Approach To The Patient
Guidelines on the treatment of Alzheimer disease are available from a number of organizations , including one developed by the American Academy of Family Physicians, in conjunction with the American College of Physicians.15 All guidelines emphasize the importance of educating patients and their families about the disease process and its expected course. Early referral to local support groups is recommended, and medicolegal issues such as driving and end-of-life planning should be addressed. Recommendations regarding pharmacologic treatment are described in Table 2,21â23 and a suggested algorithm for the treatment of Alzheimer disease is presented in Figure 1. The decision to treat with medication should be shared with the patient and caregivers, including a discussion of the modest clinical benefit, adverse effects, and cost. Physicians should consider discontinuing therapy in patients who continue to decline despite maximal therapy.16 The National Institute on Aging and the Alzheimer’s Association have released recommendations on the diagnosis of dementia and mild cognitive impairment from Alzheimer disease however, these guidelines do not address the treatment of Alzheimer disease and do not recommend the clinical use of biomarkers.52,53
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Questions To Ask The Doctor If Drugs Are Prescribed
- What are the potential benefits of taking this drug?
- How long before improvement may be noticed?
- What action should be taken if a dose is missed?
- What are the known side effects?
- If there are side effects, should the drug be stopped?
- If the drug is stopped suddenly, what happens?
- What drugs might interact with the medication?
- How might this drug affect other medical conditions?
- Are there any changes that should be reported immediately?
- How often will a visit to the doctor who prescribed the drug be needed?
- Is the drug available at a subsidised rate?
Other Important Aetiological Mechanisms
Vascular disease
While traditionally it was felt that vascular disease was the underlying factor in the development of VaD, it is clear that vascular burden also plays a role in AD pathogenesis, and that there is significant overlap between these two dementia subtypes.12 Vascular risk factors, such as high BMI, smoking, hypercholesterolemia and hypertension, have been associated with an increased risk of developing clinical AD.13 While vascular lesions such as cerebral amyloid angiopathy and white matter hyperintensities are common in patients with AD,14 hypertension is also associated with the development of specific neuropathological hallmarks of AD such as NFTs,15 and this association appears to be stronger when hypertension is present in mid rather than late life.16 Thus, vascular disease may directly affect amyloid plaques or NFTs by increasing their formation or reducing their elimination from the brain.17
Given these findings, it would seem to follow that control of vascular risk factors may slow the rate of decline of cognition in patients with AD however, this is not yet supported by data from randomised controlled trials.18
Diabetes and hyperinsulinaemia
These findings have led to the theory that drugs used in diabetes may be able to modify the pathophysiology of AD25 and a study of intranasal insulin as a therapy in mild cognitive impairment and AD is currently being conducted after encouraging results from small pilot studies.26
Apolipoprotein gene
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What Are The Side Effects
The most common side-effects are feeling sick, loss of appetite, tiredness, diarrhoea, muscle cramps and sometimes poor sleep. These may be reduced or avoided by increasing the dose slowly, or taking the medicine after food.
The side-effects usually fade after a few weeks and will go away if the medicine is stopped. More information about side-effects can be obtained from your doctor or by reading the leaflet that comes with the tablets.
Treatment Of Alzheimer’s Disease
However, treatment of Alzheimer’s disease with either – or 2-adrenergic agonists has proven ineffective, and has even exacerbated pathology, suggesting that cognitive dysfunction cannot be wholly attributed to a loss of norepinephrine or adrenergic receptor activity (Riekkinen et al., 1999
G.Z. Feuerstein, … L.J. Rutkowski, in, 2007
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Amyloid Hypothesis Fails To Find Treatments
Scientists had been hopeful that amyloid which has been the primary focus of Alzheimers treatment research for the past three decades would be the key to solving Alzheimers. The plaque builds up around neurons the cells responsible for sending and receiving signals from the brain eventually leading to impaired memory and thinking in patients.
However, the recent controversy around Biogens aducanumab, allegations of falsified research and a series of failed clinical trials over the years targeting amyloid have left some in the field demoralized.
Most recently, pharmaceutical company Roche announced in June that its amyloid targeting drug, crenezumab, failed to slow or prevent cognitive decline in people with a rare genetic mutation that causes early-onset Alzheimers disease. The phase 3 trial, which the National Institute on Aging supported, enrolled around 250 people.
The amyloid hypothesis has been taking a lot of hits lately, said Donna Wilcock, the assistant dean of biomedicine at the University of Kentucky. The drug trials keep coming through and for the most part, failing.
Experts expect diagnosis and treatment of the disease may have to consider multiple mechanisms.
“Its an all-hands-on-deck kind of situation with research to try to identify better diagnosis and treatment options,” Ramanan said.
Drugs To Treat The Cognitive Symptoms Of Dementia
A number of drugs are currently available in Australia for use by people with dementia. These drugs fall into two categories, cholinergic treatments and Memantine.
Cholinergic
Cholinergic treatments offer some relief from the symptoms of Alzheimers disease for some people for a limited time. Drugs known as acetylcholinesterase inhibitors work by blocking the actions of an enzyme called acetylcholinesterase which destroys an important neurotransmitter for memory called acetylcholine.
Current cholinergic treatments are approved for use for people with mild to moderate Alzheimers disease. A number of the acetylcholinesterase inhibitors are available as subsidised medicines under the Australian Pharmaceutical Benefits Scheme.
People may receive these drugs at nominal cost if a physician or psychiatrist has found them to have a diagnosis of Alzheimers disease.
They must show improvement on a commonly used test of mental function in the first six months of treatment in order to receive further supplies of subsidised medication.
Memantine
Memantine targets a neurotransmitter called glutamate that is present in high levels when someone has Alzheimers disease. Memantine blocks glutamate and prevents too much calcium moving into the brain cells causing damage. It is the first in a new class of therapies and acts quite differently to the acetylcholinesterase inhibitors that are currently approved for treatment in Australia.
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Treatment For Moderate To Severe Alzheimers
A medication known as memantine, an N-methyl D-aspartate antagonist, is prescribed to treat moderate to severe Alzheimers disease. This drugs main effect is to decrease symptoms, which could enable some people to maintain certain daily functions a little longer than they would without the medication. For example, memantine may help a person in the later stages of the disease maintain his or her ability to use the bathroom independently for several more months, a benefit for both the person with Alzheimer’s and caregivers.
Memantine is believed to work by regulating glutamate, an important brain chemical. When produced in excessive amounts, glutamate may lead to brain cell death. Because NMDA antagonists work differently from cholinesterase inhibitors, the two types of drugs can be prescribed in combination.
The FDA has also approved donepezil, the rivastigmine patch, and a combination medication of memantine and donepezil for the treatment of moderate to severe Alzheimers.
| Drug Name | For More Information |
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| Aducanumab |
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Fighting Depression And Anxiety
Other drugs including antidepressants, anticonvulsants, antipsychotics, anti-anxiety drugs, and sleep aids are sometimes used to treat behavioral problems associated with Alzheimers disease.
When counseling, support groups, or other nondrug methods dont help with depression or anxiety, doctors may prescribe one of the following drugs:
Because of potentially dangerous side effects, doctors prescribe other drugs with extreme caution.
Insomnia can be a problem for some people with Alzheimers, but sleep aids such as zolpidem can cause confusion and lead to falls.
Antipsychotics like risperidone can increase the risk of death in some older people with dementia, so doctors prescribe them only as a last resort to alleviate severe hallucinations, paranoia, agitation, and aggression.
Benzodiazepines, such as diazepam , should also be generally avoided in patients with Alzheimers disease. There is also some research that shows a correlation between benzodiazepine use and an increased risk of being diagnosed with Alzheimers.
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Practical Dilemmas In The Use Of Acetylcholinesterase Inhibitors
The AChEI class of drugs all affect the measured domains of dementia in much the same way. The consistency of effect is evident from Fig. 1, which shows the cognition scores averaged from the pivotal trials of the three licensed compounds. This is a symptomatic response lasting approximately 8 months, followed by a decline that remains significantly above that of the placebo group for longer periods. This supports the preclinical cholinergic hypotheses . Exciting as this is, it is only symptomatic treatment at the end of a complex disease process analogous to the use of levodopa in Parkinson’s disease. The AChEI class continues to present practical and scientific challenges that clinicians need to have resolved meanwhile, different treatments continue in development.
Fig. 1 Combined clinical trial data for the three licensed acetylcholinesterase inhibitors: rivastigmine , donepezil and galantamine versus placebo . The graph shows the change in cognition scores for patients assessed at 6-week intervals . ADAS-Cog, Alzheimer’s Disease Assessment Scale Cognitive section.
What Medications Can Help
The FDA has approved the drug aducanumab-avwa as the first therapy that targets the fundamental pathophysiology of the disease by reducing amyloid beta plaques in the brain. It is not without controversy because of concerns it may cause swelling of bleeding in the brain.
Some drugs curb the breakdown of a chemical in the brain, called acetylcholine, thatâs important for memory and learning. They may slow down how fast symptoms get worse for about half of people who take them. The effect lasts for a limited time, on average 6 to 12 months. Common side effects are usually mild for these medications and include diarrhea, vomiting, nausea, fatigue, insomnia, loss of appetite, and weight loss. There are three drugs of this type: donepezil , galantamine , and rivastigmine .
Doctors can also prescribe medicines for other health problems that happen along with the disease, including depression, sleeplessness, and behavior problems like agitation and aggression.
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Exploratory Data Suggest The Drug’s Amyloid
byJudy George, Deputy Managing Editor, MedPage Today September 12, 2022
Baseline amyloid levels predicted amyloid plaque response with donanemab, an investigational drug targeting N-terminal pyroglutamate beta-amyloid in early Alzheimer’s disease, a post hoc review of phase II TRAILBLAZER-ALZ data found.
The rate of donanemab-induced amyloid reduction at 24 weeks was moderately correlated with the amount of baseline amyloid . On average, people with a greater baseline amyloid plaque level had greater amyloid plaque removal.
Clearing amyloid plaques with donanemab was associated with less clinical decline, but exploratory analyses indicated the benefit may emerge only in certain patients, reported John Sims, MD, and co-authors, all employees of drug developer Eli Lilly in Indianapolis, writing in JAMA Neurology.
A disease-progression model showed a significant association between the percentage of amyloid reduction and changes on the integrated Alzheimer Disease Rating Scale in people who carried an APOE4 risk allele, but not in others.
Modeling also suggested a hypothesis that amyloid plaques might remain below the amyloid-positivity threshold for about 4 years after discontinuing donanemab. No substantial treatment effect on global tau load emerged, but neocortical and regional standardized uptake value ratios showed donanemab slowed tau accumulation in a region-dependent manner.
Disclosures
Drugs In The Clinical
Some Alzheimers drugs under investigation include:
- JNJ-54861911 This drug blocks one of the enzymes that makes beta-amyloid. It is in phase 3 trials to see if it slows cognitive decline in people who have elevated levels of beta-amyloid in the brain but do not have Alzheimers symptoms. Results are expected in 2024.
- AADvac1 This is a vaccine that prompts the bodys immune system to go on the offense against an abnormal form of tau protein. A two-year phase 2 trial was completed and demonstrated safety and an immunogenic response against the abnormal tau protein in Alzheimers. Larger studies are needed to demonstrate clinical benefit.
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Fdas Accelerated Approval Program
Aducanumab was approved through the FDAs Accelerated Approval Program, which provides a path for earlier approval of drugs that treat certain serious conditions. This helps people living with the disease gain earlier access to the treatment. The approval of aducanumab was based on the ability of the drug to reduce amyloid in the brain. When using the accelerated approval pathway, drug companies are required to conduct additional studies to determine whether there is in fact clinical benefit after the drug is approved. If the follow-up trial fails to verify clinical benefit, the FDA may withdraw approval of the drug. Results of the phase 4 clinical trial for aducanumab are expected to be available by early 2030.
Alzheimer Disease And The Evolving Treatment Landscape
Supplements and Featured Publications
Overview of Alzheimer Disease and Pathophysiology
Alzheimer disease is an irreversible, progressive neurodegenerative disease that leads to issues with language, memory, the ability to care for oneself, geographical disorientation, and executive function or thinking skills that are required for daily activities. It is the leading cause of dementia among the aging population, accounting for 60% to 80% of dementia cases, and is the sixth leading cause of death in the United States.1-3 Not only does AD disrupt the regular lifestyle of an individual, it can also progress to a complete loss of independence, requiring all of the individuals needs to be met by caregivers, and oftentimes leads to institutionalization.3
Clinical Presentation of Alzheimer Disease
Changes in the brain may occur long before clinical symptoms are detected, making early diagnosis of AD particularly challenging. These changes in the brain anatomy lead to neuronal death and a progressive worsening of the symptoms of dementia: memory loss, cognitive decline, and eventually the inability to perform activities of daily living.3 AD progresses on a spectrum of 3 phases: preclinical, mild cognitive impairment, and then dementia, which is further stratified into mild, moderate, or severe stages. How quickly patients progress through the continuum varies and is influenced by factors including age, genetics, and sex.3
Burden of Alzheimer Disease
Current Treatment Options
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How Long Should Alzheimer’s Drugs Be Taken For
These drugs are usually prescribed for a trial period of 3 to 4 months to see if they show signs of helping.
There is no clear view as to how long they should be taken. If the condition progresses in spite of treatment, there may come a point when you and your doctor decide that there is little point in staying on them.
How Alzheimer’s Disease Is Treated
If you or someone you know has been diagnosed with Alzheimer’s disease, you may feel scared, frustrated, and more. While there is no cure for Alzheimer’s at this time, there are many ways to treat the symptoms and even help manage the disease’s progression.
Treatment options for the behavioral and psychological symptoms of Alzheimer’s include drug therapy and non-drug approaches, such as behavioral and environmental modifications.
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New Antibody Shows Therapeutic Effects In Mice With Alzheimer’s Disease
- Date:
- University of Texas Health Science Center at Houston
- Summary:
- A newly developed agonistic antibody reduced the amyloid pathology in mice with Alzheimer’s disease, signaling its promise as a potential treatment for the disease, according to a researchers.
A newly developed agonistic antibody reduced the amyloid pathology in mice with Alzheimer’s disease, signaling its promise as a potential treatment for the disease, according to a team of researchers at UTHealth Houston.
Research led by senior author Zhiqiang An, PhD, professor and Robert A. Welch Distinguished University Chair in Chemistry at McGovern Medical School at UTHealth Houston, found that a tetra-variable domain antibody targeting thetriggering receptor expressed on myeloid 2 — dubbed TREM2 TVD-lg — reduced amyloid burden, eased neuron damage, and alleviated cognitive decline in mice with Alzheimer’s disease. The study was published today in Science Translational Medicine.
“Antibody-based therapy is a viable drug modality for the treatment of Alzheimer’s disease,” said An, director of the Texas Therapeutics Institute with The Brown Foundation Institute of Molecular Medicine for the Prevention of Human Diseases . “One of the major areas of focus at the Texas Therapeutics Institute is developing technologies to deliver antibody-based therapies across the blood-brain barrier for potential treatment of the disease.”
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Conclusion And Future Perspectives
Some of the therapies that are being designed for a specific neurodegenerative disease may potentially be applied to others, such as the antioxidants for both AD and PD treatment. Thus, nanotechnologies to facilitate the efficacy of these therapies could also benefit from each other. However, some of the nanotherapeutic strategies are especially designed for a certain type of neurodegenerative disease based on their unique pathogenesis, such as the rHDL and its multifunctional derivate for AD treatment. As more and more details on pathogenesis of neurodegenerative disease are revealed by epidemiological findings, pathological observations, and genetic discoveries, new therapeutic targets will be brought to light and nanotechnology may have more chance to show its strength.
Samia Kausar, … Amin Badshah, in, 2019
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