Approved Therapies in Alzheimer Disease

Alireza Atri, MD, PhD: Switching gears a little, let’s talk about currently approved FDA medicines for Alzheimer disease. Marc, can you tell us a little about what they are? What’s their mechanism of action, and what do you tell people about expectations with these medicines?

Marc E. Agronin, MD: Sure. We know we don’t have a cure for Alzheimer disease or for the other major forms of dementia. There is a lot of research that we’ll talk about, but we don’t yet have anything effective to slow it down. What we do have are 4 different FDA-approved medications that can improve symptoms. There are 2 different classes. The first is the class of acetylcholinesterase inhibitors. They work by increasing the amount of acetylcholine in the brain. We know that early on in Alzheimer disease, in particular—and this is likely an element of other forms of dementia—the neurons that are critical for learning and memory depend upon the neurotransmitter acetylcholine to work, to function. And so as you have those cells being damaged and levels of acetylcholine dropping, by interfering with the breakdown of acetylcholine—so interfering with the enzyme acetylcholinesterase—by inhibiting it, we can increase levels of acetylcholine. We know through lots of good research that the 3 medications—donepezil, rivastigmine, and galantamine—can increase levels of acetylcholine and can have a positive benefit. It’s a modest but still positive benefit, primarily for cognition. It’s important that we educate patients and caregivers that, at best, it’s a modest impact. It doesn’t slow it down. It doesn’t cure it. But the benefits are clear.

And so the goal is to get someone started on 1 of these. They’re all equal, in terms of efficacy. But get started on 1 of them early. Monitor for some of the most common adverse effects, especially gastrointestinal-related adverse effects, like nausea, vomiting, and diarrhea. Get them on an initial dose. Then we titrate to an effective dose, or therapeutic dose. And that’s important because sometimes doctors will start the medication, but they don’t always push it to the therapeutic range. And that’s really critical to do.

There’s another category for which there’s 1 medication called memantine, which is an NMDA [N-methyl D-aspartate] or glutamate receptor antagonist. We know that in Alzheimer disease and other forms of dementia there appear to be excess glutamate activity, which has a neurotoxic effect. Some memantine modulates that—reduces that effect. We know that similar to acetylcholinesterase inhibitors, it can have a positive impact on cognition in particular. It’s modest but positive.

Because these are 2 different mechanisms of action, we ultimately aim to combine an acetylcholinesterase inhibitor with memantine. And we know—and this is some of the research that you’re very familiar with—that the combination, over time, might be synergistic and can provide a better cognitive outcome.

There are some data suggesting that it might have a muting effect on behavioral changes. Although we know these medications have not been shown to actually treat behavioral disturbances, it just speaks to their overall benefit. This is part and parcel of the FDA-approved treatment that we give people. I would just add that there are so many other pills and potions out there that are touted to be brain tonics that do not have efficacy, even though they have good advertising behind them. They don’t have the efficacy of these medications to be effective for Alzheimer disease and other forms of dementia. And so this is why these categories are the staple of our treatment.

Transcript edited for clarity.