Plasma Biomarkers Of Ad
Other approaches using genomics, transcriptomics, metabolomics, lipidomics, and proteomics have been used to generate different AD biomarkers. One study showed that altered microRNAs resulting from the failure of synaptic function are potential plasma biomarkers of AD.5959. Siedlecki-Wullich D, Català-Solsona J, Fábregas C, Hernández I, Clarimon J, Lleó A, et al. Altered microRNAs related to synaptic function as potential plasma biomarkers for Alzheimer’s disease. Alzheimers Res Ther. 2019 11:46. Another study comparing AD patients with healthy controls showed decreased platelet levels of one member of the a disintegrin and metalloproteinase family: ADAM10, the primary -secretase of APP, which plays an important role in reducing generation of A peptide. The same study showed decreased presenilin levels in platelets and leukocytes. Presenilin is the catalytic site of -secretase, one enzyme in the reaction that generates A peptide. Levels of the -site APP-cleaving enzyme 1 , also known as -secretase, were also decreased in leukocytes and presented no differences in platelets.6060. Bram JM, Talib LL, Joaquim HP, Sarno TA, Gattaz WF, Forlenza OV. Protein levels of ADAM10, BACE1, and PSEN1 in platelets and leukocytes of Alzheimer’s disease patients. Eur Arch Psychiatry Clin Neurosci. 2019 269:963-72.
Currently Studied Dmts For Ad
The crucial step in AD pathogenesis is the production of amyloid , which forms SPs . The A derives from a protein overexpressed in AD, APP through sequential proteolysis by -secretase in the extracellular domain and -secretase in the transmembrane region. Full-length APP is first cleaved by -secretase or -secretase. The APP cleavage by -secretase leads to nonamyloidogenic pathway, whereas APP cleavage by -secretase leads to amyloidogenic pathway. Sequential cleavage of APP by BACE1 in the extracellular and -secretase in the transmembrane area results in the A production. Major sites of -secretase cleavage usually occur in positions 40 and 42 of A, thus A40 and A42 oligomers are the main products of the sequential APP cleavage, as the amyloidogenic pathway is favored in neurons because of the greater plentifulness of BACE1. On the contrary, the nonamyloidogenic processing is more favored in other cells without BACE1 predominance.
Consequently, anti-amyloid DMTs have focused on 3 major MOAs: reduction of A42 production , reduction of A-plaque burden , and promotion of A clearance .
Reduction of A42 production
Two BACE inhibitors are still elaborated: elenbecestat in phase 2 and umibecestat in phase 3. The later agent is studied in asymptomatic individuals at risk of developing AD .
Reduction of A-plaque burden
Promotion of A clearance
Treatment And Drug Options For Alzheimer’s Disease
- Some medications help control or delay symptoms for a time, particularly in the early stages of the disease.
- Other drug treatments can help manage mental or emotional health symptoms like depression or agitation.
- Behavioral or environmental strategiesactions that can help reduce stress in a patients daily activities, for examplemay reduce anxiety and manage conditions without medical intervention.
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Neurodegenerative Pathways Implicated In Ad
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
Aetiology of Alzheimer’s disease with therapeutic targets. A secretase enzyme inhibitors B NMDA receptor modulators, eg memantine C immunotherapy, including immunisation and direct anti-amyloid therapy, including monoclonal antibodies D anti-tau therapy E anti-inflammatory treatments, including NSAIDs F anticholinesterase inhibitors, eg donepezil. APP = amyloid precursor protein NFTs = neurofibrillary tangles NMDA = N-methyl-D-aspartate NSAIDs = non-steroidal anti-inflammatory drugs.
How Is Alzheimer’s Disease Treated
Alzheimers disease is complex, and it is therefore unlikely that any one drug or other intervention will ever successfully treat it in all people living with the disease. Still, in recent years, scientists have made tremendous progress in better understanding Alzheimers and in developing and testing new treatments, including several medications that are in late-stage clinical trials.
Several prescription drugs are already approved by the U.S. Food and Drug Administration to help manage symptoms in people with Alzheimers disease. And, on June 7, 2021, FDA provided accelerated approval for the newest medication, aducanumab, which helps to reduce amyloid deposits in the brain and may help slow the progression of Alzheimers, although it has not yet been shown to affect clinical symptoms or outcomes, such as progression of cognitive decline or dementia.
Most medicines work best for people in the early or middle stages of Alzheimers. However, it is important to understand that none of the medications available at this time will cure Alzheimers.
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Behavioural Therapy For Dementia
Behavioural therapy works to understand the source of the behaviour, and then suggest alternative strategies to address the underlying cause.
For example, a person with dementia may have a history of wandering out of their home because they feel restless. Therefore, encouraging such people to find another outlet for their restlessness, such as regular physical activity, might address the problematic behaviour.
Behavioural therapy is not a solution to the many behavioural problems associated with dementia , but it is a useful tool in lessening their impact. Behavioural therapy is supervised by a healthcare professional, but can often be given by a trained friend or relative, usually the main family carer.
As in all treatments for any disease, everyone is different and reacts differently results can vary by day or even parts of days. It is, therefore, important to keep checking in with the medical team if you notice any changes in your parents behaviour. It may be possible to change the dementia drugs or try a new dementia therapy to support their condition as it progresses.
To help make sure you know what to look out for, weve put together a list of the most common early signs of dementia, which you can take a look at in more detail. You can also download our free guide to dementia for information on diagnosis, legal considerations and support available.
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Medication For Other Forms Of Dementia
Unfortunately the medications for other forms of Dementia are minimal. Cholinesterase inhibitors may be offered to patients with dementia with Lewy bodies or Parkinsons disease dementia if they have particular symptoms such as hallucinations or challenging agitation or aggression. There are no firm scientific conclusions as to the efficacy of Memantine for either of these forms of dementia.
There are very small studies around the effectiveness of either inhibitors or Memantine for those with vascular dementia, mixed dementia or frontal temporal dementia including Picks disease.
Other Treatments available:
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How Cholinesterase Inhibitors Work
In Alzheimers disease, nerve cells become damaged and lose their ability to communicate. Cholinesterase inhibitors work by increasing the amount of a chemical called acetylcholine, that helps messages to travel around the brain. These messages are vital to the way we move, think and remember. Cholinesterase inhibitors can reduce the symptoms of Alzheimers for a time.
These treatments are normally given as tablets or capsules, but they are available in a liquid form too. Donepezil is also available as a tablet that dissolves on the tongue, and Rivastigmine is available in patches, where the drug is absorbed through the skin. Your doctor will discuss the most suitable form for you.
Biomarkers Of Tau Pathology And Neuronal Degeneration
MRI and FDG-PET are well-established imaging techniques for AD diagnosis and follow-up. FDG-PET measures glucose uptake in neurons and glial cells and is sensitive to synaptic dysfunction. The typical pattern of altered FDG-PET in AD is a temporoparietal and posterior cingulate hypometabolism.5050. Scheltens P, Blennow K, Breteler MM, de Strooper B, Frisoni GB, Salloway S, et al. Alzheimer’s disease. Lancet. 2016 388:505-17. Changes in MRI are seen later in the disease process. Cerebral atrophy is believed to spread from within the mesial temporal lobe , with changes in hippocampal volume and entorhinal cortex thickness, to the parietal, occipital, and frontal lobes over the years individuals with MCI show the highest rates of atrophy.4343. Counts SE, Ikonomovic MD, Mercado N, Vega IE, Mufson EJ. Biomarkers for the early detection and progression of Alzheimer’s disease. Neurotherapeutics. 2017 14:35-53.
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Who Are These Medications For And What Are The Benefits
These medications are prescribed for people with mild to moderate Alzheimers disease. Studies show that between 40 70% of people taking the drugs benefit from them with symptoms improving temporarily for between 6-12 months.
The impact of taking cholinesterase inhibitor medications can include: reduced anxiety, improvements in memory and concentration daily activities such as personal care, dressing and shopping.
Trials to determine if these drugs also bring benefits for behavioural changes such as agitation or aggression are inconclusive, with mixed results. Unfortunately the impact of these medications gradually reduces with symptoms then gradually worsening.
Medicines To Treat Related Conditions
There are some conditions, such as heart problems, that can affect symptoms of dementia, particularly vascular dementia. It’s important that these are diagnosed and treated.
These conditions include:
These changes in behaviour can be very distressing, both for the person with dementia and for the person caring for them. However, there are coping strategies that can help.
If coping strategies do not work, antipsychotic medicines such as risperidone or haloperidol may be prescribed for those showing persistent aggression or extreme distress.
These are the only medicines licensed for people with moderate to severe Alzheimer’s disease and vascular dementia where there’s a risk of harm to themselves or others.
Risperidone should be used at the lowest dose and for the shortest time possible as it has serious side effects. Haloperidol can be used only if other treatments have not helped.
The decision to prescribe a medicine should be taken by a consultant psychiatrist.
Antidepressants may sometimes be given if depression is suspected as an underlying cause of anxiety.
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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
Treatment Of Alzheimer Disease
BRADFORD T. WINSLOW, MD, Swedish Family Medicine Residency, Littleton, Colorado
CHRISTIAN M. STOB, DO, Denver Health Medical Center, Denver, Colorado
KATHLEEN A. HAZLEWOOD, PharmD, University of Wyoming School of Pharmacy, Laramie, Wyoming
Am Fam Physician. 2011 Jun 15 83:1403-1412.
Patient information: See related handout on Alzheimer disease, written by the authors of this article.
SORT: KEY RECOMMENDATIONS FOR PRACTICE
Acetylcholinesterase inhibitors are modestly effective in patients with mild to moderate Alzheimer disease, although limited by their adverse effects.
|Clinical recommendation||Evidence rating||References|
Combination therapy with an acetylcholinesterase inhibitor and memantine should be considered in patients with moderate to severe Alzheimer disease.
Atypical antipsychotic agents can improve some behavioral manifestations of Alzheimer disease but are associated with increased mortality in older patients.
Nonsteroidal anti-inflammatory drugs, vitamin E, testosterone, estrogen, statins, and insulin sensitizers are not recommended for the treatment of Alzheimer disease.
Physicians should consider discontinuing treatment for Alzheimer disease in patients who continue to decline despite maximal therapy.
SORT: KEY RECOMMENDATIONS FOR PRACTICE
Acetylcholinesterase inhibitors are modestly effective in patients with mild to moderate Alzheimer disease, although limited by their adverse effects.
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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|
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.
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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.
Mental Activity To Support Cognition
Many patients with normal cognition or those with mild impairment are concerned that they may develop AD. Many experts believe that mentally challenging activities, such as doing crossword puzzles and brainteasers, may reduce the risk in such patients. Whether such activities might slow the rate of disease progression in patients who already have AD is not known. Clinical trials are under way to determine the effect these cognitive activities have on AD progression.
Mental activities should be kept within a reasonable level of difficulty. Activities should preferably be interactive, and they should be designed to allow the patient to recognize and correct mistakes. Most important, these activities should be administered in a manner that does not cause excessive frustration and that ideally motivates the patient to engage in them frequently. Unfortunately, little standardization or rigorous testing has been done to validate this treatment modality.
Some investigators have attempted various forms of cognitive retraining, also known as cognitive rehabilitation. The results of this approach remain controversial, and a broad experimental study needs to be performed to determine whether it is useful in AD.
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Treatment For Mild To Moderate Alzheimers
Treating the symptoms of Alzheimers can provide people with comfort, dignity, and independence for a longer period of time and can encourage and assist their caregivers as well. Galantamine, rivastigmine, and donepezil are cholinesterase inhibitors that are prescribed for mild to moderate Alzheimers symptoms. These drugs may help reduce or control some cognitive and behavioral symptoms.
Scientists do not yet fully understand how cholinesterase inhibitors work to treat Alzheimers disease, but research indicates that they prevent the breakdown of acetylcholine, a brain chemical believed to be important for memory and thinking. As Alzheimers progresses, the brain produces less and less acetylcholine, so these medicines may eventually lose their effect. Because cholinesterase inhibitors work in a similar way, switching from one to another may not produce significantly different results, but a person living with Alzheimers may respond better to one drug versus another.
Before prescribing aducanumab, doctors may require PET scans or an analysis of cerebrospinal fluid to evaluate whether amyloid deposits are present in the brain. This can help doctors make an accurate diagnosis of Alzheimers before prescribing the medication. Once a person is on aducanumab, their doctor or specialist may require routine MRIs to monitor for side effects such as brain swelling or bleeding in the brain.
Which Medicines Are Used To Treat Alzheimers Disease
There is no cure for Alzheimers disease, but available medications temporarily slow the worsening of dementia symptoms and help with behavioral problems that may appear during the course of the disease.
Four medications representing two drug classes are currently approved by the Food and Drug Administration to treat the symptoms of Alzheimers disease. These drugs are the cholinesterase inhibitors and a NMDA antagonist.
Cholinesterase inhibitors. The cholinesterase inhibitors are all approved to treat the symptoms of mild to moderate Alzheimer’s disease . Cholinesterase inhibitors include:
- Rivastigmine and Exelon patch
These drugs work by blocking the action of acetylcholinesterase, the enzyme responsible for destroying acetylcholine. Acetylcholine is one of the chemicals that helps nerve cells communicate. Researchers believe that reduced levels of acetylcholine cause some of the symptoms of Alzheimer’s disease. By blocking the enzyme, these medications increase the concentration of acetylcholine in the brain. This increase is believed to help improve some memory problems and reduce some of the behavioral symptoms seen in patients with Alzheimers disease.
These medications do not cure Alzheimers disease or stop the progression of the disease. The most common side effects of these drugs are nausea, diarrhea, and vomiting. Some people may have loss of appetite, insomnia or bad dreams.
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