Chapter 12: Dementia: Causes, Symptomatic Treatments, and the Neurotransmitter Network Acetylcholine

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Welcome to the Deep Dive.

Today, we're taking on a topic that's, I mean, it's just massive on a global scale, but it's also so intensely personal.

The management of dementia.

It really is.

And we're going to try and synthesize a huge amount of research here to give you a shortcut to understanding what's going on under the hood that causes, and more importantly, how we're trying to manage the symptoms.

It's a field that changes so fast, but the basics are absolutely crucial.

We're talking about a condition that affects over 35 million people worldwide.

And that number is just, it's climbing.

It is.

Our goal today is to walk you through the core pathology, the modern diagnostics, and then really zeroed in on the pharmacology.

We're going to talk about how we try to fix the breakdown in the brain's neurotransmitter networks.

And what I find so fascinating right now is the pivot in the research.

For decades, the whole focus was on finding a disease -modifying therapy, a DMT, something to actually stop the destruction.

A silver bullet.

Exactly.

And since those efforts have largely stalled, the clinical reality has shifted.

Now the emphasis is really firmly on symptomatic treatments improving quality of life by managing memory, agitation, psychosis.

Precisely.

So we'll trace that logic.

We'll start with definitions, then the major causes, touch on the amyloid -talcascade, and then get right into the specifics of drug action.

We'll look at how we target acetylcholine and glutamate for memory, and then serotonin and dopamine for those really debilitating behavioral symptoms.

Okay, let's jump right in.

The first thing we need to clarify is a really key distinction.

The difference between just being a bit forgetful and actually having dementia.

We have to separate dementia from mild cognitive impairment, or MCI.

This is a critical clinical dividing line.

Dementia isn't just age -related forgetfulness.

It's a specific threshold.

It means the cognitive and neuropsychiatric symptoms are severe enough that they represent a definite decline, and they actively interfere with someone's ability to perform their usual daily activities.

Right.

So if you forget where you put your keys, but you can still manage your bills, that's one thing.

But if you start making major errors managing your finances, that's interference.

That's the line, exactly.

MCI, on the other hand, involves a measurable cognitive decline.

Maybe family members really notice the memory loss, but, and this is the key, it doesn't significantly affect the ability to carry out those daily living activities.

And the numbers for MCI are just staggering.

About 15 to 20 % of people over 65 have MCI, and once you're there, the risk of it progressing is high.

Very high.

Approximately 35 % of those individuals will develop Alzheimer's disease within just three years.

Wow.

Yeah.

So when a doctor is diagnosing all -cause dementia, the criteria are quite straight.

They're looking for a measurable decline, that interference with daily function, they have to rule out things like delirium or a major psychiatric illness, and they need to see impairment in at least two different cognitive areas.

And what kind of areas are we talking about?

It could be acquiring new information, problems with reasoning,

visual -spatial skills, or even, you know,

significant changes in personality or behavior.

Okay, so once that diagnosis is made, we get to the big four causes, because dementia is really an umbrella term, right?

It is.

So let's start with the big one, Alzheimer's disease,

AD.

The most common.

By far.

And at autopsy, the pathology is defined by three hallmarks.

First, you've got the amyloid beta plaques, these clumps of protein outside the neurons.

Second, inside the neurons, you have neurofibrillary tangles, or NFTs, which are made of a protein called tau.

And third, you just see substantial visible neuronal cell loss.

And the second major cause.

That would be vascular dementia, about one in five cases.

This one is more intuitive, I think.

It's basically the brain suffering from cardiovascular disease,

poor blood flow

from atherosclerosis, small strokes, microbleeds, that kind of thing.

But it's rarely that simple, is it?

I mean, a pure case of one or the other.

Almost never.

Most patients actually have what we call mixed dementia pathology.

They have a combination of those protein aggregates, the plaques and tangles, and also the underlying vascular changes.

In fact, it seems like amyloid deposition itself is linked to losing vascular integrity.

They feed each other.

Okay, what's next?

Next up, we have the Lewy body dementias, or LBD.

This group includes dementia with Lewy bodies, which is DLB, and Parkinson's disease dementia, PDD.

And they're connected by the same underlying problem protein.

Yes, they both involve abnormal accumulations of a protein called alpha -synuclein, which forms these things called Lewy bodies and neurites.

The tricky part is telling them apart clinically.

It often comes down to the one -year rule.

The one -year rule.

Right.

If the motor symptoms, like tremor or rigidity, show up a year or more before the dementia starts, it's called PDD.

But if the dementia happens at the same time or even before the motor symptoms, it's DLB.

It's a timing thing.

Which brings us to number four, frontotemporal dementia, FTD.

How is this one different?

FTD is different because of where it starts.

It targets the frontal and temporal lobes first.

So the initial symptoms are often these profound changes in personality and behavior like extreme apathy or total disinhibition, or maybe severe problems with language.

Episodic memory, remembering events, is often spared early on, which really sets it apart from a typical Alzheimer's presentation.

And imaging can help tell these apart, right, if you were to describe what a scan looks like.

Yeah, you can see differences in brain metabolism on an FDG -PEP scan.

With AD, you'd see low glucose use hypometabolism in the temporal parietal areas.

For vascular dementia, it's more in the frontosubcortical regions.

It helps, you know, confirm where the disease process is really hitting hard.

Okay, let's drill down into AD pathology, starting with the big theory that's driven so much research, the amyloid cascade hypothesis.

Right.

This has been the central theory for decades.

It's a simple idea, almost like dominoes falling.

It starts with amyloid beta, or A -beta, accumulating.

That leads to plaques, which then somehow triggers problems with the tau protein.

It gets hyperphosphorylated.

Which leads to the tangles.

Exactly.

The tangles cause synaptic dysfunction, then neuron loss, and finally, dementia.

The idea was, if you could just stop that first domino, the A -beta, you could stop the whole disease.

But the clinical trials that tried to block A -beta in patients who already have symptoms, they've mostly failed.

Which suggests that by the time you're symptomatic, the damage is already done.

The train has left the station.

That's the leading thought, absolutely.

The pathology actually starts maybe 15 to 20 years before you see any symptoms.

15 to 20 years?

That's incredible.

It is.

And that's why the whole diagnostic approach is changing.

We now use biomarkers to define three modern stages.

Stage one is pre -symptomatic, your cognition is totally normal, but we can detect A -beta in your brain, either with a PETE scan or from your spinal fluid.

Something like 25 % of cognitively normal elderly people might be in this stage.

Wow.

A quarter of people walking around with the very first signs of the pathology.

Yes.

Then you move to stage two, which is MCI, or prodromal AD.

This is where the mild cognitive symptoms appear, and they correlate with actual signs of neurodegeneration.

You can see elevated tau in the CSF, that hypometabolism on the PET scan, and even brain volume loss on an MRI.

And finally, stage three is full -blown dementia, meeting all the criteria, plus all that biomarker evidence.

So the real driver of the progression from stage one to three seems to be the neurodegeneration, not just the amyloid itself.

And that neurodegeneration is largely driven by tau.

So if you think of a neuron's axon as a kind of highway, tau's normal job is to stabilize the microtubules, which are like the railroad tracks for all the cargo transport in the cell.

Okay, so tau is like the railroad ties holding the tracks together.

Perfect analogy.

When tau gets pathologically hyperphosphorylated, it detaches from the tracks.

So the highway just falls apart and all the cargo stops moving?

Exactly.

The synaptic transport just gets crippled, which causes immediate synaptic dysfunction.

And then that detached, misfolded tau clumps together to form those toxic neurofibrillary tangles, which just makes everything worse.

So since the disease -modifying therapies are still out of reach, we have to pivot to managing the symptoms.

Let's start with cognition and memory, where the main targets are acetylcholine and glutamate.

This is all based on the cholinergic deficiency hypothesis, right?

Right.

The hypothesis is that in early AD, you lose cholinergic neurons, especially from a part of the brain called the nucleus basalis.

This causes an acetylcholine or acycete deficiency.

But, and this is the critical part, the postsynaptic receptors are still there.

They're intact.

So we can try to compensate by boosting the ACE that's still being released.

That sounds a lot like the strategy for Parkinson's disease.

You've lost the dopamine producing cells, but the receptors are still there.

So you just give L -Dopa to boost the available signal.

It's a perfect analogy.

And to understand how we boost it, you have to know how AC is broken down.

It's terminated by two enzymes.

The main one is the theocolinesterase, ACE, right of the synapse.

But there's also butylcholinesterase, BOOTE, which you find in glial cells and around amyloid plaques.

And the main drug class to tackle this is the cholinesterase inhibitors, or ACE.

So the goal is just block those breakdown enzymes, let the ACE build up, and you get more bang for your buck at the remaining receptors.

That's the whole idea.

So let's look at the three main ones.

First, you have dunpeazle.

It's kind of the standard.

It's reversible, long acting, and very selective for AC.

The downside is that selectivity means it blocks ACE everywhere, including your gut, which is why you get those classic GI side effects.

Okay, then there's rivestigmine.

What's different about that one?

Rivestigmine is unique because it inhibits both AC and BOOTE.

Now that BOOTE inhibition might be really important, especially in the later stages of the disease.

As more neurons die, you get this process called gliosis, where the surrounding glial cells become more active.

They produce a lot more BOOTE.

So by hitting both enzymes, rivestigmine might have a broader effect in advanced AD.

Plus, you can get it as a skin patch, which really helps reduce those GI side effects.

That dual inhibition is a great clinical detail.

And what about the third one, galantamine?

Galantamine is really interesting.

It has a dual mechanism.

It's an ACEI, but it also acts as a positive allosteric modulator, a PAM, at certain nicotinic receptors.

Basically, it makes those receptors more sensitive to the ACH that's now hanging around longer.

It's supposed to enhance the cholinergic boost, though whether it has a real clinical advantage over the others is, well, it's still debated.

So that's the acetylcholine side.

Now for the other half of the cognitive equation, glutamate and the drug memantine.

This gets at the glutamate excitotoxicity hypothesis.

Can you break that down for us?

Sure.

The idea is that the disease pathology, the plaques and tangles, causes neurons to have this constant low -level tonic leak of glutamate.

Now glutamate is the brain's main gas pedal, its accelerator.

And this constant low -level hum of stimulation actually interferes with normal signaling, and eventually it becomes toxic and kills the cell.

So you need to turn down the noise, but you can't turn off the engine because you need glutamate for learning and memory.

Exactly.

You need to block the noise, but not the signal.

And that's where memantine comes in.

You can think of it as a kind of artificial magnesium ion, or maybe a smart plug.

It has a low affinity for the NMDA receptor channel, and it's voltage dependent.

This means it only blocks the channel when it's being held open pathologically by that constant low -level glutamate leak.

And the smart part is that it comes off easily.

Precisely.

It has fast on -off kinetics, so it's strong enough to block that tonic noise, which reduces the neurotoxicity.

But it gets knocked out of the way very quickly by the big, powerful bursts of phasic glutamate that you need for normal learning.

This is why it avoids the kinds of psychotomimetic effects you see with stronger NMDA blockers like PCP or ketamine.

Because the two mechanisms are so different, boosting HEA and dampening glutamate, they're almost always given together.

Okay.

Let's move on to the behavioral symptoms, which are often the hardest part for families and caregivers.

We're talking about things like apathy, aggression, delusions, hallucinations.

It's so important to stress that before you even think about a drug, the first step is always non -pharmacological.

You check for pain, you look for environmental stressors, you address unmet needs.

But when drugs are needed, we run into a big problem with the traditional antipsychotics like risperidone or olanzapine.

Right.

The D2 dopamine blockers.

They can work, but they have that infamous FDA black box warning because of the increased risk of stroke and even death in elderly patients with dementia.

Exactly.

That major safety concern is what really drove the search for more targeted therapies.

So we now think about psychosis and agitation as being caused by two distinct malfunctioning neural networks.

Let's start with dementia -related psychosis.

So that's defined as delusions or hallucinations that last for at least a month after the cognitive decline starts.

It's incredibly common in Lewy body dementias, up to 75 % of patients, and often involves these very vivid visual hallucinations.

And the theory is that this is caused by a hyperactive network.

Yes.

The idea is that neurodegeneration, the plaques and tangles, kills off the inhibitory GABA interneurons.

They're like the guards of the network.

When the guards are gone, you get this runaway glutamate and dopamine hyperactivity.

So how does a newer drug like pimavanserin fix that without just broadly blocking dopamine and causing all the side effects?

Pimavanserin is a selective 5 -HT2A antagonist.

Normally serotonin acting on that 5 -HT2A receptor is excitatory.

So by blocking that receptor, pimavanserin essentially puts the brakes back on the system.

It compensates for that lost GABA inhibition, normalizing the network activity without that dangerous broad dopamine blockade.

It's proof for Parkinson's psychosis and has shown a lot of promise for all -cause dementia psychosis.

Okay, now let's switch to agitation.

This is different.

It's excessive motor activity, verbal or physical aggression.

And it seems to have a totally different network model.

It does.

We call it the agitation network model.

It's an imbalance between lost top -down cortical control and these unchecked bottom -up limbic and emotional drives.

Think of your frontal cortex as the filter and your amygdala as the alarm bell.

So in dementia, the filter starts to fail.

Exactly.

Neurodegeneration destroys those top -down cortical neurons.

So sensory and emotional information just hits the thalamus completely unfiltered.

And that unfiltered input slams into the amygdala.

It slams into the amygdala, the alarm bell, and it triggers these reflexive, emotional and motor responses.

You get a surge of dopamine from the VTA, a surge of adrenaline from the locus coeruleus.

That whole cascade is what drives the agitation.

So you need a drug that tries to restore that filter.

This is where something like Brexpiprazole comes in.

It has a bunch of different mechanisms, but what's the simple way to think about what it's trying to do?

It's basically a multimodal agent designed to put the lid back on that overactive system.

All of its mechanisms work together synergistically to try and quell that excessive cortical output and improve the thalamic filtering.

It's trying to restore order.

And there's another approach for agitation, right?

The dextromethorphin and bupropium combination.

Yes.

The hypothesis there is that you need a slightly stronger NMDA blockade than what Mementime provides to really block the excessive glutamate output that's driving the motor and parts of that agitation circuit.

The propion is added in not just as an antidepressant, but because it actually boosts the amount of dextromethorphin available in the bloodstream.

We should probably touch on a couple of other really challenging symptoms.

Depression affects about half of all dementia patients.

And it's incredibly difficult to treat because the very brain circuits that standard SSRIs need to work might already be degenerated.

So their efficacy is pretty limited.

Sometimes low -dose teracidone is used, not really for depression, but because it's sedating and has a short half -life which can help with sleep.

And then there's apathy, that profound loss of motivation.

I think the number was up to 90 % of patients.

It's not depression, right?

It's not.

It doesn't have the guilt or the feelings of worthlessness you see in depression.

It's just a loss of goal -directed behavior.

Interestingly, the cholinesterose inhibitors we talked about for memory have sometimes been shown to help with apathy, which suggests there's a cholinergic piece to that puzzle, too.

This has been an incredibly dense, but I think really clearly structured deep dive.

If we had to boil it down, what are the two biggest takeaways you want people to leave with?

I'd say first that the diagnosis of AD is conceptually moving much earlier into that pre -symptomatic stage one, thanks to biomarkers.

But our treatments are still just targeting symptoms way down the line in stage three.

Second, that our current strategy is all about balance.

We're balancing two systems for boosting HE and dampening glutamate, and then using these increasingly specialized agents to target very specific behaviors, like psychosis versus agitation, because we now see them as distinct network problems.

It really paints a picture of complex, individualized management.

You could have one patient on an HEI, mementine, and a specific anti -agitation drug, all hitting different parts of the problem.

Absolutely.

This raises a final provocative thought.

It's this idea of a spectrum hypothesis.

Given the huge overlap in the bad proteins, the beta, the tau, the alpha -subulin across AD, Parkinson's, and Lewy body dementias, how much does the unique combination, and maybe more importantly, the location of these protein clumps actually determine what the disease looks like for an individual?

It's a question of where in the brain that first pathological domino falls.

That's what decides whether you get memory loss first, or motor symptoms, or psychosis.

That's the question, and it's a fascinating one.

It certainly is.

A great place to end.

Thank you for joining us for this deep dive.