The 3 Brain Problem

We're not progressing with solving dementia - because we're sleeping at the controls.

"Aeterne pungit, cito volat et occidit"/ "Eternally it stings, switfly it flies and it kills". (on the banner)

Alzheimers’. Parkinsons. Vascular.

Dementia.

Forgetfulness, trembling hands, slurring of words. These are the traits defined by the medical profession. An entity that seems to have only experienced these diseases in casual passing. On the television. At a friend’s house.

Blank stares, sparks of memories long submerged, night terrors. Screams. Tears. Denial. Moments of joy & heavy clouds of anguish. The longest diagnosis you will ever know. Staring down the barrel of a loaded gun. A lived experience no one could possibly explain.

For my thesis, I had the painful privilege of working with one of Singapore’s largest datasets for the progression of dementia. I was developing a predictive AI model - could we pick up dementia before it got too late?

I worked with a 5-year dataset which included bloods, cognition scores and other biometric data for hundreds of patients. I remember during an early call with my supervisor I asked him why most of his researchers joined the lab - what were their backgrounds, what was the motivation of a young 20-30 something year old to work in a lab that dealt predominantly with the elderly?

“Everyone is here because they’re fighting against a beast they’ve seen with their own eyes. Trust me, there is no money in the work we do.”

But there is - surely?

We’ve seen & celebrated the news about donanemab and lecanemab, the controversial Eli Lilly and Eisai drugs that recently got FDA approval.

We’ve all read the pop-sci articles, telling us which foods to avoid and how many hours to sleep to avoid Alzheimer’s.

We know that over 55 million people globally currently suffer from dementias, a number projected to grow to 152 million by 2050.

How can this not make money?

Because the craziest thing is - we don’t really know what we’re fighting. And that’s why in the long run none of these famed ‘solutions’ work.

“By the time you’re my age, you’ll realise that everything you once thought mattered so much turns out to mean very little” - Liu Cixin, The Three Body Problem

Dementia's tangled history

Contrary to popular belief, dementia is not a single disease, but rather a family of conditions relating to general cognitive decline.

Like the disease, its root is not pretty.

Derived from the latin word “Demens” meaning “out one’s mind” or “mad” - it draws direct inspiration from the symptoms of the disease as the brain slowly degrades to nothingness.

In ancient history, it was considered a simple disease of aging. You get old & you lose your mind. You go senile. Such was the normal course of the world.

It was only until the 19th century, that Pinel coined the term “Dementia” - number 4 in his list of “mental derangements” - defined as the “abolition of thinking”. You’re slipping when you used to be sharp. A catch-all term, that marked the first time we accepted that it was perhaps not normal to lose your mind. (”canine cognitive dysfunction”, is in a similar state as this now - but that’s for another article).

In 1906, a professor, Alois Alzheimer, noticed that these brains didn’t simply decay but they showed clear signs of disease.

In this one disease lied three different brains:

Clumps of proteins viewed outside the neurons - rust collecting on the neurological mesh of the brain. Known as "Amyloid-Beta"(AB) plaques - this is brain 1.

Tangles within the neurons, cobwebs growing inside the base unit of cognition. Neurofibrilliary Tangles ("NFTs") was brain 2.

And brain 3? Inflammation of the entire structure. A generalised swelling - as if stung by a hidden hornet lying deep in the nest. Neuroinflammation.

The pathology bears his namesake, and was quickly accompanied by existing cognitive diseases - Parkinson’s, Vascular dementia, Lewy Body Dementia, Frontotemporal dementia, Huntington’s. But Alzheimers remains the most prevalent.

And since his discovery over 100 years ago, scientists have fought to determine which "brain" starts it all.

Brain 1

Imagine this if you will. A small object, the size of two fists put together, made up of a three dimensional mesh of wires. Infinitesimal links, to the point where one could be mistaken for believing that it was one solid piece. This is the mesh of neurons within a human brain. Run a liquid through it, and you could watch it flow through the intricate cracks, realising that it is not solid piece but rather that it is a framework of many tiny subunits.

The spaces between the connections are side routes for the information highways. Here, a biological highway service team clears up the debris of a recent crash, a fallen log, a shattered windshield, a cardboard box crushed beyond recognition. Clearing this allows traffic to move faster. Less brakes, less traffic, faster movement. Everyone gets to where they need to be, when they need to be there. Information gets channeled through the neuron with no distractions.

Yet, the roads of brain 1 lie on the edge of a metaphorical cliff. They were carved out of the rough yet soft rock, and its walls have stayed firm for time immemorial. Over time, nature takes over, and one day a rock crumbles off the hillside and lands on the highway. It is small yet sizeable, and causes significantly more disruption to traffic. Cars pass and veer around it, but things move slowly, trying to carve alternative routes into the once seamless landscape.

Curses, the blaring of horns. The highway teams take more time to clear it - but clear it they do.

But the same cliff isn’t as stable as it once was - a chunk being taken off the side of it - and its lack of structure exposes a gap - urging nature to take another bite out of its side. And so slowly these blockages get bigger. A boulder the size of a small car falls next. It takes teams longer to clear them. Traffic is delayed first by hours, then days, finally weeks.

… until one day, the highway becomes totally occluded. The barrage has overwhelmed the service staff. Traffic doesn’t go through anymore. And so, travellers are forced find alternative routes.

In our brain, these are spots of rust-like clumps. These boulders are amyloid-beta (”AB”) plaques outside the neurons. Deposits of natural proteins - debris that are expected to be cleared but over time overwhelm the system and impede the function of the brains traffic. These are the markers of Brain 1.

Brain 2

Look deeper into the main highways now - the single strands, the main channels of traffic transfer. On the surface these have not changed. The roads are laid, the markings clear, and everything is smooth. There is no need for traffic lights, nor traffic cones. As the road gets worn out, teams replace the markings delineating different lanes, hazards, road shoulders for the wary travellers.

But the service staff are losing focus.

Lanes aren’t painted as they were before.

Routes are drawn on existing highways that curl and snake and veer from side to side. Drivers slow down - they are concerned with causing an accident. Yet the service staff can’t do anything more - the correct lanes have been painted over so many times that there is no reference as to what a straight lane might look like.

These are Neurofibrillary tangles or NFTs - distortions deep within the neuron itself. Damage to the interior of the brain’s base transport mechanism. The road. The neuron.

Brain 2 has the roads. But they have become lost in themselves.

Brain 3

And so what of brain 3? Our mesh consists of the same links, the same wires. But the structure is swollen - two times the size of what it should be.

Our highways are there. As are the side roads. Yet the parts of the road that were carved into the soft limestone start to give way, until eventually, they slip off the side of the cliff. An 8 lane highway becomes 6, then 4, then a dual carriageway. The same traffic has now turned into a snarling jam. Travellers look for alternative routes but these too are clogged. Our destination seems further than ever. We have no choice but to wait.

Generalised neuroinflammation, swelling of the brain, the constriction of traffic, a contribution to overall decay - this is the hallmark of Brain 3.

Treacherous, boulder-strewn, chaotic - this is where the field of dementia research has brought us. How do we get ourselves out?

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So where does this leave us as scientists? We peer from the control room. All we know is that traffic is an absolute mess. The route that was supposed to take us 5 minutes will now take us and hour. But we were called in too late - and so it is impossible for us to know where this all began.

Was it the boulders of Brain 1? Occluding the road and forcing us to seek alternative paths?

The perverse road markings of Brain 2? Leading our travellers astray?

Or perhaps it can all be traced back to the narrowing of Brain 3 - after all, how can we expect 8 lanes of traffic to squeeze through a single channel?

This is the debate that has been thrown back and forth amongst scientists for the past hundred years. Some defend the service staff, claiming that its not their fault that the lines were drawn incorrectly. Some argue that the boulders that block the road are what we should clear first. Others still force us to look deeper - after all, such an important road shouldn’t have been built on structurally unsafe and soft limestone.

Do the Neurofibrillary Tangles in the neurons cause dementia? Or the AB plaques outside them?

Or perhaps is it the swelling of the brain that causes everything to slowly break down?

But while we debate, chariots become abandoned. They’ve decided that its not worth the wait. And as the shells of these vehicles of all shapes and sizes lay strewn across the highways, roads close, for they are now unusable. Urgent deliveries are missed. The roads become unused.

We don’t know what to do. So we panic and shoot from the hip.

"Clearing those boulders is probably a good start" we say, which is what most of those famed FDA approved drugs aim to do. But traffic is still a mess. And we’re running out of time.

Stare into the blank eyes of a dementia patient, look at the light slowly dim from behind them, hear the anguish of the family looking for solutions - do something, anything! - to which doctors slowly shake their heads and shrug and you’ll understand.

We’re running out of time.

Brain 4?

People are often surprised to learn that those general caricatures of dementia - forgetfulness, trembling, slurring - are actually the final phase of a long drawn out disease. It is estimated that most forms of the disease group have an incubation phase of up to 10 years. Yet we, those who have been tasked with managing the traffic, are asleep at the controls. Only when the first traffic jam occurs do we sit up and take notice. The first forgetful moment. The first tremble. The first blank stare.

The answer to the question is that the roads have broken down due to all 3 brains - a combination of all 3 gradually catastrophic events. But why did we let it get so far in the first place? Why weren’t we warned that traffic was slowing down?

Why didn’t we assess proxies - perhaps the number of vehicles passing through per minute, or the level of exhaust emitted from our cars - to assess that things were slowing down?

No one wants to be caught with sleeping at the controls. So we send in dynamite to blow up the AB plauqes - the boulders - to show our superiors that we’ve found a solution.

We haven’t.

The solution to solving dementia lies in understanding what is going wrong before it occurs.

Placing a mesh to catch the boulders before they fall on the road & preventing plaques from forming in the first place. Monitoring the line demarcations, painting them over in advance and ensuring NFTs don’t ruin individual neurons.

Checking the overall structure of the roads before they slip off the mountain and limiting generalised inflammation of the brain.

Don’t be fooled by the articles or the hype. The single most important way of solving dementia is developing an early warning system. Figuring out when something is going to go wrong, before it does.

With 500 patients, thousands of datapoints over 5 years - my thesis’ conclusion?

We need more data.

Every manifestation of dementia - Parkinsons, FTD, Vascular, Prion - manifest in ways that differ slightly to Alzheimers. But the result and the conclusions are largely the same.

Unless we stop taking a myopic view to one of the worlds most challenging conditions, we are sleeping at the controls.