded as nontoxic.
The formation of amyloid oligomers triggers neurotoxicity and the amyloid cascade. There is a number of elements associated with the cascade. These include tau hyperphosphorylation, oxidation, localinflammation and excitoxicity (excessive glutamate).
The developments eventually lead to the folding of tau proteins into intraneuronic tangles. This contributes to cell death. As a result, a wide variety of neurotransmitters, including serotonin, dopamine and acetylcholine face shortage and imbalance.
Findings of various research studies on Alzheimer’s disease pathogenesis are shaping the nature of novel treatments that are under development. The therapies are aimed at interfering with pathogenic steps in the early stages of the disease.
Disease-modifying approaches to Alzheimer’s disease
The highly insoluble and proteolysis-resistant fibrils formed by Aß are known as senile plaques (SPs). They contribute to Alzheimer’s pathogenesis. On another level, NFTs consist of tau protein, which is a component of microtubules in healthy subjects. Microtubules, on the other hand, form the internal support structures for the transport of chromosomes, vesicles, mitochondria as well as nutrients on a cellular level.
Microtubules also contribute to the stabilization of growing axons, which are required for the development and growth of neurons. In Alzheimer’s, tau protein forms insoluble fibrils and tends to be abnormally hyperphosphorylated. This leads to the accumulation of deposits within the cell.
Both tau and Aß are targeted by disease-modifying therapies in AD. For this reason, Alzheimer’s can be treated or prevented by lowering the production of Aß and tau. This approach achieves the objective by counteracting misfolding or aggregation of the proteins. Alternatively, it can remove or neutralize the toxic aggregate or misfolded protein elements.
Disease-modifying treatments: modulation of amyloid deposition
The synthetic glycosaminoglycan 3-amino-1-propaneosulfonic acid (3APS) is the only Aß aggregation inhibitor capable of reaching phase three. It can interfere with the binding process involving Aß and glycosaminoglycanes. Researchers concluded that 3APS is ready for commercialization as a branded nutraceutical.
However, further studies revealed that tramiprosate can contribute to the abnormal aggregation of the tau protein in neuronal cells. These findings highlighted the importance of conducting testing of potential AD medications on both amyloid and tau.
Researchers are also testing the colostrinin molecule, which is derived from sheep colostrum. This proline-rich polypeptide complex can inihibit neurotoxicityin cellular assays andAß aggregation.
It has been shown to improve cognitive performance in animal models. Initial trials showed modest improvements for patients with mild Alzheimer’s over a period of one year and three months. However, this positive outcome was not sustained during a period of additional treatment.
Another compound known as scyllo-inositol can provide a viable way to stabilize oligometric aggregates of Aß. Additionally, it is capable of inhibiting Aß toxicity in mouse hippocampus. However, clinical trials conducted in Canada recorded inconclusive efficacy results. Similar studies planned for the future will target earlier stages of Alzheimer’s.
Drugs that have been shown to interfere with metals copper (Cu) and (Zn) play an active role in the aggregation of Aß42. A significant number of Zn/Cu chelators inhibit Aß aggregation in animal and in vitro studies.
An 8-OH quinoline metal-protein-attenuating compound known as PBT2 has been cleared for further development. The approval is based on its favorable safety profile. Responses to treatment in a clinical trial revealed that the number of patients registering improvement is greater in the PBT2 250mg group than the PBT2 50mg placebo group. Hence, the need for larger-scale testing of this second-generation metal-protein-attenuating compound.
Treatment options for Alzheimer’s that are currently available (donepezil, galantamine, rivastigmine and memantine) are considered symptomatic. This means they cannot prevent or slow down the progression of the disease. Yet, these drugs provide modest benefit for functional, global status and cognition ability.
The majority of research studies focus on compounds targeting the Aß pathway. However, current therapies targeting this pathway have not demonstrated efficacy. Additional strategies are focused on evaluating the neuroprotective activity of disease-modifying drugs. This is being done with the help of biomarkers that predict disease progression.
Although medical science has not yet found a cure, those suffering from Alzheimer’s Disease now can benefit from the assistance of a home care aide. Life will not be perfect, but it will be better and more comfortable for both the Alzheimer’s suffer and her family by contacting a home care service. In Miami-Dade contact Miami Home Care Services at (305)749-0445
For Boca Raton and the cities of both Broward and Palm Beach Counties contact Boca Home Care Services at: (561) 989-0611