Alzheimer’s and Diabetes: Finding the Common Origin

Posted April 4, 2012

Answers to webinar questions have been posted below. We will continue to post additional answers as we receive them.

On April 4, 2012,  Cure Alzheimer’s Fund Research Consortium member Sam Gandy, M.D., Ph.D., and David Shenk, author of the national bestseller, The Forgetting, presented a webinar about the linkage between Alzheimer’s disease and diabetes.

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.

To learn more about the clinical connection of Alzheimer’s and diabetes, read the lead science article in Cure Alzheimer’s Fund’s 1st Quarterly Report of 2012.

Answers to questions from this webinar.
Please note additional answers to your questions coming soon.

Will treating T2D reduce AD risk?

  • This is a question we are testing right now in Alzheimer’s clinical trials with the insulin sensitizers metformin and liraglutide. Stay tuned! We’ll post the results here as soon as the data are available!

How much of the risk of AD in T2D is due to SORCS1?

  • Aside from APOE e4, which accounts for part of the risk in ⅓ to ½ of AD, each of the other genetic risk factors contributes a relatively small increase in the relative risk. For example, the risk for AD is tripled (3-fold) with every APOE e4 allele (gene) you carry, so if you have two APOE e4 alleles (genes), the risk is increased by 3-fold x 3-fold = 9-fold.  Each of the other known genetic risks (of which there are one to two dozen) contributes less than a 50 percent increase (1.5-fold), and some contribute less than a 20 percent increase (1.2-fold).

Is there a certain amount of exercise that is needed to prevent or stop AD?

  • This is an area of intense investigation right now. We know how much and what sort of exercise slows progression, so the natural question is “how much is required to prevent or stop AD?” There is a randomized clinical trial showing that 60 minutes of brisk exercise twice each week slows progression. The study was not powered for this sort of quantification, but, at the end of the exercise trial, those who participated in the exercise had a mental status score that was 25 percent better than that of nonparticipants.  Does this mean that quadrupling the exercise (60 minutes daily) would arrest or stop progression altogether? That sort of followup is ongoing now. Stay tuned here for more on what kind and how much exercise is important for reducing risk for AD!

Are greater inflammatory effects linked to the role of SORCS1 in AD and T2D?

  • Among all the metabolic changes associated with T2D, the insulin resistance is the feature that is most closely linked to the AD risk. We now know from a patent published by a Danish group that mice deficient in Sorcs1 are insulin resistant. Right now, the smart money is on the insulin resistance as the key to unraveling this conundrum.

The other two SORCS genes also show association with AD in the Alzheimer’s Genome Project.

  • Yes, Rudy Tanzi from CAF is a leader in this area. He has linked SORCS2 and SORCS3 to AD. To our knowledge, these are not linked to T2D. The key linking the SORCS family to AD may be due to some property shared by all members of the family. In that case, the T2D associated with SORCS1 might be attributable to, for example, sorting of both APP (or a processing enzyme) and the insulin receptor or an insulin receptor substrate. In this case, the insulin sensitivity is a marker for SORCS1 deficiency but does not, in and of itself, cause the AD. We are testing such a scenario right now. In our paper from 2010, Rachel Lane showed that levels of SorL1 and Vps35 were reduced in Sorcs1-deficient mice. We already know that deficiencies of both of these can accelerate brain amyloid accumulation. What we want to do next is to look at mice deficient in each or both of these and see whether any of them is insulin resistant.

Will NAPA result in increased funding for Alzheimer’s research?

  • A 130 million dollar one-time increase has been proposed in Congress, although that bill (like all bills in Congress these days) has its opponents and may or may not make it into law.  At present (May 1, 2012), the research community is waiting and watching to see what happens to NIH in the upcoming federal budget “sequester.”  As of this writing, NIH is slated for an 11 percent across-the-board annual cut. This may not sound enormous, but such a cut would set research back by at least 10 years.

Please discuss the role of red wine and chocolate in modifying AD risk.

  • All foods contain many chemicals; in fact, they are composed entirely of chemicals. Some foods are rich in chemicals which, in isolation and at high doses, can modulate AD risk and/or lifespan. Both red wine and chocolate contain protective chemicals known as polyphenols; red wine also contains a chemical known as resveratrol. Each of these has shown benefit in mouse models of AD. In general, the amount of wine or chocolate one would need to consume would be enormous in order to take in a dose of polyphenol or resveratrol equivalent to that used in the mouse experiment that showed benefit. Identifying so-called natural products is a major focus of the pharmaceutical industry. Digitalis, one of the most widely used drugs for heart failure, was discovered as a component of extract of the foxglove plant, based on a folk remedy. On the other hand, ginkgo biloba was claimed to benefit AD but failed in human clinical trials. There are biotech and academic efforts aimed at turning polyphenols and resveratrol into effective AD medicine, but so far, no beneficial effects have been documented.

Please comment about the role of carbohydrate restriction in treatment for both AD and T2D.

  • One of the most robustly effective life extension interventions in the laboratory has been caloric restriction (CR). CR extends life in flies, worms and mice, and has been shown to have a cognitive benefit in monkeys. However, the “severity” of CR used in the lab would be intolerable to humans over the long term. Just like with red wine/resveratrol and chocolate/polyphenols, there is intense interest in drugs known as mTOR inhibitors that appear to mimic the CR effect. mTOR inhibitors also delay or prevent AD in mouse models, but they are relatively ineffective in mice that already have progressed to the stage of brain damage. So, a pill that mimics CR would be a potential “fountain of youth,” since CR extends lifespan while also maintaining cognition. As you can imagine, there is great interest in the pharmaceutical industry in finding a clinically tolerable and useful CR-mimetic. The current generation of mTOR inhibitors are used to treat cancer, and derivatives of those are being evaluated for possible usefulness in maintaining cognition. Again, stay tuned to for updates!

Is there a positive effect of ketogenic diet on AD?

  • Ketogenic diet is effective in slowing AD progression in mouse models but has not been proven effective in humans.

Why is the focus not on lifestyle, which could be implemented immediately, rather than searching for a drug?

  • I prescribe exercise for my patients, friends, family and myself so that they (we) reduce the risk for (of progression of) dementia. Much of science research is driven by quests for money or glory. Physical exercise regimens are unpatentable and unlikely to be rewarded with major prizes and recognition. There is certainly no reason not to do both; i.e., to exercise while waiting for a pill to come along.

Please comment on coconut oil.

  • The response here is similar to that for red wine and chocolate above. The bad news is that an antioxidant supplement similar to fat was recently shown to actually make dementia worse. The lesson here is that even things that sound logical and/or work in mouse models don’t always work in humans; moreover, they might actually make sick humans more sick. Even the most robust mouse result (such as the recent bexarotene paper in Science) requires years of clinical trials before we can tell whether it works for AD.