But were they told what to expect, and how to judge if the medication is worth continuing?
I’ve noticed that patients and families often aren’t told much about how well these medications generally work, and or how to determine if it’s likely to help in your situation.
So in this post, I’ll explain how the four medications in wide use work. I’ll also address some of the frequently asked questions that I hear from older adults and families.
If someone in your family is taking one of these medications or considering them, this will help you better understand the medication and what questions you might want to ask the doctors. It’s especially important to understand the pros and cons if finances or medication costs are a concern.
Note: This article is about those drugs that have been studied and approved to treat the cognitive decline related to dementia. This is not the same as treating behavioral symptoms (technically called “neuropsychiatric” symptoms) related to dementia, such as paranoia, agitation, hallucinations, aggression, sleep disturbances, wandering, and so forth. There are no drugs FDA-approved to treat the behavioral problems of dementia. The off-label use of psychiatric medications, such as Seroquel, in dementia is covered here: 5 Types of Medication Used to Treat Difficult Dementia Behaviors.)
4 Medications FDA-Approved to Treat Dementia
FDA-approved medications to treat Alzheimer’s and related dementias basically fall into two categories:
Cholinesterase inhibitors. These help increase the amount of the neurotransmitter acetylcholine in the brain. Acetylcholine helps neurons function well.
- Three such medications are FDA-approved to treat Alzheimer’s in “mild to moderate” stages:
- Donepezil (brand name Aricept)
- Rivastigmine (brand name Exelon)
- Galantamine (brand name Razadyne)
- Tacrine is a fourth cholinesterase inhibitor which was FDA-approved but is no longer in use due to a much higher risk of side-effects
- Donepezil and rivastigmine have also obtained FDA-approval for the treatment of more advanced dementia
(For more on what “mild-to-moderate Alzheimer’s disease” means, see “How to Understand the Stages of Alzheimer’s & Other Dementias.”)
Memantine. This is the name of an actual drug rather than a class of drugs, but since it’s the only one available of its type, experts consider it the second category of dementia treatment drug.
- Memantine (brand name Namenda) is FDA-approved to treat “moderate to severe” Alzheimer’s disease
- Memantine is an “N-methyl-D-aspartate (NMDA) receptor antagonist.” It dampens the excitatory effect of the neurotransmitter glutamate in the brain.
Since over-excitation of the neurons has been associated with neurodegenerative disease, memantine is considered a “neuroprotective” drug. Hence it is potentially a “disease-modifying treatment.”
In comparison, cholinesterase inhibitors are considered “symptomatic treatment,” as they affect the function of neurons but not the underlying health of neurons.
In other words: memantine might slow down the underlying progression of Alzheimer’s, even if it doesn’t appear to be helping a person. Cholinesterase inhibitors don’t change the underlying progression of Alzheimer’s, but they can potentially help a damaged brain work a little better.
What about the “new” Alzheimer’s drug?
You may have also heard that on June 7, 2021, the FDA approved a new drug for the treatment of Alzheimer’s disease, aducanumab (Aduhelm). The approval was controversial, as the FDA’s scientific advisory panel had recommended not approving this treatment. In 2022, Medicare announced limited coverage and essentially will only cover the cost of the drug for those who are in clinical trials and meet certain other criteria.
Aducanumab is an antibody treatment that works by reducing amyloid-beta plaques in the brain. In the studies that led to FDA approval, it was only used in patients who had proven amyloid in the brain on PET scan, and were otherwise in the “mild cognitive impairment” stage or early-stage of Alzheimer’s disease.
In studies, aducanumab did seem to reduce amyloid-beta in the brain. However, it’s not yet known if this will translate to meaningful improvements in cognition or if this will delay the progression of Alzheimer’s. (It certainly is not going to reverse or “cure” Alzheimer’s.) Furthermore, serious side-effects such as brain swelling or small bleeds in the brain affected at least 10% of patients.
Here is a good overview of the aducanumab controversy: Aducanumab for Alzheimer’s disease?
The remainder of this article will focus on cholinesterase inhibitors, memantine, and other options widely available to people with Alzheimer’s and other forms of dementia. I will also explain what is known about these medications for mild cognitive impairment.
Frequently Asked Questions About Dementia Medications
How well do cholinesterase inhibitors work?
This is a topic that has been intensively studied and somewhat debated. Of note, most major studies of cholinesterase inhibitors are industry-funded; only the AD2000 trial was not industry-funded.
Overall, in mild to moderate Alzheimer’s disease, the average benefit seems to be a small improvement in cognition and ability to manage activities of daily living. The effect has been sometimes compared to a few months delay in progression of symptoms. (It is not clear that treatment with cholinesterase inhibitors affects long-term outcomes such as the need for nursing home level of care.)
A 2008 review of the scientific evidence concluded that the effect of these drugs is statistically significant but “clinically marginal.” This conclusion was also reached by a 2018 review of the evidence.
But there’s a catch to consider: studies also suggest that although a fair number of people (30-50%) seem to experience no benefit at all, up to 20% may show greater than usual response. So there seems to be some individual variability in how these drugs work for people.
It may also depend on the type of dementia a person has, with some studies suggesting cholinesterase inhibitors have an effect in many people with Parkinson’s disease dementia, and perhaps also dementia with Lewy bodies.
To date, we have not developed any good ways to tell ahead of time who will respond to these drugs.
So it’s important to follow a person’s cognitive symptoms, and side-effects, once they start taking a cholinesterase inhibitor. If it doesn’t seem to be helping, it’s reasonable to consider stopping the medication after a few months.
How well does memantine work?
In people with moderate to severe Alzheimer’s, memantine seems to provide some benefits, in terms of slowing the deterioration of Alzheimer’s. But again, the benefit overall seems to be fairly modest.
It’s not at all clear that people with mild to moderate Alzheimer’s benefit from memantine; a 2011 review concluded that the scientific evidence doesn’t support this claim. This was confirmed by a 2019 review of memantine for dementia.
Do these medications work for dementias other than Alzheimer’s disease?
Bear in mind that the older people get, the more common it is to have mixed dementia, and the harder it is to make a specific determination of the underlying cause of dementia. In geriatrics, we generally assume there is mixed dementia if people are over age 85. (For more on how common mixed dementia is, see this article about the Religious Orders Study and Rush Memory and Aging Project.)
Studies generally find that cholinesterase inhibitors are associated with modest improvements in symptoms in Lewy Body dementia and Parkinson’s dementia.
A 2021 review of cholinesterase inhibitors for vascular cognitive impairment concluded that there is evidence of “a slight beneficial effect on cognition in people with VCI, although the size of the change is unlikely to be clinically important.” (Of note, the mean age of participants in those studies was 73.)
For memantine, some research suggests it can help with vascular dementia, although the benefits again seem to be quite modest.
The effect of memantine on Lewy-Body dementia and Parkinson’s dementia is less clear, with some research suggesting a small benefit but also reports that some people experience worsening hallucinations and delusions with memantine.
Do these medications work for mild cognitive impairment?
Not as far as we know. The research evidence so far indicates that dementia medications do not improve outcomes for mild cognitive impairment.
However, it remains very common for patients with mild cognitive impairment to be prescribed donepezil (brand name Aricept) or another cholinesterase inhibitor.
In principle, this should be done as a trial, meaning that the patient and clinician decide to “try” the medication, see if it’s helping with memory or other thinking difficulties, and stop if it doesn’t appear to be helping.
In practice, many people with mild cognitive impairment end up taking the cholinesterase inhibitor indefinitely. They may be reluctant to stop, but in other cases, it may be that the prescribing doctor doesn’t get around to checking on whether the medication is helping or not.
For more on mild cognitive impairment, see How to Diagnose & Treat Mild Cognitive Impairment.
What are the side-effects of these medications?
Doctors — including geriatricians — consider these medications to be “well-tolerated.” This means that most people don’t experience more than mild side-effects, and serious adverse events are rare.
For cholinesterase inhibitors:
- The most common side-effects are gastrointestinal and include nausea, diarrhea, and sometimes vomiting. These affect an estimated 20% of people.
- People tend to adjust to gastrointestinal side-effects with time. It helps to start with a small dose and gradually increase. Rivastigmine is also available in a patch formulation, which tends to cause less stomach upset.
- In the oral formulations, donepezil tends to cause fewer side-effects than rivastigmine and galantamine.
- Some people also experience dizziness, a slowed heart rate, headaches, or sleep changes.
- Dizziness is probably the most common side-effect.
- Some people seem to experience worsened confusion or hallucinations.
- Memantine generally seems to cause fewer side-effects than cholinesterase inhibitors do.
Is it common to take more than one medication for dementia at the same time?
It’s quite common for patients to be prescribed a cholinesterase inhibitor plus memantine.
This “combination therapy” has been studied in people with moderate-to-severe Alzheimer’s, and some research suggests a small benefit compared to treatment with just one medication. However, the benefit again appears to be modest at best.
A study of combination therapy in people with mild-to-moderate Alzheimer’s did not show benefit.
Although there is no good research evidence indicating that combination therapy is beneficial in mild Alzheimer’s, in my experience it’s common for people with mild Alzheimer’s to be prescribed combination therapy. Probably this happens because patients — and doctors — want to try anything that “might” work. In most cases, combination therapy for people with mild Alzheimer’s doesn’t seem to be harmful. But, it’s probably not doing much, other than increasing medication costs.
There is no reason to take more than one cholinesterase inhibitor at the same time.
At what point do you stop dementia medications? We’re not sure it’s making a difference.
Many patients and families feel these medications don’t have much effect. This isn’t surprising, since the research results usually find that the effect in most people is small to non-existent.
As cholinesterase inhibitors are “symptomatic” treatment and not disease-modifying, if there’s no sign of improvement after a few months on the maximum dose, many experts agree that it’s reasonable to stop the medication.
That said, as these medications are well-tolerated by most patients and are unlikely to cause harm to anything more than one’s wallet, it’s common for people to remain on cholinesterase inhibitors indefinitely.
As for memantine, this drug is potentially “disease-modifying.” So it may make sense to continue memantine for a few years, even if no improvement is noted by the clinician or family.
Experts generally agree that there’s not much value in continuing either category of medication once a person has reached the stage of advanced dementia, at which point a person is bedbound, unable to speak, and shows little sign of recognizing familiar people.
Do people get worse when they stop dementia medications?
Research suggests that some patients do appear to get worse after stopping cholinesterase inhibitors.
If this appears to be the case, it’s reasonable to resume the cholinesterase inhibitor.
The discontinuation of memantine hasn’t yet been rigorously studied. An observational study of nursing home residents suggested some worsening after stopping memantine.
A Canadian consortium of experts published guidelines on the deprescribing of dementia medications in 2022.
Do any vitamins help treat dementia?
Vitamin E — which works as an anti-oxidant in the body — has been studied for the treatment of Alzheimer’s, and may be beneficial.
In 2014, a large study of patients with mild-to-moderate Alzheimer’s disease found that daily treatment with 2000 IU/day of Vitamin E resulted in less functional decline than treatment with placebo, memantine, or a combination of memantine and vitamin E.
Of note, since the study was conducted in the VA (Veteran’s Affairs) health system, most participants were men. And again, the benefit seen was modest.
It is not clear that vitamin E helps for mild cognitive impairment. Always talk to a doctor before trying vitamin E for brain health, as vitamin E can increase bleeding risk in some people.
No other vitamins have been shown to slow cognitive decline in Alzheimer’s or other dementias. In particular, although low vitamin D levels have been associated with a risk of developing dementia, no clinical research has shown that treatment with vitamin D helps people maintain cognitive function.
A study of vitamin B supplementation in the treatment of people with mild to moderate Alzheimer’s disease did not show any benefit. Note that participants in this study had normal vitamin B12 levels at baseline; the very common problem of vitamin B12 deficiency in older adults can cause or worsen cognitive problems.
A practical approach to dementia medications
It’s easy to get a bit lost in the weeds, when it comes to medications to treat the cognitive decline of Alzheimer’s and other dementias.
Overall, these are medications that seem to offer only a little — if any — benefit to most people.
In particular, using these medications is unlikely to help a person with Alzheimer’s remain cognitively well enough to live at home safely, or otherwise provide the type of improvements that families are often hoping for. (The effect of these drugs is just not that strong.)
These drugs are indeed widely prescribed, because patients are usually anxious to do everything possible to preserve their mental abilities, and because doctors want to be able to offer *something*. And most of the time, they don’t seem to harm patients or cause significant side-effects.
I think it’s reasonable for people to take or try these medications, as long as they are aware of the evidence regarding the usually modest benefits.
So what should you do about medications, if you or your older relative has been diagnosed with Alzheimer’s or another dementia?
If you have already been on dementia medications for a while:
If you aren’t experiencing side-effects, you may want to continue on the medications indefinitely.
But if you are concerned about medication expenses and pill burden, consider a trial of stopping the medication.
After all, the overall benefit of these medications is small. And you can always restart dementia medications if you think the dementia symptoms got worse off the medication.
If you are just starting the dementia journey:
If you are debating whether to start medications for dementia, keep in mind the following points:
- Only cholinesterase inhibitors are FDA-approved for mild to moderate dementia. You should definitely ask questions if a clinician proposes starting memantine during the early stages.
- Cholinesterase inhibitors are for symptomatic treatment and do not alter the underlying neurodegeneration. They provide a modest benefit to some people but many people don’t seem to benefit. We are not yet able to tell ahead of time whose symptoms will improve with these medications.
- A reasonable and careful approach is to work with the doctor on a “trial” of a cholinesterase inhibitor. This means:
- Carefully documenting cognitive symptoms before starting the medication.
- Starting the medication at a low dose, and increasing to a full dose over time.
- Monitoring for side-effects, such as nausea, vomiting, or diarrhea. These do usually get better with time. Consider lowering the dose or switching to a patch formulation if the side-effects are difficult to handle.
- Working with the clinician to reassess cognitive symptoms after 2-3 months. If no improvement has been noted by the patient, family, or clinician, consider stopping the cholinesterase inhibitor.
Other ways to preserve cognition and brain function in dementia
Here’s the most important thing to keep in mind, when it comes to managing the cognitive decline of Alzheimer’s and other dementias:
Medications are only a small part of the solution.
In fact, there are many non-drug ways to optimize brain function. They work for people who don’t have dementia too, so I’ve listed them in this post: How to Promote Brain Health: The Healthy Aging Checklist Part 1.
If you’re concerned about preserving brain function and delaying cognitive decline, you’ll want to review the ten approaches I cover in the brain health article.
For instance, people often don’t realize that many commonly used medications are “anticholinergic,” meaning they interfere with acetylcholine in the brain and worsen thinking. In other words, these medications essentially have the opposite effect of the cholinesterase inhibitors. Which is not so good for the brain.
In a perfect world, your doctors and pharmacists would notice this problem and stop the anticholinergic medications, or at least discuss the pros and cons with you. But as our healthcare system is still highly imperfect, this may not happen unless you ask for a medication review.
Delirium is another common problem that can worsen dementia and often accelerates cognitive decline. So to manage dementia and delay cognitive decline, it makes sense to learn about delirium prevention.
The bottom line on medications to treat dementia
In short: the medications we currently have available to treat Alzheimer’s disease and other medications may help a little. The main harm people experience will be to their wallets. Don’t expect these drugs to work miracles and consider stopping them if you are concerned about drug costs or pill burden.
And above all, don’t forget to think beyond medications, when it comes to optimizing brain function and delaying cognitive decline in dementia.
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