Alzheimer's Disease Treatment Options: A Healthcare Professional's Guide
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).
Roughly 5.5 million people in the U.S. are living with AD, and one in three seniors dies with Alzheimer's or another dementia. It is the 6th leading cause of death in the U.S. and over 60% of those with AD are women. In fact, it's the only top 10 cause of death in the US that can't be prevented, cured, or slowed. Also concerning, by 2050, the healthcare costs of Alzheimer's and other dementias are projected to approach $1.1 trillion.
Overview: Treatment Options
The limited treatment options available in Alzheimer's dementia include:
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, rivastigmine, and galantamine. Tacrine was the first approved AChEI in 1993, but was later removed from the U.S. market due to unacceptable 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/day 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. 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 GI tolerability, but rash could be an issue. Dose adjustments in renal or hepatic 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 an IR oral solution, or in 8, 16, and 24 mg extended-release (ER) capsules. Generics are available.
The starting dose in mild to moderate Alzheimer dementia is typically 4 mg twice a day, increased in monthly intervals by 4 mg twice daily increments to the 12 mg twice daily maintenance dose. The ER form usually starts with 8 mg each morning, titrating the dose by 8 mg ER every 4 weeks to a maximum of 24 mg ER per day.
Give doses with food, and be sure the patient maintains adequate hydration. Nausea is a common side effect. Dose adjustments are required with renal or hepatic impairment.
Common ADRs With Cholinesterase Inhibitors
Gastrointestinal adverse effects are common with AChEIs: diarrhea, nausea, vomiting, weight loss and anorexia. 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 rash.
Other common side effects with AChEIs may include headaches, dizziness, agitation, insomnia, and urinary tract infections. 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
- AV block
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 (GI) side effects than donepezil. Donepezil is dosed once daily and is most affordable. The patch form of rivastigmine is associated with significantly less GI 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 AD. Memantine, a NMDA receptor antagonist is purported 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 (AD), does have modest benefits in these patients.
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 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.
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 are still issues, 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.
A Donepezil/Memantine Combo
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 in patients already taking the IR form of memantine 20 mg/day or the ER form of memantine 28 mg/day - plus 10 mg/day of donepezil (Aricept).
Namzaric is available in two strengths: memantine ER 14 mg/donepezil 10 mg IR and memantine ER 28 mg/donepezil 10 mg IR strengths. The cash price is high, costing roughly $400 per 30 capsules without insurance. 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 here for a full overview of specific drug interactions with AChEIs and memantine, or any other drug combination.
Just a Sampling of Possible Drug Interactions
- 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?
In a large VA study published in JAMA in 2014, 613 patients 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 percent slower rate of functional decline than study volunteers who received a placebo. Less benefit was seen in groups taking memantine plus Vitamin E. This study suggested a 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 AD.
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.
Besides disease progression, other medical issues and environmental conditions may play contributing roles. 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. Physical or mechanical restraints should be avoided. However, according to the Alzheimer's Association, there may be instances where risk to individuals and families living with dementia are greater than risk from antipsychotic medications. Read the Alzheimer's Association position statement on behavioral disturbances, restraint and antipsychotic use. 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.
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 promising clinical studies being conducted at nearly 700 trial sites across the country as of April 2017. Patients, caregivers, or providers may also call 800-272-3900.
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. 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
- 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.
- Up To Date. Treatment of dementia. Accessed January 9, 2017 at http://www.uptodate.com
- Seritan AL. Prevent drug-drug interactions with cholinesterase inhibitors. Vol. 7, No. 2 / February 2008. Accessed January 9, 2017 at http://www.currentpsychiatry.com/home/article/prevent-drug-drug-interactions-with-cholinesterase-inhibitors/956e1f600ba13c2ed287aca3d113fe7d.html
- 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 January 9, 2017 at http://jama.jamanetwork.com/article.aspx?articleID=1810379