Alzheimer’s: Why Learn to Live With Failure?

• Alzheimer's

We are too often satisfied with failure. Not believing we can succeed, we eschew further thinking, and we call it quits. In the case of Alzheimer’s therapy, we define statistical flukes as “hope”, declare victory, and retire into platitudes and misconception. Rather than cure disease or improve human lives, we content ourselves with pessimistic delusions and hype the importance of “living with Alzheimer’s”. Simple-minded mottos and political cant, can’t hide reality. We’re not living with Alzheimer’s, we’re dying with Alzheimer’s.

A dozen years ago, when I was the Executive Director of the American Aging Association, we wondered whether or not vitamin E (tocopherols) could delay Alzheimer’s by a few months. The results were minimal and subsequent studies undermined any of the initial optimism. Similar claims came and went over the years, at best suggesting we might delay the disease by a few months, if even that much. Years have passed and hopes have faded. Even the Alzheimer’s Association slowly acquired an emphasis on futility, with a focus not on curing AD, but on living with it (as if we could). Yet even with our latest approaches, even with monoclonal antibodies and huge FDA studies, success escapes us. In July 2015, the results of a large solanezumab study came out and were hyped as having a “distinct impact on Alzheimer’s disease”, and it was claimed that the results “may well illustrate the disease-modifying effect” of the drug.

Figure A

How big an impact? How modified was the disease? Not much.

At best, the statistics suggest that solanezumab might delay the symptoms by three months (see figure A, above). Given that average course of the disease — often 7-8 years from diagnosis to death — the 3 month statistical claim s is not much of a reprieve. And what does it give us? A longer sentence to the nursing home? Prolonged financial and human costs? Does it offer anything more than an illusion of hope?

Figure B

If we look at the published results, the most obvious fact is that the vectors — control versus treated patients — are parallel as they decline toward death (see figure B, above). How can we claim to treat Alzheimer’s when the direction of the disease process has the same slope whether you are treated or not? If we fall off a cliff regardless of treatment, does it matter if we hit the bottom now or a few moments from now? Either way, it’s the same cliff, the same fall, the same outcome. Either way, the same fact remains: we’re not living with Alzheimer’s, we’re dying with Alzheimer’s. If there is any “distinct impact”, then it’s not the questionable impact on Alzheimer’s disease, it’s the unquestionable impact as the patient hits the ground.

We are too easily satisfied with failure. We work hard and we invest millions of dollars in research, but we don’t think hard enough and we don’t invest in the right trials. We use a faulty disease model and achieve disappointing results, then resign ourselves to fate and claim that we have succeeded by redefining failure as, oddly enough, a clinical success. A lack of meaningful success becomes a “distinct impact” and a failure is touted as “success”. Where is the success in being unable to alter the vector of a disease?

We could do much better: we can actually succeed. We can cure Alzheimer’s disease. What it takes is not more effort and money invested in failed models, but more insight and a deeper appreciation of how the Alzheimer’s disease actually works. We must come to see it in a broader context of the age-related CNS pathology that underlies not only Alzheimer’s (and not merely beta amyloid or tau protein changes), but Parkinson’s disease, microvascular dementia, and even animal models of age-related cognitive decline. We become so lost in the genetic and protein changes specific to Alzheimer’s that we lose track of the parallel changes (with different genes and different proteins) in Parkinson’s disease. We become so lost in the neuronal changes specific to the histology of these two diseases that we lose track of the overlapping changes that occur in the vascular pathology. And, finally, we become so lost in the pathologies specific to our human patients that we lose track of how much we can learn from the typical age-related CNS dysfunction that occurs in other animals, such as mice.

Figure C

The pathology may differ, the pathways may differ, yet each of these age-related changes still share an underlying process, one that we can take advantage of, allowing us to intervene effectively. Once we grasp the broader process that underlies the specifics of these CNS pathologies, we can finally cure them. Rather than merely claim we have achieved a minimal displacement of the same downhill vector, we can alter the vector (see figure C, above) and achieve what so many have hoped for and so few have come to believe in: a successful cure of Alzheimer’s.

Ignore the hypocrisy of “living with Alzheimer’s”.

Let’s succeed at living WITHOUT Alzheimer’s.