Alzheimer's Disease Treatment Options: A Healthcare Professional's Guide
Medically reviewed on Apr 30, 2018 by L. Anderson, PharmD.
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.
- It's an area where more robust research is needed.
- 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.
AD: 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 (AD).
Consider these Alzheimer's disease facts:
- Roughly 5.7 million people in the U.S. are living with AD in 2018, and one in three seniors dies with Alzheimer's or another dementia.
- Alzheimer's disease is the 6th leading cause of death in the U.S. and over 60% of those with AD are women.
- 16.1 million Americans provide unpaid care for people with Alzheimer’s or other dementias.
- Early and accurate diagnosis could save upwards of $7.9 trillion in medical and care costs.
- 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)
- Memantine, an NMDA receptor antagonist
- Memantine + an AChEI
- Possibly Vitamin E
- In certain situations, behavioral treatments.
- Patients with mild dementia are typically titrated slowly on a Acetylcholinsterase inhibitor (AChEI).
- As the disease progresses, memantine may be added or used alone.
- 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. However, 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 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, Aricept ODT)
- galantamine (Razadyne, Radazyne ER)
- rivastigmine (Exelon), and the combination agent memantine/donepezil (Namzaric).
Tacrine was the first approved AChEI in 1993, but was later removed from the U.S. market due to liver toxicity.
AChEIs may be modestly helpful in cognition and memory in a subset of patients. However, only about half of those using this drug class can expect to have any meaningful improvements in AD symptoms.
Dosing With Donepezil (Aricept, Aricept ODT)
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. The higher doses are titrated for severe dementia.
Dosing initially starts at 5 mg once daily at bedtime for 4 to 6 weeks, then is increased to the 10 mg dose at bedtime. Patients should tolerate the donepezil 10 mg per day dose for at least 3 months before starting the 23 mg dose.
The 23 mg tablet is significantly more expensive than the lower doses, even in a generic form.
Dosing With Rivastigmine (Exelon)
Rivastigmine (Exelon) comes as an oral capsule (1.5, 3, 4.5 and 6 mg) and as a patch (4.6 mg, 9.5, 13.3 mg per 24 hours). Generics are available, too.
For mild to moderate AD, the initial oral rivastigmine dose is 1.5 mg twice a day and titrated slowly over 2 weeks as tolerated. The maximum dose is 12 mg per day, and all doses should be given with food.
With the patch, patients start with the lowest dose and increase every 4 weeks as tolerated. The patch may offer better stomach tolerability, but a skin rash could be an issue. Dose adjustments in kidney or liver disease may be needed.
As with all AChEIs, nausea, vomiting, and diarrhea can be common side effects at treatment onset.
Dosing with Galantamine (Razadyne, Razadyne ER)
Galantamine comes in an immediate-release (IR) 4, 8 and 12 mg tablet, as a liquid, or in 8, 16, and 24 mg extended-release (ER) capsules. Generics are available.
The starting dose with the immediate-release in mild to moderate Alzheimer's dementia is typically 4 mg twice a day with morning and evening meals. Doses should be slowly titrated every 4 weeks to a maximum dose of 16 to 24 mg per day.
The ER form usually starts with 8 mg each morning with breakfast, titrating the dose by 8 mg ER every 4 weeks to a maximum of 16 to 24 mg ER per day.
Give doses with food, and be sure the patient drinks plenty of fluids. Nausea is a common side effect. Dose adjustments are required with kidney or liver impairment.
Common ADRs With Cholinesterase Inhibitors
Gastrointestinal (GI), or stomach side effects are common with AChEIs:
- weight loss
Most GI symptoms tend to be transient and dose-related. Donepezil appears to be the best tolerated with regards to GI symptoms. 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 common side effects with AChEIs may include headaches, dizziness, agitation, insomnia, vasodilation, and urinary tract infections. Constriction of the pupils, increased secretion of bodily fluids such as sweat, saliva and tears, a slower heart rate (bradycardia), mucus secretion in the respiratory tract and constriction of the airways may also occur.
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:
have been reported, as well as seizures, stomach bleeding, anemia, and urinary obstruction.
Cholinesterase Inhibitors: How to Choose?
A trial with an AChEI for patients with mild to moderate Alzheimer's dementia - although patient specific - is usually a rational option. Determining which AChEI to use depends on patient tolerability, patient and clinician preference, and overall cost.
- Rivastigmine and galantamine are linked with more severe gastrointestinal (stomach) side effects than donepezil.
- Donepezil is dosed once daily and is most affordable.
- The patch form of rivastigmine is associated with significantly less stomach issues than the oral, but may be more costly.
- Studies have shown that the efficacy among the three available agents appears similar but modest, and not all patients may see positive benefits.
MOA: Memantine (Namenda)
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, an NMDA receptor antagonist is thought to be neuroprotective, but in patients with early, mild AD, benefits are limited.
Memantine, FDA-approved in 2003 for the treatment of moderate-to-severe Alzheimer's dementia, does have modest benefits in these patients.
Memantine comes in several strengths and dose forms to help ease dosing for the patient.
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. The maintenance dose for the IR form is 10 mg twice a day and 28 mg once daily for the ER form.
- To start treatment, the initial dose is 5 mg IR once daily, titrated once weekly to a max dose of 20 mg/day IR in twice daily divided doses.
- The initial dose for the ER formulation is 7 mg once daily and titrated weekly to a max dose of 28 mg/day. Patients taking the 10 mg IR tab twice a day may switch to the 28 mg ER once daily form starting the day after the last IR dose.
It's important to titrate slowly between dose increases; one week in the typical time frame between dose changes. Only increase dosage if the patient is tolerating the previous dose.
The ER formulation and liquid dose form is considerably more expensive then the IR tablets, so comparing prices might be needed when determining dosing.
Memantine: ADRs and Place In Therapy
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, delusions, and hallucinations may also occur.
- GI symptoms such as constipation, diarrhea, and vomiting can occur, but not as severely as with the AChEIs.
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.
How to Dose Namzaric
Namzaric (donepezil/memantine), FDA-approved in 2014, is a combination drug containing donepezil and extended-release memantine given once daily. It is approved for moderate to severe Alzheimer's dementia.
Namzaric is available in two strengths: memantine ER 14 mg/donepezil 10 mg IR and memantine ER 28 mg/donepezil 10 mg IR strengths.
- If your patient is only taking donepezil 10 mg, the recommended starting dose of Namzaric is 7 mg memantine/10 mg donepezil taken once a day in the evening. Increase the dose gradually, if well tolerated, from the 7 mg/10 mg to the maximum daily maintenance dose of 28 mg/10 mg over at least 4 weeks. The minimum recommended interval between dose increases is one week.
- Patients on memantine hydrochloride (10 mg twice daily or 28 mg extended-release once daily) and donepezil hydrochloride 10 mg once daily can be switched to Namzaric 28 mg/10 mg, taken once daily in the evening.
- 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 Dosing in Renal Impairment
For patients with severe renal impairment (creatinine clearance 5-29 mL/min):
- If your patient is only on the donepezil 10 mg once daily dose and not on memantine, the recommended maintenance dose for Namzaric is 7 mg/10 mg once daily in the evening. If well tolerated and after a minimum of one week, increase to the recommended maintenance dose of 14 mg/10 mg once daily in the evening.
- If your patients is stabilized on memantine hydrochloride (either 5 mg twice daily or 14 mg extended-release once daily) and donepezil hydrochloride 10 mg once daily, they can be switched to Namzaric 14 mg/10 mg, taken once daily in the evening.
The cash price for Namzaric is high, costing roughly $450 per 30 capsules without insurance and using an online coupon. The generic form of extended-release memantine is not expected until 2025.
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 (2D6 and 3A4). The use of drugs with anticholinergic properties should be avoided as they can worsen cognition and cause delirium.
Caregivers and healthcare providers can check Drugs.com for a full overview of specific drug interactions with AChEIs and memantine, or any other drug combination.
Just a Sampling of Possible Drug Interactions
In AD patients taking AChEIs and/or memantine:
- Azole antifungals (potent 3A4 inhibitors) + AChEIs
- Anticholinergics + AChEIs (pharmacologic antagonism)
- Other NMDA antagonists (amantadine, dextromethorphan) + memantine
- 2D6 or 3A4 substrates/inhibitors + donepezil or galantamine
- AChEIs + some cardiovasculars > bradycardia, syncope
- AChEIs + cholinergics
- AChEIs + antipsychotics (all antipsychotics contraindicated in elderly w/ dementia; see boxed warning)
What About Vitamin E?
Overall, the benefits of taking a vitamin E supplement are likely to be modest in patients with Alzheimer's dementia. Cardiovascular safety may be a concern.
In a large VA study published in JAMA in 2014, 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 functional decline (a delay of approximately 6.2 months) than study volunteers who received a placebo. 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.
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:
- Problems with hearing or vision
- Changes in caregiving
- Hospital admission
- Lack of privacy
- 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.
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.
- However, 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.
Physical or mechanical restraints should be avoided unless the patient presents an immediate risk of physical harm to themselves or others.
Families and practitioners should have a frank discussion on the risks of antipsychotic therapy early on. 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 2018.
Patients, caregivers, or providers may also call 800-272-3900. Healthy participants are need, too.
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, and sleep disturbances. Not a 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
- 2018 Alzheimer's Disease Facts and Figures. The Alzheimer's Association. Accessed April 30, 2018 at https://www.alz.org/documents_custom/2018-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 April 30, 2018 at https://www.alz.org/research/clinical_trials/find_clinical_trials_trialmatch.asp
- Press D, et al. Treatment of dementia. Up To Date. Accessed April 30, 2018 at https://www.uptodate.com/contents/treatment-of-dementia
- Press D, et al. Management of neuropsychiatric symptoms of dementia. Up to Date. Accessed April 30, 2018 at https://www.uptodate.com/contents/management-of-neuropsychiatric-symptoms-of-dementia
- Seritan AL. Prevent drug-drug interactions with cholinesterase inhibitors. Vol. 7, No. 2 / February 2008. Accessed April 30, 2018 at https://www.mdedge.com/psychiatry/article/63014/prevent-drug-drug-interactions-cholinesterase-inhibitors
- 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 April 30, 2018 at http://jama.jamanetwork.com/article.aspx?articleID=1810379
- Namzaric Product Labeling. Allergan 2016. Accessed April 30, 2018 at http://www.allergan.com/assets/pdf/namzaric_pi
- The Alzheimer's Association. Behavioral Symptoms. Accessed April 30, 2018 at https://www.alz.org/professionals_and_researchers_14310.asp#managing
- The Alzheimer's Association. Health Care Professionals and Alzheimer's. Accessed April 30, 2018 at https://www.alz.org/health-care-professionals/clinical-guidelines-dementia-care.asp