As I understand Alzheimer's is a neurodegenerative disorder, impacts the hippocampus, among other structures. There's been some debate in recent years as to whether or not the whole amyloid hypothesis is real or not. There's a bunch of unfortunately false data accusations and that whole thing. But my understanding is that if you look at a slice of human brain from a patient that died with Alzheimer's, maybe even from Alzheimer's, that you see plaques and tangles.

You see these sub-cellular structures and buildup and that our basic understanding of Alzheimer's that's in the textbook and that most people have heard of is still correct, right? Yes. Okay. Because I think a couple of years ago it was, you know, unfortunately the way social media sometimes can work is that, you know, the idea was that it was all wrong, you know, all wrong.

And somebody fudged data, they made up data and that's terrible. But Alzheimer's is a neurodegenerative disorder, includes the hippocampus, plaques and tangles are present in the neurons. Those are not good for neurons as I understand. So what's the controversy like and why don't we have a treatment for Alzheimer's yet?

I feel like almost every other psychiatric disease, including Parkinson's, like there are certain things you can do to at least push the system in the right way. Why is Alzheimer's and other dementias so tricky? Yeah, I mean it's very frustrating because the neurodegenerative disorders, it's so many factors that are probably involved in the pathology that there's not, you know, one single transmitter.

The Parkinson's disease, it's a decreased dopamine and so one transmitter can make a very big difference. Early on in Alzheimer's it was discovered that there was low acetylcholine in the brains and the only approved treatment for Alzheimer's disease is a drug that boosts acetylcholine. What's the drug? It's called Donepezil.

There's a few of them, they're anticholinesterase inhibitors that boost acetylcholine. They've been around for 20 years or more and, you know, the reality is when you give it to your patients they don't see much of a difference because it's not the primary deficit. So the real problem has been trying to find out what is the primary mechanism that's leading to this wide range of cognitive behavioral issues and there doesn't seem to be at least one neurotransmitter that can make the difference and so now the push has been is there one, is there something else that we can do?

Can we block amyloid? Can we block something in the pathology and again it just has not been successful. It's very frustrating because I think it was over probably 35 years ago I saw my first Alzheimer's patients and I don't believe I say that much different to them now, you know, except that we have a lot more things we can do just on the social side of things.

But unfortunately for drugs we don't have anything that's been really transformative. But again that's I think part of being a neurologist it sounds very depressing but I think part of what the family isn't always looking for a cure, of course that's they'd like to have a cure but I think them understanding what's going on, what to expect, how to handle the behaviors is what they're really after at least until we find, you know, a cure.

Parkinson's, you mentioned, is a deficit in dopaminergic function due largely to degeneration of dopaminergic neurons. There there's some effective treatments, right? L-Dopa. Did you know there's this over-the-counter stuff that's sold that a lot of people take who don't have Parkinson's? I'm not suggesting they take it called mucuna prurines, it's the velvety bean.

Yeah, I've heard of it. It's 99% L-Dopa. I've heard of it, yeah. It's in present in like some energy drinks and supplements and people can go buy it. I'm not suggesting they do that. I actually tried it, boy, I feel being really dopamined out does not, to me doesn't feel that good.

Yeah, I felt kind of agitated, my vision got a little, you know, twinkly, it did not feel like a high of any kind and then I felt lousy for a couple hours after it wore off. Yeah, I don't think you can really get in enough L-Dopa to get enough into your brain.

That happened early in neurology when it was discovered we couldn't give our patients enough L-Dopa without them feeling bad because it's also metabolized in the periphery. And so it wasn't until we, Sinemet came along, which has this decarboxylase inhibitor that blocks sort of the breakdown of dopamine that we were able to sort of get enough dopamine into the brain.

So I'm not sure, yeah, so that's why I think it's not going to probably get the levels up high enough in the brain. So Parkinson's patients are given L-Dopa or bromocriptine or drugs like that. Going back to Alzheimer's for a moment, I mean, what do you tell somebody who has early stage Alzheimer's?

You just say, listen, try and get good sleep, try and keep people around you, stay cognitively engaged, try and keep those circuits going through behavioral induced neuroplasticity. But we're just going to watch the steepness of the decline. Is that really all we've got? - All we've got is to help them with everything that comes up on a day-to-day basis.

A lot of the problems, the memory problems tend to be something that families can help compensate for, but you do get to a point where you can't be with someone for 24/7. It's a real burnout for caregivers. A lot of the behaviors that come up, patients get kind of delusions and agitated, and some of the medications that we use for other conditions are helpful for treating that.

But it's really just a purely symptomatic therapy. And the more socialization that patients get, they tend to do better. There was a study back at Penn, way back, that if you showed patients some family movies or family albums, it was better than any drug you could give them to sort of help their behavior.

So there's still those memories that are in there, and they were making some type of contact that was helping them emotionally that you couldn't turn off with a drug. So I think the more we do things like that, the more we'll be helpful for them, at least symptomatically. - I've seen a number of videos on social media of people with Alzheimer's who listen to a piece of music, or people with Parkinson's that hear a piece of music, and that seems to resurrect some at least context-appropriate emotional state, where it kind of brings the person to the surface again.

Yeah, it's kind of a tragic situation for Alzheimer's right now. It seems like if ever there was a call to arms for the neurology community and biotech and behavioral tech, it would be for Alzheimer's, for the treatment of Alzheimer's. I will never ask a guest to comment on the good or bad behaviors of other people, except my own.

But there's a Nobel Prize-winning neuroscientist, and I visited him, he's at a Big East Coast school back in 2010, and during the course of our one-hour meeting, he consumed no fewer than four pieces of Nicorette gum. And I said, "I got to ask, what's this about?" By the way, he's extremely sharp still.

And he said, "Oh, yeah, yeah, yeah, you know, I used to be a smoker, but smoking is really bad for you because you can get lung cancer, dipping is bad for you because you can get mouth cancer, but nicotine," these are his words, by the way, "is protective against Parkinson's and Alzheimer's, and it keeps my brain sharp, so I chew Nicorette all day long." And I thought, "Okay, well, he's not, he is an MD, actually." And I thought, "Oh, that's interesting." And I did an episode of this podcast on nicotine.

It, by the way, can raise blood pressure. It's certainly smoking, vaping, dipping, or snuffing, not good, bad, don't do it. But there is some interest in the use of nicotine as a cognitive enhancer. So I'd love to know your thoughts on that. And I'd love to know your thoughts on his statement about nicotine being a potential way to stave off Parkinson's and Alzheimer's, with the caveat that he just kind of threw that out there, and this guy's sort of known for just kind of throwing stuff out there every once in a while.

I have a feeling you know who this person is, but in any event, what gives? Yeah, well, I don't know anything about nicotine staving off any neurodegenerative disorder, but nicotine was used, and it was used in a number of early Alzheimer's studies just because of its effect on the cholinergic system.

So there is some truth to that. The cholinergic system is dysfunctional in Alzheimer's disease, and boosting the cholinergic system probably is beneficial. I mean, the patients that we give the anticholinesterase inhibitors, there are some families that say, "Yeah, he's remembering more, and he's just doing better." So I've seen positive things to it.

It doesn't really slow the course of the disease. That's the problem. The disease just carries on, even though we're symptomatically improving the symptoms. But again, I think it's going to take both acetylcholine and something else. I think we don't know, should we give dopamine with the nicotine or the acetylcholine?

Should we give norepinephrine? I think it's going to be a cocktail, which, again, pharmaceutical companies have not tried a cocktail of neuromodulators for Alzheimer's disease. They've just tried acetylcholine.