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A key part of treating a disorder, is identifying what it's not. It turns out what we thought was one form of dementia may be multiple problems.

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Dementia is a neurodegenerative syndrome that affects memory, behavior, and cognitive function. Around 50 million people worldwide have a condition that causes it, such as Alzheimer's, and there are 10 million new diagnoses every year.

Though we pour a whole lot of money into researching cures for conditions that cause dementia, so far we've not really turned up anything truly effective outside of mouse models. Thankfully, after years of observations and studies, scientists have uncovered another piece of the puzzle. A previously unidentified type of dementia has been flying under the radar, and it's quietly been messing up our research efforts.

A paper published in 2019 in the journal Brain has formally defined a condition known as LATE. After years of studying dementia caused by the accumulation of a protein called TDP-43, it's only now that scientists have been able to formally say ‘yes, this is its own condition'. When TDP-43 is working correctly, it hangs out in the nucleus of a cell, where it binds to DNA and regulates the production of proteins.

Normally, TDP-43 can also have a limited role outside of the cell's nucleus in protein production. But in cases of LATE, there are certain brain areas where TDP-43 starts to build up outside of the nucleus in tangles. These tangles are associated with damage to brain tissue.

This can be observed in limbic brain regions - which are involved with memory - in three stages. In the first stage, TDP-43 accumulates in the amygdala. In stage two, it spreads to the hippocampus.

And in stage three, wandering TDP-43 can be found in the middle frontal gyrus. We don't yet know what's causing this to happen. Genetic studies have so far indicated five different gene variants associated with a higher risk of LATE.

Many of these variants are also implicated in other types of neurodegenerative conditions, which indicates they're likely doing something similar in each case. But so far, there are no definitive answers. We do know that LATE produces symptoms that closely mimic Alzheimer's disease.

Things like forgetfulness, changes in behavior and personality, and other cognitive issues. They're so similar, that, like… we didn't know they were different for a long time. But /unlike/ Alzheimer's disease, LATE occurs, well… late.

LATE appears predominantly in those aged over 80 years. Autopsy studies suggest evidence of LATE is present in anywhere from 20 to 50% of people in this age bracket. However, not everyone with TDP-43 accumulating in their brains will develop LATE symptoms, perhaps because they die of other causes before LATE symptoms emerge.

But this can happen with other forms of dementia, too. For whatever reason, just the presence of disease-associated proteins doesn't seem to be sufficient. Right now, it's next to impossible to tell the difference between Alzheimer's and LATE while someone is still alive.

You'd have to take samples from limbic regions of the brain and stick them under a microscope, and… well, that's way too invasive, and could cause further damage. This has lit extra fire under researchers to develop less invasive tests to determine exactly what patients have, so that they can get the most suitable treatment as soon as possible. In the future, clinicians hope to be able to identify specific markers in blood to make more definitive dementia diagnoses.

But we're not there yet. And it turns out it's hard to research clear answers about a disease when you don't actually know for sure that people have it. Since the presentations between LATE and Alzheimer's are so similar, researchers are concerned that we may have been accidentally labelling cases of LATE as Alzheimer's.

In fact, they estimate that 15 to 20 % of all Alzheimer's diagnoses could actually be due to LATE. And as if it isn't complicated enough, many people with dementia will have multiple underlying conditions that cause it. It's likely that many even have a combination of Alzheimer's and LATE.

This is important, because it means LATE has been diluting possible effects in our research for an Alzheimer's cure. In order to conduct a clinical trial properly, scientists need to be able to minimize interference from confounding variables - things that influence final measurements, without being the variable of interest. These are usually things like age, sex, or the presence of another health related condition.

But when you're recruiting participants for a study on Alzheimer's, trying out a drug designed to treat Alzheimers, and it turns out that actually, some participants had this other thing that kinda looked like. Alzheimer's…. Well, you're studying the wrong thing, and you don't even know it.

While your shiny new drug might have helped out some of the sample with Alzheimer's, the ones with the Alzheimer's look-a-like with a completely different cause may not have been helped at all. And that drives down the measures of how effective your drug was, leading people to conclude that it was no good. It might have been great!

It's just that you had such a massive confounding variable that it totally threw off your analysis. To combat this issue, the next step is to find ways to detect LATE in living patients. If they can do that, researchers will be able to effectively control for it in studies, begin working on a cure, and re-examine some of their old findings on Alzheimer's.

Which should be good for people with both conditions. It's not likely to happen overnight. But with LATE identified, we've now got more pieces to dementia's puzzle, and we can continue to progress towards a cure.

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