Alzheimer’s disease and Type II diabetes long have been observed to have a clinical connection, with patients with diabetes more than twice as likely as those without the disease to develop Alzheimer’s. But the precise nature of this connection has been a mystery until recently. Over the last few years, research projects funded by Cure Alzheimer’s Fund and others have helped bring us much closer to an understanding of the molecular connection—and, potentially, to effective treatments for both diseases.
It began a few years ago with Rudy Tanzi’s Alzheimer’s Genome Project™ (AGP), which was able to identify more than 100 candidate genes previously unassociated with Alzheimer’s. Researchers across the world were given access to this new list, to see what unexpected connections might be made. Such a connection is exactly what happened when, in July 2006, Cure Alzheimer’s Fund Research Consortium member Sam Gandy attended the prestigious, off-the-record Gordon Conference in New Hampshire to present some data on the Alzheimer’s protein Abeta (also known as Amyloid ß or Aß). Gandy, who studied diabetes as a graduate student in the early 1980s, was curious about the state of diabetes genetics, and so went to a lecture by University of Wisconsin diabetes geneticist Alan Attie, who was focused on a sorting protein called SorCS1 (pronounced “sorx-one”). Sorting proteins act as a cell’s “postal workers,” reading every molecule’s unique “zip code” and delivering proteins to their proper destinations inside the cell. Tanzi’s AGP had just discovered a possible Alzheimer’s link to the gene controlling the same protein. Hearing Attie’s presentation, Gandy wondered: Was this the missing Alzheimer’s-diabetes connection? “We had a hunch, but we hadn’t done a single experiment and we had no data,” recalls Gandy. Perhaps Alzheimer’s and diabetes were both connected to this SorCS1 “postal worker” protein. Perhaps SorCS1 was responsible for reading the “zip code” on amyloid precursor protein (APP)? Gandy recruited post-doctoral fellow Rachel Lane to lead a very speculative high-risk study, in which Lane first used Attie’s armamentarium of SorCS1 tools to study cell cultures and then examined SorCS1-deficient mice, also developed by Attie. Lane found that when SorCS1 was under-expressed, more Abeta was generated—particularly in female mice. This was significant, because Attie already had shown that SorCS1 was linked especially to Type II diabetes in women.
Diabetes isn’t causing Alzheimer’s. Rather, they’re both being caused by the same thing. “Until this link,” explains Gandy, “it was hard to figure out what was cause and what was effect—what was the chicken and what was the egg? Identifying a gene that increased the risk for both diseases gave us a starting point. Now we know that both diseases can begin whenever the SorCS1 ‘postal worker’ fails to read the ‘zip code’ on APP and then deliver it to its proper destination.” Alzheimer’s is driven by the accumulation of Aß between and among brain cells. Aß is created by two aberrant cleavages in a larger protein called amyloid precursor protein (APP). In healthy cells, APP is sorted into the plasma membranes and the membranes of intracellular organelles, and assists the healthy functioning of cells. What Gandy discovered is that, in both Alzheimer’s and diabetes, there’s something going wrong with that “postal” sorting process. The sorting protein SorCS1, when present at inadequate levels, interferes with the correct sorting of APP and therefore leads to the creation of the destructive Aß. This same malfunctioning sorting process also can start a cascade that leads to diabetes. Further, the mis-sorting by other proteins in this same family recently have been linked to other major metabolic and neurological illnesses, such as frontotemporal dementia and atherosclerosis. SorCS1, diabetes and Alzheimer’s are just the tip of the iceberg—these “postal workers” hold the keys to major diseases affecting millions of people.
The power of ‘venture philanthropy’
In a recent interview, Gandy stressed that his initial study was exactly the sort of high-risk/high-payoff study that Cure Alzheimer’s Fund has become known for. “It took a while from my hunch to even get going, because this was so speculative. NIH usually requires extensive preliminary data. At the beginning, all we had was an intriguing idea. We went to the Cure Alzheimer’s Scientific Advisory Board and said, ‘Here’s this idea we have...’ Then we had to find a postdoc—Rachel Lane—who would risk a few years of her early career on it.” But it paid off. Since Gandy’s discovery, further progress has been made to flesh out the Alzheimer’s-diabetes connection by Columbia University’s Richard Mayeux and others. Tanzi also has made new links to other genes in the same gene family. A recent pilot study at the University of Washington has reported promising results on the possibility of treating Alzheimer’s with an insulin nasal spray, and NIH has followed up with funding for a full-blown drug trial. Meanwhile, there’s much more to understand about the basic connection between Alzheimer’s and diabetes; Rob Moir, at Massachusetts General Hospital, is pursuing this connection further, with the help of Cure Alzheimer’s Fund dollars. And Gandy is now circling back to diabetes.
“Unraveling the Alzheimer’s-diabetes story,” he says, “has pointed to molecules and pathways that have never been linked to insulin sensitivity before. Here we have the tantalizing prospect that one gene, first studied on the basis of a hunch, might lead to a new understanding—and new drugs—for both Alzheimer’s and diabetes. We hope to pick up the SorCS1-insulin sensitivity lead as a separate project.”
Want to Know More? Read "Exploring the Diabetes and Alzheimer's Link", an article we published in 2010, when our researchers were first hypothesizing about the connection between the two diseases.
Catch Our Next Webinar: Alzheimer’s and Diabetes: Finding the Common Origin Join Cure Alzheimer’s Fund Consortium member Sam Gandy, M.D., Ph.D., and David Shenk, author of the national bestseller The Forgetting, Alzheimer’s: Portrait of an Epidemic, for a discussion about the linkage between Alzheimer’s disease and diabetes on Wednesday, April 4, at 2:30 p.m. Eastern Time. To register or for more information, visit www.curealz.org/webinar.