Drug treatment for Alzheimer's disease
Clinical Guidelines for Dementia Treatment 2021 Click Here
The causes of cognitive decline and dementia are still unclear. In most cases, dementia appears when the cumulative damage to brain tissue is severe and causes the loss of cognitive functions. Because brain cells are usually unable to renew themselves, dementia often describes an incurable process. Currently, there is still no effective treatment for dementia. However, although dementia cannot be cured, nor can its deterioration be significantly delayed over time, there are treatments that can alleviate and slow down the clinical symptoms.
The standard therapeutic approach includes:
A. Preventive measures and treatment of known risk factors. See more in the section Maintaining brain health and preventing dementia.
B. Symptomatic treatment of cognitive impairments, mental symptoms, and behavioral disorders. Symptomatic treatment is treatment that does not affect the causes of the disease, but rather its symptoms.
C. Treatments that affect the causes of the disease and change its course.
D. Non-pharmacological treatments, treatment with therapists.
Symptomatic medications: which treat cognitive, mental, and behavioral symptoms
Medications to treat mental and behavioral symptoms
Mental and behavioral symptoms, such as depression, apathy, delusions, hallucinations, restlessness, anxiety, and more, are very common in all types of dementia, and often precede the decline in memory or other cognitive functions. These symptoms can be the result of various factors – the disease itself, the emotional reaction to the disease, environmental factors (such as the behavior of loved ones), another disease (such as a urinary tract infection), pain, discomfort, and boredom. The first line of treatment for these symptoms is non-pharmacological and includes determining the manner in which the symptoms appear (gradually or acutely), examining the patient's health and environmental status, and determining factors that may exacerbate or reduce the symptoms. Existing medications were mostly developed for other diseases. In patients suffering from dementia, these medications are less effective and may cause side effects. Their use should be considered only after non-pharmacological treatment methods have been exhausted, and the potential harm that may be caused to the patient should be considered in light of his suffering and the consequences of his behavior on the support system.
The following is a specific reference to drug treatment for the common types of behavioral disorders in dementia, or those that cause the greatest distress.
Drug treatment of depression in patients with dementia: Studies conducted in patients with depression during dementia do not unequivocally support treatment with antidepressants. Also, there is insufficient information on the optimal duration of treatment. The decision to intervene with medication should be based on the severity of the depression, the patient's health status, other medications being taken, and the depressive symptoms they are experiencing.
Drug treatment options for restlessness in dementia patients include antidepressants, antipsychotics (such as risperidone, olanzapine, etc.) or sedatives from the benzodiazepine family (such as Lorivin or Vabene). These drugs are sometimes effective, but they are associated with risks (falls, increased risk of death or stroke, worsening of cognitive status), so their use must be weighed against the expected benefit. The antipsychotic drug Rexulti (Brexipiprazole) was recently approved for the treatment of restlessness in patients with Alzheimer's disease. The rules and considerations that apply to other antipsychotics in patients with dementia also apply to it.
Medical cannabis : The Ministry of Health has approved the indication for treatment with medical cannabis (preparations rich in CBD and not THC) for patients with dementia who suffer from severe behavioral disorders that have not responded to conventional treatments.
Common Dementia-Related Sleep Disorders and Treatment Recommendations : Many older adults have sleep problems, but people with dementia often have a harder time. Sleep disorders tend to worsen as dementia progresses, affecting up to 25% of people with mild-to-moderate dementia and about 50% of people with severe dementia.
Common sleep disorders include:
* Excessive daytime sleepiness and insomnia, which manifest as difficulty falling asleep, disrupted sleep, and early awakening. Another sign of dementia is sundown syndrome, which occurs mainly in the evening or during the night. Patients may feel agitated, anxious, aggressive, and confused. They may wander during the night, which increases the risk of falls and injuries.
* Obstructive sleep apnea is also common in people with dementia. Obstructive sleep apnea is characterized by repeated pauses in breathing during sleep, nocturnal awakenings, and unrefreshing sleep.
* REM sleep behavior disorder: REM sleep (an acronym for "rapid eye movement") is the stage of sleep during which we dream. During the REM stage in a healthy person, the body is in a state of limb paralysis. In those suffering from REM sleep disorder, muscle paralysis does not occur, and this causes hyperactivity (flagging of arms, legs, falls). REM sleep disorder is common in dementia with Lewy bodies.
Sleep disorders impair the patient's quality of life and are a burden on the caregiver. In order to improve sleep quality, it is recommended to:
* Treat underlying diseases : Sometimes conditions such as depression, sleep apnea, or restless legs syndrome cause sleep problems.
* Maintaining a daily routine, regular times for eating, waking up, and going to bed have been found to be helpful.
* Avoid the use of stimulants such as alcohol, caffeine, and nicotine, which can cause hypervigilance. It is recommended to limit the use of these substances, especially at night.
* It is recommended to avoid watching television during awake periods at night.
* Physical activity is recommended and has been found to be beneficial for improving sleep quality.
* It is recommended to limit the duration of naps during the day (no more than one hour of sleep).
* A calm atmosphere in the evening improves sleep quality. Reading out loud, playing soothing music, and a comfortable room temperature have been found to improve sleep quality.
* Lighting : Exposure to bright light in the evening has been found to moderate sleep-wake cycle disturbances in people with dementia. Adequate lighting during the night has been found to reduce restlessness and aggressive behavior in dark environments. Regular exposure to daylight may treat conditions of day-night reversal.
* Medication : Some antidepressants, such as bupropion and venlafaxine, can cause insomnia. Cholinesterase inhibitors, such as donepezil, can improve cognitive and behavioral symptoms in people with Alzheimer's but can also cause insomnia. Taking the medication no later than dinner will usually improve sleep. Consult a doctor regarding medication.
* Melatonin therapy: Melatonin may improve sleep quality and reduce twilight syndrome in people dealing with dementia.
* Sleep medications: Despite the lack of support in the literature for the use of sleep medications in patients with dementia, in practice, medications from the benzodiazepine family (e.g. Bondormin), other families (e.g. zolpidem), melatonin, antipsychotics (e.g. Seroquel) or antidepressants (e.g. Miro) are often used. Recently, a drug (Dayvigo Lemborexant) has been marketed in Israel, whose mechanism of action is different from that of other drugs. Dayvigo reduces the urge to be hypervigilant and may be beneficial for people who have difficulty falling asleep and/or who suffer from insomnia.
Recommendation : Before deciding on drug treatment for sleep disorders, consult a doctor and ensure that there is no other cause for the sleep disorder (for example, shortness of breath due to heart failure) or lack of sleep hygiene (excessive daytime sleepiness). In any case of administering sleep medications, regardless of the mechanism, excessive daytime fatigue should be monitored and ensure that there is no decrease in stability and an increased risk of falls.
Medications to treat cognitive and behavioral symptoms
Existing treatments are based on what is known about the pathology of Alzheimer's disease. Alzheimer's disease is characterized by deposits of the proteins amyloid and phospho-tau in the brain, which are considered toxic to brain cells. The cellular damage disrupts the activity of the cells and their ability to secrete neurotransmitters. Neurotransmitters are molecules responsible for the communication between nerve cells in the brain.
In the early stages of Alzheimer's disease, damage occurs to the cells responsible for secreting the neurotransmitter acetylcholine. The lack of acetylcholine is paralleled by a decline in concentration and memory, and worsens as Alzheimer's disease progresses.
Donepezil, Rivastigmine, Remenil
The drugs donepezil (Aricept, Asenta, Memrise, Donepezil), rivastigmine (Exelon in capsules and patches), and galantamine (Reminyl) increase the level of acetylcholine in the brain by inhibiting its breakdown. Acetylcholine is naturally broken down by a catalyst called acetylcholinesterase. The above drugs inhibit this catalyst and are therefore called acetylcholinesterase inhibitors.
Side effects common to these drugs include nausea, vomiting, diarrhea, and excessive sweating and are usually dose-dependent. Gradual dose increases and/or switching to another inhibitor, or to a drug administered in a different way, such as patches, are helpful in preventing them. Clinical studies have demonstrated an improvement in attention, concentration, and memory functions in treated Alzheimer's patients. The effect of the drugs lasts for about two years and sometimes longer. Treatment may delay the need for the patient to be hospitalized in a nursing home. Moderate efficacy of these drugs has also been demonstrated in patients suffering from vascular dementia and dementia due to Lewy bodies. Acetylcholinesterase inhibitors are approved in Israel for the treatment of Alzheimer's disease only, are included in the health basket, and are sold under various trade names.
memantine
Another neurotransmitter whose activity is disrupted is glutamate. Glutamate is one of the most common neurotransmitters (quantitatively) in the brain. Its activity is to stimulate brain cells to function. As the disease progresses and cells in the brains of Alzheimer's patients are destroyed, the activity of glutamate becomes toxic. The drug memantine (Memox, Abixa, Nameda, Exora) inhibits glutamate receptors and blocks the pathological effect of increased glutamate levels on brain cell function. It has been found that treatment with memantine slows cognitive decline and improves behavioral disorders in patients suffering from moderate to severe dementia. Common side effects: abdominal pain, diarrhea, and restlessness. The drug is not included in the health basket. Health insurance funds partially participate in financing the drug, usually through supplementary insurance.
Prescription drugs and dietary supplements:
Extraction of the leaves of the Ginkgo biloba plant: Ginkgo biloba has a beneficial effect on the neurotransmitter system. In Israel, the preparation Egb761 cervonin , a measured and high-quality extract of the leaves of the Ginkgo biloba plant, is registered as a prescription drug for conditions of cognitive decline in adults. The substance is relatively safe to use. A tendency to bleed has been reported. Cervonin is not included in the health basket in Israel. Dietary supplements of the Ginkgo biloba plant can be purchased without a prescription.
Phosphatidylserine : Marketed in Israel as a dietary supplement. Tested in several studies in adults with cognitive complaints, in subjects with mild cognitive decline, and in those diagnosed with dementia. Some studies found a slight improvement in performance on cognitive tests and in daily functioning. The substance is relatively safe to use. Phosphatidylserine is not included in the Israeli health basket.
To date, the clinical efficacy of additional supplements has not been tested.
Specific medications to treat the cause of the disease and change its course Disease-modifying therapies
Specific drugs for the treatment of diseases that cause dementia are in the research stages. At this stage, the drugs that have proven clinically effective are intended for the treatment of Alzheimer's disease.
Based on the assumption that the amyloid protein in the cell is toxic and harmful to brain cells, specific drugs have been developed to remove and/or reduce the concentration of this protein in brain tissue using an immune mechanism (antibodies against the amyloid protein in the cell).
Aducanumab . The drug was developed by the pharmaceutical companies Biogen and Eisai.
The drug was approved for use by the FDA in June 2021 under an accelerated process. Biogen stopped manufacturing and using the drug in January 2024, reporting that the discontinuation of production was due to financial problems. Aducanumab was the first drug to show both clearance of amyloid deposits from the brain and a slowdown in the rate of cognitive decline in patients diagnosed with mild Alzheimer's disease. Due to inconsistent results in its registration studies, it was not accepted by the medical community, and as mentioned, production of the drug Aducanumab was discontinued.
LecanemabThe drug was developed by Eisai and marketed under the name Leqembi. The drug was initially approved by the FDA under an accelerated process in January 2023. In July 2023, Lecamb became the first-ever drug to receive full FDA approval for the treatment of Alzheimer's disease with an antibody-based mechanism for removing amyloid deposits. Lecamb was registered for use in Israel in July 2024. The EMA (European Medicines Agency) has not approved the product for marketing in Europe. Lecanemb was tested in a multicenter, double-blind study in 1795 patients diagnosed with Alzheimer's disease with a severity of moderate cognitive decline or mild dementia.
The results of the CLARITY-AD study, which lasted 18 months, demonstrated a slowdown in the rate of cognitive and functional decline in patients on lecanamba (by 27% in the cognitive index and 37% in the functional index). This figure is equivalent to a delay in progression of about six months during the months of the study. A substudy, which examined the effect of lecanamba on the amyloid protein load in brain tissue, demonstrated significant clearance of the amyloid protein. During treatment, side effects were reported, most of which were related to the administration of the drug by infusion and some were related to the clearance of amyloid from the brain tissue (events of edema and bleeding). It was found that homozygous carriers of the ApoE4 gene (carrying two copies of this gene) are at increased risk of side effects and cerebral hemorrhages. To avoid side effects, brain MRI tests should be performed before and during treatment, in order to identify edema and hemorrhages in the brain tissue and treat accordingly.
Treatment with Lekambim is available at memory clinics in Israel. The treatment is not included in the health basket. In order to avoid side effects, the appropriate people for treatment must be carefully selected.
Donanemab: The drug was developed by Eli Lilly and marketed as Kisunla. On July 17, 2023, Eli Lilly published the results of the TRAILBLAZER-ALZ 2 study, which found that in patients diagnosed with Alzheimer's disease in its early clinical stages, treatment with donanemab statistically significantly reduced clinical deterioration during 76 weeks of treatment. The drug was approved for clinical use by the US FDA in July 2024.
Recommendation: Only a physician is qualified to make decisions regarding medication treatment. It is recommended to consult a specialist physician before deciding on treatment with new or experimental medications.
The above is a summary only and cannot be used as a substitute for a diagnosis.