Alzheimer's Disease Treatment Options: A Healthcare Professional's Guide
Medically reviewed by Leigh Ann Anderson, PharmD. Last updated on Oct 7, 2021.
Pharmacotherapy of Alzheimer's Disease
While medical treatment of dementia associated with Alzheimer’s disease (AD) is making strides, current therapy still revolves around treating symptoms of the disease.
- Medications are available that can mildly enhance cognition deficiencies, but ultimately the disease progresses.
- Control of behavioral disturbances via adjustment of the surrounding environment and safety education for the caregivers are also paramount to effective care of the patient.
- It's an area where more robust research is needed. As published in the NEJM in 2019, major clinical trials in Alzheimer's disease aimed at lowering amyloid levels, such as with verubecestat and atabecestat, are not meeting study targets. Research is often halted midstream.
Alzheimer's disease: What's the Impact?
There are various classifications of dementia, but the most common cause of dementia in almost half of patients is Alzheimer's disease.
Consider these Alzheimer's disease facts:
- Roughly 6 million people in the U.S. are living with Alzheimer's disease in 2021, and one in three seniors dies with Alzheimer's or another dementia.
- Alzheimer's disease and dementia deaths have increased 16% during the COVID pandemic.
- 11 million Americans provide unpaid care for people with Alzheimer’s or other dementias, providing 15.3 billion hours of care valued at $257 billion.
- By 2050, the healthcare costs of Alzheimer's disease and other dementias are projected to approach $1.1 trillion.
Overview: Treatment Options
The limited treatment options available in Alzheimer's dementia include:
- Acetylcholinsterase inhibitors (AChEIs). Patients with mild dementia are typically titrated slowly on an AChEI.
- Memantine, an NMDA receptor antagonist. As the disease progresses, memantine may be added or used alone.
- Memantine + AChEI
- Aduhlem (aducanumab-avwa) injection: an an amyloid beta-directed antibody given accelerated approval in June 2021 and indicated for the treatment of early stage (mild) Alzheimer’s disease. Aduhelm is given as an intravenous infusion over one hour every four weeks.
- Possibly Vitamin E (although study results are mixed). The benefits of vitamin E, an antioxidant, are likely to be modest in Alzheimer's disease. Some studies have only shown a slight offset in decline in activities of daily living.
- Patients should first consult with their healthcare provider about use of any over-the-counter medicine or dietary supplement for Alzheimer's treatment.
In certain situations, behavioral treatments are also used in conjunction with medication. In advanced forms of dementia, discontinuing drug treatment may be recommended by the clinician and preferred by the family.
MOA: Cholinesterase Inhibitors
Cholinergic transmission involves the release of acetylcholine to specific receptors.
- Patients with Alzheimer’s disease have a reduced ability to synthesize the neurotransmitter acetylcholine due to low levels of choline acetyltransferase.
- In addition, cholinesterase enzymes are present in the cholinergic synaptic clefts and break down the available acetylcholine further decreasing its availability in the brain.
Cholinesterase inhibitors work by binding to the cholinesterase enzyme resulting in increased acetylcholine in the synapses. For most patients, cholinesterase inhibitors may offer a modest benefit in mild-to-moderate AD.
Cholinesterase Inhibitors: Modestly Effective at Best
There are three approved cholinesterase inhibitors (CI) on the U.S. market:
- donepezil (Aricept)
- galantamine (Radazyne ER)
- rivastigmine (Exelon)
- the combination agent memantine and donepezil (Namzaric)
AChEIs may be modestly helpful in cognition and memory in a subset of patients. However, not everyone using this drug class can expect to have a meaningful improvement in AD symptoms.
Tacrine was the first approved AChEI in 1993, but was later removed from the U.S. market due to liver toxicity. Generics are approved for most brands and dose forms. Aricept ODT and Razadyne brands have been discontinued, but Razadyne ER brand is still available.
In Jan. 2020, Corium, Inc announced acceptance of an NDA for Adlarity (donepezil transdermal system) by the FDA. Adlarity is an investigational, once-weekly transdermal formulation of Aricept (donepezil HCl) in development for the treatment of Alzheimer’s disease.
Dosing With Donepezil
- Donepezil (as 5, 10 and 23 mg tablets) is generally well-tolerated, can be given once daily, and is available in a lower-cost generic form.
Generic donepezil is also available in an ODT (orally disintegrating tablet, 5 and 10 mg) formulation, which makes administration easier. Allow the ODT tablet to dissolve completely on the tongue and follow with water.
Note: A higher dose of 23 mg may not provide a greater clinical benefit than lower doses and may results in greater side effects.
The 23 mg strength is a film-coated formulation different from the 5 mg or 10 mg strengths, which results in an altered pharmacokinetic profile. The 23 mg tablet can be more expensive than the lower doses, even in a generic form.
Dosing With Rivastigmine
Rivastigmine (Exelon) comes as an oral capsule (1.5, 3, 4.5 and 6 mg) and as a patch (4.6 mg, 9.5, and 13.3 mg per 24 hours). The patch is still available as a brand name product and generic, but the capsule only comes in a generic.
As with all AChEIs, nausea, vomiting, and diarrhea can be common side effects at treatment onset. The patch may offer better gastrointestinal tolerability, but skin rash could be an issue.
Discontinue rivastigmine in case of disseminated allergic dermatitis, which may occur after oral or transdermal administration. In patients with suspected allergic contact dermatitis after transdermal rivastigmine use, switch to oral rivastigmine only after negative allergy testing.
Dosing with Galantamine
Galantamine comes in an immediate-release (IR) 4, 8 and 12 mg tablet, in 8, 16, and 24 mg extended-release (ER) capsules. Generics for all dosage forms are available. Slow titration is important to improve tolerability.
Razadyne immediate-release and oral solution brands have been discontinued, but the ER brand name is still on the market.
Give doses with food, and be sure the patient drinks plenty of fluids. Nausea is a common side effect. Dose adjustments are required with renal or hepatic impairment.
Common ADRs With Cholinesterase Inhibitors
Gastrointestinal (GI), or stomach side effects are common with AChEIs, and may include:
- decreased appetite
GI symptoms may be transient and dose-related, but doses should be taken with a meal to improve tolerability. In patients using rivastigmine, the patch may render less GI symptoms than the oral, but may be associated with application site reactions like a rash.
Other side effects with AChEIs may include headache, dizziness, insomnia, fatigue, asthenia (weakness), and muscle cramps.
If treatment is stopped with any AChEI, a re-titration will be needed to avoid abrupt high-dose side effects.
More Serious ADRs with Cholinesterase Inhibitors
Common, but more serious side effects with AChEIs include issues related to the cardiovascular system:
- Symptomatic bradycardia (slowed heart rate)
- Hypotension (low blood presaure)
- Syncope (fainting)
- AV (heart) block
- Arrhythmias (abnormal heart rhythm)
Severe hypersensitivity (allergic) reactions, including:
- Stevens-Johnson syndrome
- Erythema multiforme
have been reported, as well as seizures, stomach bleeding, anemia, and urinary obstruction.
Because of their vagotonic action, cholinesterase inhibitors may lead to bradycardia or heart block in patients both with and without known underlying cardiac conduction abnormalities. This can increase the risk of syncope, falls, and fractures.
Memantine (Namenda, Namenda XR)
The N-methyl-D-aspartate (NMDA) receptor is known to be involved in learning and memory. Sustained activation of the NMDA receptors by the excitatory amino acid glutamate is theorized to aggravate Alzheimer's dementia.
Memantine, FDA-approved in 2003 for the treatment of moderate-to-severe Alzheimer's dementia, does have modest benefits in these patients.
Memantine, an NMDA receptor antagonist is thought to be neuroprotective, but in patients with early, mild Alzheimer's dementia, benefits are limited.
Memantine comes in several strengths and dosage forms to help ease dosing for the patient with moderate-to-severe Alzheimer's disease.
Immediate-release (IR) memantine comes in oral 5 and 10 mg tablets, as well as an oral solution. An oral extended-release (ER) capsule is available in 7, 14, 21, and 28 mg strengths. Titration packs are also available.
It's important to titrate slowly between dose increases; one week is the typical time frame between dose changes. Only increase dosage if the patient is tolerating the previous dose.
The ER capsule and liquid dose form is more expensive then the immediate-release tablets, so comparing prices for the patient who must pay cash might be useful when determining dosing.
For some patients, memantine may be better tolerated than the cholinesterase inhibitors.
- Dizziness seems to be a common side effect, with other CNS symptoms like headache and confusion reported.
- Agitation, hallucinations, and hypertension may also occur.
- GI symptoms such as constipation and vomiting can also occur.
Due to mixed reports of effectiveness and tolerability, use should be decided based upon individual efficacy, tolerability, and cost, coupled with patient and clinician preferences. Memantine may be used alone or in combination with the AChEIs.
Namzaric (donepezil and memantine), FDA-approved in 2014, is a combination cholinesterase inhibitor-NMDA receptor antagonist drug containing donepezil and extended-release memantine given once daily. It is approved for moderate to severe Alzheimer's dementia in patients stabilized on 10 mg of donepezil once daily or stabilized on both donepezil and memantine.
- View Namzaric dosing. Namzaric can be taken with or without food, or sprinkled on applesauce (without chewing) for easier administration; because of the extended-release property, do not divide, chew, or crush.
Namzaric requires dosing adjustment in severe renal impairment (creatinine clearance 5 to 29 mL/min).
There are currently no generic options yet for the fixed-dose combination Namzaric. The full cash price for Namzaric is high, costing roughly $500 per 30 capsules without insurance and using an online coupon. However, both donepezil and memantine ER are now available generically as separate products.
In June 2021, the U.S. Food and Drug Administration (FDA) granted accelerated approval to Biogen’s Aduhelm (aducanumab-avwa), an amyloid beta-directed antibody intended to target an underlying disease process of Alzheimer’s disease.
- Treatment with Aduhelm should be initiated for treatment of Alzheimer's disease in patients with mild cognitive impairment or mild dementia stage of disease, the population in which treatment was initiated in clinical trials.
- There are no safety or effectiveness data on initiating treatment at earlier or later stages of the disease than were studied.
As part of the accelerated approval, Biogen will conduct a Phase 4 confirmatory trial to verify the clinical benefit of Aduhelm. If Biogen is unable to verify clinical benefit, the FDA can withdraw approval of the drug. Previously, the scientific advisory advisory board to the FDA had voted against approval of this drug.
- Accelerated approval was based on the reduction of amyloid beta plaques found in the brain, a biomarker that may predict clinical benefit, according to the FDA.
- In studies with over 3,400 patients with early-stage Alzheimer’s disease, Aduhelm showed a statistically significant reduction of amyloid beta plaque by 59% to 71% at 18 months of treatment, while the control arm had no reduction. One of two studies met the primary endpoint, showing reduction in clinical decline.
- Aduhelm is given as an intravenous infusion over one hour every four weeks. A recent (within one year) brain MRI is obtained prior to initiating treatment. Brain MRI is also required prior to the 7th and 12th infusions to assess for radiographic severe ARIA-H.
Aduhelm labeling contains a warning for Amyloid Related Imaging Abnormalities (ARIA), a common side effect seen with an MRI that usually resolves with time, but can be serious in some patients.
- ARIA can involve edema (ARIA-E) and / or microhemorrhage (ARIA-H). People with ARIA had clinical symptoms such as headache (13%), confusion (5%), dizziness (4%), vision changes (2%), and nausea (2%).
- Serious symptoms due to ARIA were reported in 0.3% of patients. Clinical symptoms resolved in the majority of patients (88%) during the period of observation.
Serious allergic reactions may also occur (angioedema and urticaria have been observed).
Drug Interactions: Educate Caregivers
Drug interactions in AD can be serious and even life-threatening. AD patients may have co-morbid conditions and take multiple medications, putting them at higher risk of interactions. Caregivers should be educated on the importance of drug interactions.
Rivastigmine and memantine do not undergo CYP450 enzyme metabolism, but donepezil and galantamine do.
The use of drugs with anticholinergic properties should be avoided as they can worsen cognition and cause delirium.
Caregivers and healthcare providers can ultilize the Drugs.com Interaction Tool for a full overview of specific drug interactions with AChEIs and memantine, or any other drug combination.
What About Vitamin E?
Overall, the benefits of taking a vitamin E (alpha-tocopherol) supplement, an antioxidant, are likely to be modest in patients with Alzheimer's dementia. Cardiovascular safety may be a concern, too, although studies in the AD population are lacking.
In a large VA study published in JAMA, 613 patients (primarily men) with mild to moderate AD taking AChEIs were randomized to 2000 IU per day of Vitamin E, 20 mg per day of memantine, both agents combined, or placebo.
- After 2 years, those on vitamin E had a 19% slower rate of decline in activities of daily living (ADLs) per year (a delay of approximately 6.2 months over the roughly 2.3 years of follow-up) than study volunteers who received a placebo.
- A reduction of approximately 2 hours of caregiver time per day in the Vitamin E group was reported.
- The authors found no significant increase in mortality with vitamin E.
- No benefit was seen in groups taking memantine plus Vitamin E or memantine alone.
This study suggested a slight positive benefit of vitamin E in mild to moderate AD by decreasing functional decline and caregiver burden. However, other studies have not shown benefit or have shown increased mortality in patients with cardiovascular disease.
Vitamin E is not recommended for routine prevention of Alzheimer's dementia. A 2017 study published in JAMA Neurology found that vitamin E has no anti-oxidative benefit for Alzheimer's dementia prevention in older men.
Behavioral Disturbances in Dementia
Behavioral and psychiatric disturbances can be a source of great stress for patients, families and caregivers. These disturbances may be a determining factor in residential care placement. Dementia-related behaviors, as described by the Alzheimer's Association, may include:
- sleep disturbances
- agitation (physical or verbal aggression, general emotional distress, restlessness, pacing, shredding paper or tissues and/or yelling)
- delusions (firmly held belief in things that are not real)
- hallucinations (seeing, hearing or feeling things that are not there
Healthcare providers should proactively investigate issues of delusions, hallucinations, physical violence and aggression, sleep disturbances, and depression in AD patients. A full evaluation of drug treatment side effects, dosing, and possible aggravating drug interactions should be initiated before permanent placement in a facility.
Besides disease progression, medical and environmental conditions may play contributing roles, according to the Alzheimer's Association.
These may include:
- infections, medical condition (for example: UTI, ear infection, pneumonia)
- problems with hearing or vision
- changes in caregiving
- hospital admission
- lack of privacy, bathing
- moving to a new home or traveling
- entering long-term care
- difficulty with expressing needs and wishes
- fear and fatigue from trying to make sense out of an increasingly confusing world
Nondrug strategies should always be tried first. When drug treatment is used for behavioral issues in AD, frequent evaluation with a goal of short-term use is preferred. Review this document from the Alzheimer's Association for nondrug treatment for behavioral and psychiatric symptoms and tips to prevent agitation.
Challenging Behaviors in Alzheimer's Dementia
No drugs are approved by the FDA for specifically treating behavioral disturbances in AD patients; drug treatment is usually "off-label."
- The FDA specifically contraindicates the use of antipsychotics in dementia due to higher mortality.
- A Boxed Warning is in place on all antipsycotic medications.
- Some drugs may be prescribed “off label” in Alzheimer's dememtia, when a physician prescribes a drug for a different purpose than the ones for which it is FDA-approved.
Guidance from the Alzheimer's Association states that, based on scientific evidence, drug label warnings and guidance from experts, individuals with dementia should use antipsychotic medications only under one of the following conditions:
- Behavioral symptoms are due to mania or psychosis.
- The symptoms present a danger to the person or others.
- The person is experiencing inconsolable or persistent distress, a significant decline in function or substantial difficulty receiving needed care.
Antipsychotic medications should not be used to sedate or restrain persons with dementia. Physical restrains are rarely needed unless the patient is in immediate danger of causing harm to themselves or to others.
Sleep disturbances can be common in patients with dementia. Nondrug tactics, including appropriate sleep hygiene, morning light, and daily exercise are generally preferred to medications.
Caregivers, families, and practitioners should have a frank discussion on the risks of antipsychotic therapy early on, and the mortality potential. A one-on-one family discussion with nursing and medical staff regarding their plans for addressing behavioral issues, including ongoing communications with family, should be a priority.
Alzheimer's Clinical Trials for Patients
Healthcare professionals can play a crucial role in recruiting and retaining clinical trial participants for the next generation of Alzheimer's medical treatments.
- The Alzheimer's Association TrialMatch is helping to aid in this recruitment.
- The continuously updated database of Alzheimer's clinical trials includes more than 250 clinical studies being conducted across the country as of April 2019.
- Studies are both pharmacological and non-pharmacological.
- Patients, caregivers, or providers may also call 800-272-3900. Healthy participants are needed, too.
Learn More: Alzheimer's treatments: What's on the horizon?
Join Hands To Gain Strength
Caregivers carry an especially heavy burden in the treatment of Alzheimer's disease. Not only do they physically care for the loved one, they must also unravel issues related to nutrition, medications, behavioral issues, sleep disturbances, and healthcare costs. For anyone, this is no small task.
- Caregivers should be encouraged to seek community support and education from recognized resources such as the Alzheimer's Association.
- Patients and caregivers may consider joining the Drugs.com Alzheimer's Support Group to voice concerns, ask questions, and keep up with latest news.
- No caregiver should have to support an Alzheimer's patient alone -- healthcare providers should be sure they are directed to appropriate and reliable resources.
Finished: Alzheimer's Disease Treatment Options: A Healthcare Professional's Guide
Someone is diagnosed with Alzheimer’s in the U.S. every 65 seconds. What are the signs and symptoms you should look for? And how do they compare with those features of just getting older?
Society tends to treat menopause as a disease; something to be avoided at all costs. But menopause can be positive. No more monthly mood swings, period accidents, or pregnancy worries. Self-confidence and self-knowledge...
- Press D. Treatment of Alzheimer Disease. Up to Date. Updated Sep. 30, 2021. Accessed Oct 7, 2021 at https://www.uptodate.com/contents/treatment-of-alzheimer-disease
- Treatments for behavior. Alzheimer's Association. Accessed Oct. 7, 2021 at https://www.alz.org/alzheimers-dementia/treatments/treatments-for-behavior
- 2021 Alzheimer's Disease Facts and Figures. The Alzheimer's Association. Accessed Oct. 7, 2021 at https://www.alz.org/media/Documents/alzheimers-facts-and-figures-infographic.pdf
- Watkins PB, Zimmerman HJ, Knapp MJ, et al. Hepatotoxic effects of tacrine administration in patients with Alzheimer's disease. JAMA. 1994;271(13):992.
- Gill SS, Anderson GM, Fischer HD, et al. Syncope and its consequences in patients with dementia receiving cholinesterase inhibitors: a population-based cohort study. Arch Intern Med. 2009;169(9):867.
- The Alzheimer's Association. TrialMatch. Accessed Oct. 7, 2021 at https://www.alz.org/research/clinical_trials/find_clinical_trials_trialmatch.asp
- Press D, et al. Management of neuropsychiatric symptoms of dementia. Up to Date. Updated Sept. 7, 2021. Accessed Oct. 7, 2021 at https://www.uptodate.com/contents/management-of-neuropsychiatric-symptoms-of-dementia
- Dysken MW, Sano M, Asthana S, et al. Effect of vitamin E and memantine on functional decline in Alzheimer disease: the TEAM-AD VA cooperative randomized trial. JAMA. 2014 Jan;311(1):33-44. Accessed Accessed Oct. 7, 2021 at http://jama.jamanetwork.com/article.aspx?articleID=1810379
- The Alzheimer's Association. Health Care Professionals. Accessed Oct. 7, 2021 at https://www.alz.org/professionals/healthcare-professionals