Goals of Therapy With the Modern Armamentarium for AD

Jeffrey L. Cummings, MD, ScD: Elaine, could you go over the available therapy for the treatment of Alzheimer disease?

Elaine R. Peskind, MD: As you know, Jeff, the FDA-approved medications for Alzheimer disease include 3 cholinesterase inhibitor drugs and one NMDA [N-methyl-D-aspartate] receptor drug. And I’ll tell you what I tell my patients. I say to my patients and their families, “My goal is to keep you the way you are now for as long as we can.”

It is really to try to plateau them for several years, try to slow progression. And I’ve been in research and clinical practice in Alzheimer disease for 40 years now, and I have had the experience of taking care of patients in the era before these drugs were approved, and the era since. I’ve even taken care of siblings with mutation-caused Alzheimer disease, 1 before and 1 after, and I feel that it is different. I didn’t used to have patients who would stay level for a year or 2 years, maybe even 3. I had patients who would sink like a stone in the era before. And I really do think they’re a benefit.

Jeffrey L. Cummings, MD, ScD: Ali, I think you’ve written about the benefit of combination therapy in terms of disease stabilization.

Alireza Atri, MD, PhD: I have, Jeff, and I think your experience, Elaine, is true, and it’s backed up by evidence now: 20 years of meta-analysis and reviews for both randomized clinical trials, and then observational cohorts beyond that show that there are benefits for patient groups. And the question is really, which individuals have greater benefits? Some may have fewer benefits. We don’t know that, so that’s why as part of the strategy it’s actually explained to individuals, the patients and the care partners, what the expectations really are. People want maintenance of a personhood and quality of life. They want to delay disability.

I think that the totality of evidence shows that these medicines can actually do that and help. In mild-to-moderate stages of Alzheimer disease, as a group, patients decline within 6 months quite a bit, even in randomized controlled trials in the placebo arms. We know that this is actually an aggressive disease. So having stability for 6 months or a year overall is a win for us. In the long-term decreasing decline, we can’t stop the aging process and other things. We do lose function.

For me, I really want to make sure that people have the knowledge and appreciation and the right expectations for these drugs, so that’s one. But actually the first thing that I do is a medication review and get rid of the redundant medications. I look at Beers Criteria to make sure if they’re on anticholinergic medications, I get them off that. I get some benefit from that.

The other things I do is, I want to make sure that comorbid conditions are treated correctly, so their blood pressure and glucose and things like that. There are data that if you do that people actually benefit and are on a slower path of decline. The other thing I do is if there are other comorbid conditions, like true depression, I want to treat that. And I’m somebody who actually still uses vitamin E in the right individuals. Because 2 randomized control studies have shown that actually it could decrease decline by about 20%. But I would say using the cholinesterase inhibitors, stage appropriate, starting on the earlier timescale, and then adding memantine is a good strategy, and there are a lot of data for that.

Jeffrey L. Cummings, MD, ScD: Sticking with the theme of cholinesterase inhibitors, Marwan, I wonder if you could talk a little bit about the mechanism of action of these drugs, where they’re indicated, and what are the efficacy expectations?

Marwan Sabbagh, MD: The cholinesterase inhibitors have 3 in the class: donepezil, rivastigmine, and galantamine. They are acetylcholinesterase inhibitors, so the neurotransmitter, acetylcholine, is released from 1 neuron. It’s supposed to be bound to the postsynaptic neuron through 2 receptors, either the muscarinic or nicotinic receptor. It’s degraded by an enzyme called acetylcholinesterase. And the inhibitors basically prevent that degradation from occurring, so the acetylcholine will stay, the neurotransmitter stays in the synaptic area longer and has a pro effect on electrical discharge transmissions, etcetera. That’s how they work, and the data suggest it’s a normal mechanism. We borrowed that from peripheral disease 25 years ago when we did the same thing with myasthenia gravis for pyridostigmine, so this is a central adaptation of that concept. Because we understand very early on that there’s a cholinergic deficit.

Memantine or NMDA antagonists are partial glutamate sensitive, a partial antagonist of the glutamate receptor. They’re not a total antagonist like ketamine would be, so because some of the absolute antagonists of NMDA receptors have been shown to cause psychotic features, whereas memantine does not. Memantine is supposed to normalize calcium homeostasis and therefore restore glutamate function back to a normal state. I find these drugs work synergistically. I would not say 1 excludes the other. I will say that the cholinesterase inhibitors do have a strong class effect around GI [gastrointestinal] adverse effects: nausea, weight loss, anorexia. I’ve spent a lot of my day job managing those. I tend to use these drugs in conjunction with the others, meaning a cholinesterase inhibitor with a memantine, not cholinesterase inhibitors ever together. I would never do that.

Jeffrey L. Cummings, MD, ScD: Never together, right. Ali?

Alireza Atri, MD, PhD: The major thing about that, Marwan, is one of the things I really make sure to do is teach people the strategies about monitoring. I find that a lot of the reported adverse effects are in individuals who are taking the medicines themselves, so they go on and off. They may double up. They may be dehydrated. One of the other issues is that they may take it at night and it keeps them awake. So I really make sure that they have a partner, and they’re not leaving it up to the individual with a memory disorder to actually take their medicines. For cholinesterase inhibitors, take them in the morning after breakfast. It’s something to supervise and monitor with a pillbox. I think those things are really important that can diminish really the adverse effects.

Jeffrey L. Cummings, MD, ScD: That’s a great point on the practical management of these medications. Elaine, how would we know whether the cholinesterase inhibitors and memantine are working? What are the measurement strategies?

Elaine R. Peskind, MD: Well, there are a number of things you can do, and I do a structured cognitive screening test every year like the MoCA [Montreal Cognitive Assessment] or the Mini-Mental State Exam. However, you never know in a single patient whether they would be doing worse if they weren’t taking the cholinesterase inhibitor and memantine. So I take a fairly informal approach. If the caregiver feels that the patient is doing pretty well, I continue, and I think this means continue until very late-stage disease.

Jeffrey L. Cummings, MD, ScD: The information from the caregiver is the key.

Elaine R. Peskind, MD: To me that’s the most important thing, and I supplement that with a cognitive screening test taken yearly.