PHARMACOLOGIC AND MEDICAL MANAGEMENT

The current basis of management of patients with Alzheimer’s dementia continues to be symptomatic, including treatment of behavioral disturbances, environmental manipulations to support function, and counseling regarding issues of safety. However, some FDA-approved medications can help improve or maintain the patient’s cognitive and functional status and help lessen symptoms such as memory loss and confusion. Some medicines also improve the behavioral and psychological symptoms and can be used in addition to nonpharmacologic strategies (Alzheimer’s Association, 2021d).

NEW DRUG FOR TREATING DISEASE PROGRESSION

Aducanumab (Aduhelm) was approved in the United States in 2021 for patients with mild cognitive impairment or the mild dementia stage of Alzheimer’s. Aducanumab is an antiamyloid antibody intravenous infusion therapy that works by targeting beta-amyloid. This drug is the first to demonstrate that removing amyloid from the brain is reasonably likely to reduce cognitive and functional decline in people living with early Alzheimer’s. Aducanumab must be used in patients with confirmed evidence of amyloid plaque buildup in the brain.

FDA approval, however, has been controversial. Aducanumab was approved under the accelerated approval pathway, which provides patients with a serious disease earlier access to medications when there is an expectation of clinical benefit despite some uncertainty about the benefit. The FDA advisory committee, however, stated that clinical trials did not demonstrate sufficient evidence of effectiveness (FDA, 2021; Alzheimer’s Association, 2021b).

No European country has approved this drug, and most major U.S. hospital systems have refused to prescribe or administer it. Many private insurers have declined payment for the drug as well. Medicare’s decision specifies that coverage can only occur “in CMS-approved, randomized controlled trials and in trials supported by NIH.” None of the trials completed to date, however, have demonstrated that use of this medication results in meaningful improvement in outcomes for AD patients (Sachs, 2022).

The most common side effects include amyloid-related imaging abnormalities (ARIA), headache, and falls. ARIA is a temporary swelling in areas of the brain that usually resolves over time. Patients should not be offered aducanumab if they have a high risk of hemorrhagic side effects (Press & Buss, 2021).

Treating Cognitive and Memory-Related Symptoms

As Alzheimer’s progresses, brain cells are damaged and cognitive symptoms worsen. While the following medications do not stop the damage caused by AD, they may help temporarily lessen or stabilize symptoms related to memory and thinking by affecting chemicals involved in carrying messages among and between the brain’s nerve cells (Alzheimer’s Association, 2021d).

CHOLINESTERASE INHIBITORS

Cholinesterase inhibitors are prescribed to treat symptoms related to memory, thinking, language, judgment, and other thought processes. These drugs support communication between nerve cells by preventing the breakdown of acetylcholine, a chemical messenger important for memory and learning. These medications include:

  • Donepezil (generic & Aricept), approved for all stages of Alzheimer’s
  • Rivastigmine (Exelon), approved for mild to moderate Alzheimer’s and Parkinson’s diseases
  • Galantamine (generic & Razadyne), approved for mild to moderate Alzheimer’s

Newly diagnosed patients should be offered a trial of cholinesterase inhibitor. The average benefit of cholinesterase inhibitors in patients with mild to moderate dementia is modest. The medications should not be continued indefinitely in those who do not appear to be benefiting or who have significant side effects.

Cholinesterase inhibitors cannot reverse Alzheimer’s disease or stop the progressive destruction of nerve cells. The medication eventually loses its effectiveness because dwindling brain cells produce less acetylcholine as the disease progresses. Common side effects include nausea and diarrhea, anorexia and weight loss, bradycardia and hypotension, and sleep disturbances (Press & Buss, 2021; Alzheimer’s Association, 2021b).

GLUTAMATE ANTAGONIST

Glutamate is the principal excitatory amino acid neurotransmitter in cortical and hippocampal neurons. One of the receptors activated by glutamate is the NMDA receptor, which is involved in learning and memory. Glutamate regulators are prescribed to improve memory, attention, reason, language, and the ability to perform simple tasks by regulating the activity of glutamate, a chemical messenger that helps the brain process information. Glutamate has been shown to improve cognition and global assessment of dementia, but with small effects that are not of clear clinical significance. Improvement in the quality of life and other domains are suggested but not proven.

The glutamate antagonist approved for moderate to severe Alzheimer’s disease is memantine.

  • Memantine (generic & Namenda)
  • Memantine XR, Namenda XR

Memantine appears to have fewer side effects than the cholinergic agents. Dizziness is the most common side effect, as well as headache and constipation. Confusion and hallucinations have been reported to occur at a low rate. Memantine use does, however, seem to increase agitation and delusional behaviors in some patients with Alzheimer’s.

Memantine is commonly added to cholinesterase inhibitor therapy when patients reach a moderate stage of Alzheimer’s disease. This combination leads to modest improvements in cognition and global outcomes in patients with advanced disease (Press & Buss, 2021).

ANTIOXIDANT VITAMIN E

The antioxidant vitamin E (alpha-tocopherol) has been studied in the treatment of Alzheimer’s due to its antioxidant properties. The data suggests that overall vitamin E at a dose of 2,000 IU per day provides modest benefit in delaying progression of functional decline in patients with mild to moderate Alzheimer’s disease, but with no measurable effect on cognitive performance. The benefits of vitamin E could also be cancelled out by combination therapy with memantine. Vitamin E, however, is not recommended for the routine prevention of AD (Press & Buss, 2021).

DRUGS WITH UNPROVEN BENEFIT

Several other therapies have been studied in patients with dementia, with largely negative results, including:

  • Estrogen replacement
  • Anti-inflammatory drugs
  • Ginkgo biloba
  • Vitamin B supplement
  • Omega-3 fatty acids
    (Press & Buss, 2021)

Treating Behavioral and Psychological Symptoms

Behavioral and neuropsychiatric symptoms are common, and as mentioned earlier, are often more problematic than memory impairment. Such symptoms can include:

  • Depression
  • Anxiety
  • Apathy
  • Agitation
  • Aggression
  • Aberrant motor disturbance
  • Aberrant vocalizations
  • Hallucinations
  • Delusions
  • Disinhibition
  • Sleep disturbances
  • Wandering

Suvorexant (Belsomra) is the one drug approved by the FDA to address insomnia in those with dementia. This drug, an orexin receptor antagonist, is thought to inhibit the activity of orexin, a neurotransmitter involved in the sleep-wake cycle. Side effects of suvorexant may include impaired alertness and motor coordination, worsening of depression, suicidal thinking, sleep paralysis, compromised respiratory function, sleep-walking, and sleep-driving.

Other medications are used “off label,” a practice whereby a drug is prescribed for a different purpose than the ones for which it is approved. These include the following:

Antidepressants. Selective serotonin reuptake inhibitors (SSRIs), in particular citalopram (Celexa), are useful in the management of agitation and paranoia, since symptoms are often driven by a mood disorder that is poorly verbalized. Trazodone is an alternative and is often used for sleep onset.

  • Citalopram (Celexa)
  • Fluoxetine (Prozac)
  • Paroxeine (Paxil)
  • Sertraline (Zoloft)
  • Trazodone (Desyrel)

Anxiolytics. Benzodiazepine antianxiety medications are used for anxiety, restlessness, verbally disruptive behaviors, and resistance. They include:

  • Lorazepam (Ativan)
  • Oxazepam (Serax)

Antipsychotics. When nonpharmacologic interventions and approaches fail to manage symptoms that result in severe distress or safety issues, antipsychotic medication may be required. Such symptoms may include hallucinations, delusions, aggression, agitation, hostility, and uncooperativeness. Antipsychotic agents have limited effectiveness and are associated with increased mortality. When deemed necessary, low doses are suggested, and for short-term use when possible. They include:

  • Aripiprazole (Abilify)
  • Clozapine (Clozaril)
  • Haloperidol (Haldol)
  • Olanzapine (Zyprexa)
  • Quetiapine (Seroquel)
  • Risperidone (Risperdal)
  • Ziprasidone (Geodon)

Analgesics. Pain is an important source of behavioral issues. Using analgesics requires careful monitoring to balance risks and benefits of pain treatment versus persistent pain. Adequate pain control may be observed as improvements in behavior and function. Recommended medications include:

  • Acetaminophen
  • Low-dose morphine
  • Buprenorphine patch
  • Pregabalin

(Alzheimer’s Disease, 2021b; Press & Alexander, 2021)

Managing Coexisting Health Problems

People with Alzheimer’s disease often have other health problems common to older adults. Eighty percent of seniors have at least one chronic health condition, and 68% have two or more.

Self-management is a lifelong task for people with long-term conditions. The symptoms of dementia frequently reduce an individual’s ability to organize and plan self-care. The most commonly described impact is the diminishing ability to administer medication safely. Most people with dementia require assistance in management of care for comorbid long-term conditions (NCoA, 2021).

Comorbid health issues, alone or in combination, can further diminish the patient’s ability to function. For example, people who do not see or hear well may be easily confused in unfamiliar situations. Couple those limitations with Alzheimer’s disease, and the confusion intensifies. Recognition and treatment of any and all coexisting conditions can help improve the patient’s functional ability and quality of life.

IMPAIRED VISION AND HEARING

Impaired vision is not uncommon among older adults. It can diminish quality of life and sometimes lead to depression. Basic eye care services to detect and correct impaired vision can improve quality of life and increase a person’s participation in activities, hobbies, and social interaction. Because people with Alzheimer’s may be unable to communicate about their visual impairment, it may go undetected.

Medicare beneficiaries diagnosed with dementia are less likely to receive eye care than those without diagnosed dementia. Depending on visual acuity and functional status, this may have implications for injury prevention, physical and cognitive function, and quality of life. Barriers to receiving care need to be identified and measures to improve access to appropriate eye care need to be implemented.

Deterioration in a person’s hearing may interfere with his or her conversational ability. Questions may be misinterpreted, and answers may be inappropriate. Hearing impairment can also contribute to errors in judgment. Some improvement may occur with hearing aids, and an ear exam should be done to assess for excessive cerumen in the external canal (Perhing et al., 2020).

DEPRESSION

Depression is linked to cognitive impairment and overall functional capacity in AD patients. Although many antidepressant treatments are available, clinical trials indicate that antidepressants for treatment of depression in AD patients appear to be ineffective, and to this date no medication has been approved by the U.S. FDA for the treatment of depressive symptoms in AD. Numerous mechanisms underlying resistance to antidepressants in patients with AD have been hypothesized, with no clear results to date (Cassano et al., 2019).

Nondrug approaches for depression can include involvement of the person in support groups or counseling. It can be helpful to keep a predictable daily routine, taking advantage of the person’s best time of day to undertake difficult tasks, such as bathing, assisting with daily exercise, and scheduling activities the person enjoys (Alzheimer’s Association, 2021b).