Aliens, Firemen, and Why We Can't Seem to Make a Drug for Alzheimer's Disease

Alazheimer's Disease holds a special place in my heart - nearly twenty years ago, I got my start in a lab that studied AD and it launched me on this... interesting trajectory I've experienced. Even though I don't work on AD anymore, I still think about it from time to time. Recently, on one of my sentimental voyages, I learned of the passing of Dr. Mark Smith, the AD researcher from Case Western. I met Mark only once, shortly after starting in bench research as a chubby-cheeked undergraduate assistant who didn't know his ass from his elbow. Mark was a (much more advanced) AD researcher, and he came to Duke to give a talk that was both interesting and accessible to a neophyte like me. I actually still remember parts of his seminar, which is a rare thing indeed considering the coincidence of scientific lectures and napping.

We often hear about how real impact-makers see the world differently. In my estimation, Mark was one of those people.  Hearing about Mark's death inspired me to write a bit about his interesting viewpoint on AD, in hopes it inspired someone out there to think differently. 

OK, let's start with a basic primer. The dominant hypothesis on AD posits that the disease symptoms come from the accumulation of either/both extracellular beta amyloid (a short peptide fragment that's cleaved away from a larger protein) and/or another protein called tau, which acumulates inside brain cells. In some older individuals, these proteins accumulate and are linked together in increasingly large rafts that (it is believed) increasingly frustate normal brain processes, the symptoms of which we see in the form of progressive cognitive decline. In short, beta amyloid and/or tau is the enemy to healthy brain function. 

While this might sound like a relatively clean explanation, there is not a perfect association between pathophysiology and disease in this case - there are patients who are cognitively normal whose brains are full of amyloid and/or tau and AD patients whose brains are relatively clean. Combine this with the fact that diagnostic tests for AD are not very good/reliable, and it becomes difficult to diagnose (much less treat) the disease. The AD lab I worked in attempted to explain this variability through a combination of genetics and environment, specifically the interplay between blood lipid levels (think triglycerides and blood cholesterol) and diet. We studied a gene called apolipoprotein E, which was responsible for removing lipids from the blood. Certain isoforms (or flavors) of the apoE gene seemed to protect their owner from developing AD, while others led towards developing the disease. Our theory was that the gene isoform that preferentially sucked lipid out of the blood resulted in a relatively high level of sugars (which are normally used up first; most of us store the fat in a frosted donut), which could form a sort of glue that would irreversibly connect proteins like beta amyloid and/or tau. This would be particularly true for people who ate high-fat, high-sugar diets like Americans (who, back then, accounted for half the worldwide cases of AD). In the framework of our theory, a cure would stem from either preventing the formation of these protein/sugar moieties (oops, a science word slipped out) or removing them (or getting our diets cleaned up, but we never discussed that. I guess we'd conceded it wasn't going to happen).

As an undergraduate, I knew jack shit about science. Our plan seemed reasonable, and I whole-heartedly (and naively) thought we were on to the ultimate solution. I hadn't considered any other viewpoints. After all, everyone knew that amyloid deposits were bad.  

The I met Mark, who injected a little independent thinking into my along-for-the-ride mentality. During his seminar, it was immediately apparent that Mark wasn't toeing the party line on the whole amyloid thing. While most people viewed amyloid as the villian, he viewed it as a protector, or at least the tombstone of a great battle that raged in our brain. In Mark's view, the ultimate source of AD was oxidative stress stemming from the production of free radicals (dangerously unstable molecules). While Mark wasn't certain of the source, he posited that the brain coped with the stress by. The glycosidic (sugar) linkages between beta amyloid are readily formed in the presence of free radicals. Thus, the amyloid rafts are possible evidence of a native defensive mechanism in which the brain deals with damaging molecules by creating relatively benign proteous structures. The biological principle under which this thesis is derived, Wolff's Law, supports this, stating that a biological system placed under stress will inherent adapt itself to deal with that stress. Thus, the formation of the plaques and tangles we see so often in AD patients could signify the byproducts of a great battle within our gray matter. 

In the majority of research, amyloid has gotten a bad rap, Mark explained. In the field of molecular neurobiology, scientists are often (especially in the late 90s) deprived of real-time observation of this largely invisible world. This can lead to misinterpretation of data. To illustrate this, Mark told the following story: 

"Imagine that you're a member of an alien civilization tasked with studying earth through a large telescope. You know nothing of life on our planet, but are assigned the job of learning about what causes fire. Since you really only have one tool to study the phenomenon, you start by pointing your telescope at a fire every time you spot one. However, every time you see a fire, you also notice that there are little men in yellow coats scurrying around the conflagration, doing something you can't quite distinguish. Over time, you're hard-pressed to even glimpse a fire without the men in yellow coats being there. Furthermore, you see a direct relationship - the bigger the fire, the more men in yellow coats there are. Just to be thorough, you follow some of the yellow men. When they're alone, there are virtually no fires, but suddenly, without warning, they coalesce and and a fire pops up. Confident that there's definitely a relationship between the two things, you sit down and write a manuscript for the intergalactic journal of xenobiology that confidently concludes that firemen cause fires." 

In subsequent years, the role of oxidative stress has become outsized. We now know that there are numerous sources and consequences from oxidative stress - perineuronal net degradation, synaptic bouton formation impairment, and dozens of other science words that you would inevitably skim over. Unfortunately, few people with power listened to Mark at the time he was spreading his message. Drug trials churned away, aimed at targets that would lessen or reverse the deposition of amyloid or, in other cases, remove the accumulations similar to the way the body destroys invading pathogens. 

Many years later, evidence from these same trials increasingly supports Mark's position. Thus far, virtually all of the drugs aimed at preventing and/or removing beta amyloid and tau (and I'm not an expert, so take that with a grain of salt) have been ineffective. 

When a drug fails, it can happen for several reasons, one of which is the drug failing to accomplish the biological function it was intended to perform. However, in many cases, there was ample evidence that the drugs were successful in preventing new accumulation of amyloid/tau, but still failed to reverse the disease (or even prevent it from worsening). This supports (but does not prove) the idea that a cause other than amyloid deposition ultimately underlies AD.

Long story short, there's a decent chance that we have dumped billions of dollars into treatment strategies for AD that are just plain wrong and - by virtue of being off-target - have no chance whatsoever of success*. It's impressive then that, knowing none of this at the time, Mark Smith looked at this complex issue and saw something different. Moreover, he stuck to his guns and pushed the idea until his death. This is not easy to do in academia, where a herdlike mentality exists and challenging existing dogmas is, at best, an uphill fight and, at worst, career suicide.

Circumstances as they are, there's little chance I'll ever work on AD again. Passing on the unique perspective of guys like Mark is the best way I can think of to promote the independent thought necessary to make the big leaps forward that define the practice of bench research. 

*Don't read this footnote if you have a relative with AD and/or believe that ignorance is bliss. There is one AD-specific compound on the market as I write this. It's called Aricept, and it doesn't work for shit. Everyone in the industry knows it, yet it's still prescribed, probably to make the patient (and maybe the doctors) feel like they're doing something.