Alzheimer’s disease is frightening. Incurable, progressive, burdensome and still biologically mysterious, it afflicts primarily the elderly and inexorably degenerates the brain tissue of patients. In doing so, it robs millions of people of their memory and cognitive function—and spouses, parents and friends of their company—often years before death actually occurs.
It’s a huge health problem, and it’s getting worse as the population ages. The number of Alzheimer’s patients in the U.S. alone was 4.5 million in 2010, and that number is projected to increase to 7.1 million by 2025 and to more than 100 million worldwide by 2050. Yet, despite a concerted effort to investigate the biology underlying Alzheimer’s disease, its exact mechanisms are still subject to debate. Worse, therapies that have looked encouraging in preclinical research have failed to fulfill their promise in human clinical trials to this point, leading one commentator to observe: “Alzheimer's is a graveyard for expensive drug tests.” Billions of dollars and countless hours of labor have been spent by government and private industry in the last five years alone, with essentially nothing to show for it. Why is this the case?
Well, first of all, Alzheimer’s disease is very complicated. We know its telltale signs in the brain: the accumulation of “plaques” of beta amyloid, a protein fragment, in neurons, as well as the prevalence of “tangles” of a protein known as tau. But while we know beta amyloid and tau are there and likely contribute to brain cell death, their exact roles and mechanisms in Alzheimer’s remain unclear, especially in the early stages. Indeed, many of the trial therapeutics have focused on blocking beta-amyloid accumulation, with some looking good right through the final drug development hurdle, Phase 3 clinical trials. But not one therapy has emerged that confers significant benefit—only one in 244 was even approved between 2000 and 2012!—and current care seeks only to help alleviate symptoms, not address root causes or slow disease progression. Despite this, more therapeutics targeting beta amyloid are currently going through clinical trials, with billions of dollars still at stake. (For more information about these trials, the beta-amyloid debate and Alzheimer’s disease therapeutic development in general, a recent podcast from pharmaceutical industry experts Meg Tirrell and Luke Timmerman provides excellent insight.)
Developing effective therapeutics is made even more difficult because human Alzheimer’s has not been modeled well in experimental organisms, such as mice. The issue has been partly man-made—the stakes are high (whoever develops a preventative or cure stands to reap huge rewards) and intellectual property issues have dogged the Alzheimer’s disease research field. For example, it took The Jackson Laboratory, with help from the NIH, to break the hold a patent “troll” had on a particular mutation—called the Swedish mutation because it was first found in a Swedish family with early-onset Alzheimer’s—and its use in Alzheimer’s research using mice engineered to carry it. Nonetheless, intellectual property restrictions still limit Alzheimer’s disease researchers seeking to use certain animal models. Also, as might be expected, it’s terribly difficult to mimic years of mental wear and tear and recreate gradual neural degeneration in a short-lived, non-primate animal. Indeed, many of the current mouse models over-accumulate beta amyloid and/or tau in their brains, but in general they don’t exhibit neurodegeneration. And while some have been engineered to carry early onset Alzheimer’s mutations similar to those found in humans, the mechanisms underlying the more common late onset Alzheimer’s are far less clear-cut or well understood, making it impossible to reproduce them in the laboratory.
Given that it is now apparent that the Alzheimer’s disease puzzle in humans involves far more than just beta-amyloid and tau, it’s important to expand research inquiries. Fortunately, new patient data have provided clues about what other factors might come into play in the development of late-onset Alzheimer’s disease. Research is underway to assess the role of inflammation, the importance of the blood-brain barrier, the complex interplay of neurological systems, and more to broaden biological understanding of the disease. Researchers are also considering the contributions of environment and behavior, particularly in late onset Alzheimer’s. They are extremely hard to tease out, because small influences that have no effect over a few years may add up to be important if they persist for decades, but some robust associations are emerging.
Another piece of good news is that there are powerful new tools and methods available to researchers that will help them investigate the disease in ways that simply weren’t possible only a few years ago. The use of these tools—including but not limited to CRISPR and high throughput DNA sequencing—provides a way to translate findings in human patients to animal experiments with high speed and precision. The hope is, of course, that the findings from these new animal models will translate back to the clinic far more quickly and effectively than before.
By assessing the biological consequences of each variant and each disrupted system and learning how they might contribute to brain cell death, researchers are getting to work on assembling many more pieces of the Alzheimer’s puzzle.
The task remains formidable and the challenges significant, but the technology is now in hand to better understand—and hopefully prevent or cure—this terrible disease. There is reason for hope that research will soon find the right path and connect the dots between biology, therapy development and clinical relevance to bring effective interventions to the patients who need them.
Mark Wanner followed graduate work in microbiology with more than 25 years of experience in book publishing and scientific writing. His work at The Jackson Laboratory focuses on making complex genetic, genomic and technical information accessible to a variety of audiences. Follow Mark on Twitter at @markgenome.