Can I have that if you're done with it?

Let’s play a game of “Good News, Bad News, Worse News.” The good news, and this is one that doesn’t get told very often, is that the incidence rate of dementia (the per capita chance of developing the disease) may actually be falling over time, with one meta-analysis showing a 13% decrease each decade from 1988 to 2015. The bad news is that while the average lifespan post-diagnosis seems to be increasing, it’s still generally in single-digit years and any increase could be attributable to earlier diagnosis. The worse news is that despite the decreasing rate of dementia, the overall number of people living with the disease is projected to more than triple by 2050 due to a rapid aging of the population.

This is, of course, assuming that there aren’t any breakthrough cures or preventative medicines developed by then, which could drastically reduce or eliminate one or more type of dementia. Yet successful treatments, let alone cures, have remained elusive despite many billions of dollars spent on research (annual federal funding for Alzheimer’s Disease research alone reached $3.8 billion in 2024). While there is no shortage of reasons for this, one of the simplest is that there’s still a fundamental lack of understanding about the disease biology. Selfish as it may seem, most people are unwilling to give up their brains while they’re still alive. So unlike diseases in other organs, where biopsies can be taken while the patient is living to study its progression, you pretty much only get to take a look after the patient passes when studying the human brain.

Still, this approach has led to crucial observations about what happens at the end stages of dementia and neurodegenerative diseases: we can see excess buildup of proteins in neurons (like beta-amyloid, alpha synuclein, or microtubule-associated protein tau), we can see that many neurons have died, and we can even see holes develop in the brain. We know that these things shouldn’t happen in the brain because we can compare them to the brains of people who did not have these diseases. But we also know that seeing what brains look like before and after neurodegenerative disease hasn’t actually helped us cure them so far – many drugs that specifically remove protein buildup (plaques) in the brain have failed to make it out of the clinic. 

It seems it’s not enough to know the beginning and end stages. To get a complete picture of the trajectory of disease, you need to know everything in between as well. 

To illustrate why this might be the case, imagine I ask you to guess a word. I’ll spot you the first letter (F) and the last letter (K). To fill in the rest, you pick Scrabble tiles out of a bag at random – these letters are guaranteed to be in the word but you don’t know where, and they can repeat. If your bag is biased to letters towards the end of the word, your first 10 picks might be 5 “U’s” and 5 “C’s”, and you might start to think you have a pretty good idea what the word could be. 

With a more representative distribution of letters from across the entire word, however, the letters I, R, E, and T would appear much more frequently, and the word could accurately be decoded to “Firetruck,” just like you thought.

Similarly to pulling letters, getting a fuller picture of a disease as it progresses would mean a whole lot of random sampling, which in this case means a whole lot of brains. “Healthy” brains are particularly needed, since we’d be looking for those who have not been diagnosed but are nevertheless at various stages along the disease trajectory (the earlier letters in the word). This poses a challenge: it’s actually incredibly difficult to get this type of brain, with the lack of control brains “the greatest limitation” in national database. Not only do you need enough controls to match the diseased tissue being studied, it’s not a given that your “healthy” tissue will be a perfect control, either. This is because most brains procured are on the older end and, at advanced ages, a majority of brains exhibit some sort of pathology. Cognitively healthy brains with mild pathology are often used as control tissue due to lack of other options. 

Even though acquiring healthy brains is critical for research, strategies to increase the number of banked brains, particularly younger, healthier brains, are limited. 

The first thing that comes to mind might be registered organ donors, and here’s where we get to play another exciting round of “Good News, Bad News.” The good news: the U.S. organ donor registration rate, which has been historically low (estimated at 28% of adults in 2003) has more than doubled to about 60% currently. And while organs are primarily marked for transplantation, those deemed unfit can be used for medical research. The bad news is that brains are exempt from this and require a separate authorization from the one you’d normally give at the DMV (or RMV if your state is overly pretentious). Doctors can ask families’ permission to donate brain upon death, but rates are understandably low (exact numbers are hard to find but one estimate has it at 43%) because it is a difficult decision that needs to be made quickly under stressful circumstances. Prior authorization by the patient can increase these rates by giving comfort to the family that this was what their loved one wanted. The best way to donate is through the Brain Donor Project which partners with the National Institute of Health’s NeuroBioBank which collects healthy and diseased brains to distribute to researchers.

The real task comes in increasing the sign-up rate for brain donation. By my quick back of the napkin math, if everybody reading this decided to sign up immediately it would still be... not quite enough people. So what are our options? 

Providing any incentives for brain donation is surprisingly tricky, since the U.S. (and just about every other nation) has laws that prevent payment for human organs, but this includes even things like tax breaks for donating. I’m certainly not against giving Americans a tax break to donate their brain as part of a national service-type program. Given the rapidly aging population and declining birth rate, it’s easy to see neurodegenerative diseases becoming a national emergency within our lifetimes. Barring that, simply allowing brain donation to research to be included in the normal organ donation registry would be a massive boon to the available tissue for research.

For now, unfortunately, progress depends on more of us taking two extra minutes while we’re alive to sign a separate consent. If you’ve already checked the organ-donor box, consider adding your brain to the list (as I just did). You won’t need it, and it could help someone else figure out how to keep the next generation from losing theirs.