Aducanumab update

Recent work (Sevigny et al (2016)) has been making the rounds on social media. I have seen exaggerated headlines such as "New drug that halts mental decline.." and "A cure for Alzheimer's" making the rounds.

So, what's the dealio, yo? Have we done it? Have we cured Alzheimer's? Let's get into the facts here ---

1. What's this drug called?
Aducanumab - it's marketed by Biogen.

2. How does it work?
This is a drug that targets aggregated beta-amyloid. (Click here for my review on amyloid).

3. How is it different from other drugs that have been tried?
Well, for one, it isn't a "drug" per se. It is an antibody which targets the aggregated beta-amyloid.

4. What's an antibody?
An antibody is something all our immune systems generate to fight off infection. Think of it as your Superman to a Lex Luther. An antibody's role is to identify bad stuff, bind to it, and neutralize it's threat.

Up, up and antibodyyyyy (I'll show myself out)

5. Okay, so what did the study find?

The study found that in one year, patients who were given aducanumab showed less of the amyloid burden than placebo (not given the antibody). And, rather excitingly, this was a dose-dependent effect.

6. What's a dose-dependent effect?

It's a fancy way of saying, the greater the amount of aducanumab given, the better the patients seemed to do.

7. What did they measure?

They looked at amyloid in the brain as well as behavioral symptoms. Both improved dose-dependently with aducanumab.

8. Does this mean anyone suffering from Alzheimer's would benefit from this drug?

Not quite. The effects seemed most pronounced in those who were in early stages of AD?

9. Is this a cure for AD?

Too early to say. The sample size of this drug trial was small. Biogen is currently conducting Phase III drug trials (~1500 patients). Those results will become available in 2021. Also, important to note that the effect was in early stages of AD. 

10. Why the hesitation, bro?

We have been here before. other drugs showed promise in Phase I/II trials only to show no effect in larger trials. Also, don't call me bro, bro.

11. So what's the takeaway?

Very promising data. But, if someone tells you that "they found a cure for Alzheimer's", tell them that statement is still premature.

CTE in a soccer player with no history of concussion

Football/Soccer/Scientist friends,

This is a landmark study (see Grinberg et al. (2016). It shows the confirmation of chronic traumatic encephalopathy (CTE) in the post-mortem brain of a soccer player WITHOUT any history of concussion. By the way, the player (though he isn't named) is almost certainly Hilderado Bellini - a legend of the game. Bellini won the world cup with Brazil and played for some of the premier Brazilian clubs of his time.

The no-history of concussion is important, b/c it supports the idea that subconcussive impacts in soccer may be sufficient to produce CTE. And, honestly, as an aficionado of the beautiful game, this is somewhat troubling.

Why is it troubling? Because for the longest time, I (and many) assumed that CTE would rear it's ugly head in the world of soccer, and while there have been some reports of possible CTE in soccer players (see Hales et al. (2014) , this is the first (to my knowledge) which highlights the history of no-concussion.

There are caveats to over-interpreting this study-

1. This gentleman was playing soccer in the 50s - a time where diagnosing concussions wasn't the norm. Therefore, it is entirely possible that he did experience concussions - but were never diagnosed.

2. This is one anecdotal report. It's possible that his CTE is independent of his history as a soccer player and that his CTE was consequential of some other genetic/environmental effect.

Why is this study relevant to soccer?
Subconcussive injuries are asymptomatic. Therefore, they pose a greater risk to athletes than concussions because they are impossible to diagnose. If the link between subconcussive injuries and soccer is confirmed, perhaps we need to have a serious discussion about heading.

Do we know for sure that heading leads to subconcussive injuries?
No, far from it. There's little evidence for it, except this one study that suggests that heading in amateur soccer players leads to abnormal white matter (the stuff that allows brain cells to send messages to each other) restructuring ( see Lipton et al. (2013)). But, this is far from confirmation of the above.

It is interesting to note that Bellini was a central defender - a position which involves the most heading in a game (I don't have data to support this, but, it would be fairly obvious to anyone that plays/watches soccer). Therefore, the repeated subconcussive injury issue is consistent with what we might expect.

As more and more soccer players donate their brains to science, I expect us to see an increase in CTE diagnosis. With the suicides of Robert Enke and Gary Speed - two well known, high profile, footballers, the interest in CTE was always going to rise.

I'm not sure what the long-term impact will be on soccer. But, we are at the beginning stages of raising awareness for what might be an insidious beast preying upon our beloved soccer-playing heroes.

Pubmed link: Link to original study

Hallucinations and delusions in Alzheimer's disease?

When most people think of psychosis -- hallucinations and delusions -- the image that comes to mind is of a person with schizophrenia.

In fact, modern research suggests that psychotic symptoms are prevalent in many disorders and even appear in non-clinical populations. Individuals with Alzheimer's disease have an unusually high rate of psychosis, with best estimates putting the figure at over 40%. 

With a prevalence rate that high, you'd think that psychosis would get more attention in the literature on Alzheimer's. When these two conditions appear together they tend to cause particular difficulties in functioning and contribute to unusually high levels of caregiver burden, even by the standards of this already challenging disorder. 

However, the phenomenon gets little attention when compared to other commonly co-occurring symptoms. A Google search for "Alzheimer's psychosis" currently yields 500k hits, whereas "Alzheimer's depression" gets nearly 100 times that number at 40 million. The academic literature shows a similarly extreme imbalance.

The neglect of Alzheimer's and psychosis in research and in the media has had consequences. The FDA has yet to recognize any approved drugs for the treatment of this condition, and unlike the copious amounts of lay information available to family members interested in helping their loved one's handle other complexities of alzheimer's such as agitation and depression, there are few resources available for public consumption that address psychosis. 

I wish I could end this post with "a few simple tips" for family members and loved ones of people suffering from Alzheimer's and psychosis. There is some information out there, including limited scholarly work. But the truth is that the field simply has not gotten that far. Moving forward, we owe it to our patients -- and to our field -- to take a harder look at psychosis in Alzheimer's and how to help people more effectively.