Posted August 12, 2011
Thank you to all who attended our Symposium on Oct. 18 in Boston. Below are questions and answers that were submitted that day.
MODERATOR
Robert Bazell, Chief Science & Health Correspondent, NBC News
PANEL
Rudolph Tanzi, Ph.D., Harvard Medical School/Massachusetts General Hospital; Chairman, CureAlz Research Consortium
Robert Moir, Ph.D., Harvard Medical School/Massachusetts General Hospital
David Shenk, Author of the national bestseller The Forgetting, Alzheimer’s: Portrait of an Epidemic
Are we seeing an increase in Alzheimer’s disease (AD), and if so, why?
Yes: A larger percentage of the population is entering the age range where Alzheimer’s symptoms are apparent. As the baby boomers flood this zone, the number of diagnosed cases will increase.
Methods for diagnosing the presence of the disease are getting better. This suggests that the number of people having the disease may be about the same as in earlier generations, but we are now better at identifying it. Therefore, the percent of the population with the disease is probably about the same, but the numbers, given the increase of people over 65 years of age in the population and better diagnosis, are greater.
What is the “morbidity rate” of Alzheimer’s compared with other “major” diseases? Is this going up or down?
The most reliable comparative numbers we have is for the period between 2000 and 2008. The “trends in the causes of death” in percentage terms between those years is:
Alzheimer’s disease: increase of 66 percent
Breast cancer: decrease of 3 percent
Prostate cancer: decrease of 8 percent
Heart disease: decrease of 13 percent
Stroke: decrease of 20 percent
HIV/AIDS: decrease of 29 percent
Are more women than men affected by the disease?
There is some data that suggests more women than men are diagnosed with the disease. However, that number may be affected by the fact that women tend to live longer than men, although the gap is narrowing. As important as diagnosis is, it is also important to have and know people caring for Alzheimer’s patients. Women rank much higher in this category than men.
How does the number of Alzheimer’s patients in the U.S. compare to the number of diabetes patients? Cancer patients? Heart disease patients?
The most reliable comparative numbers we have are for 2007.
Alzheimer’s disease: 5,100,000 (5,400,000 in 2010)
HIV/AIDS 1,100,000
Stroke 5,700,000
Cancer, all forms 10,500,000
Diabetes 15,000,000
Heart Disease 16,000,000
Is it a good idea or not, and if so, how and where can I do it?
There are three possible ways to “test” for predisposition for the disease.
One is family history. If one or more “first-degree” relatives (mother, father, sister, brother) have the disease, your odds are higher than the general population.
Second, genetic testing is available. However, genetic testing for Alzheimer’s through commercial testing is generally limited to the identification of the APOE gene and its APOE4 variant. The APOE4 gene is found in about a quarter of the population; not everyone who has APOE4 will develop Alzheimer’s. People who inherit one copy of APOE4 have up to four times the normal risk of developing the late-onset variety of the disease. People who have two copies of the gene (one from each parent)have roughly 10 times the normal risk. To restate, having the APOE4 gene does not guarantee the disease, but does increase the likelihood of Alzheimer’s developing. Should one want to test for this gene, it is extremely important to accompany the test with qualified genetic counseling for an explanation of the nuances of the test results.
Early-onset Alzheimer’s is determined by the presence of one or both of the “presenilin” genes, Presenilin 1 and Presenilin 2. If one has either of these genes, onset of Alzheimer’s is almost certain. However, the presence of these genes in the population is extremely rare; less than 3 percent of the total Alzheimer’s population. There are roughly 500 families known worldwide with this mutation.
Summary of genetic testing:
If you have Alzheimer’s in your family and you want a better idea of your odds of getting the disease, careful genetic counseling in conjunction with a genetic test can be useful to help either relieve anxiety or plan your future differently than you might if you knew you were not as susceptible. Such testing is available in selected clinical settings or from commercial genetic testing companies.
Third, there are now techniques available through certain kinds of protein biomarker tests (lumbar puncture) and imaging (brain scans) to detect the amount of Abeta in either the regular spinal fluid or directly in the brain. Less Abeta in the spinal fluid indicates that there is more in the brain than there should be, while looking into the brain with certain scanning technologies allows doctors to see if there are abnormal depositions of Abeta in plaques and on blood vessels. Again, none of these “tests” are definitive, but they may be helpful to researchers and may be an element in a diagnostic process initiated by an Alzheimer’s specialist.
A 50-year-old man was diagnosed with AD with no history of AD in the family. Is this the garden-variety AD, or truly “early-onset”? How much does this increase the risk for his children?
If the diagnosis is accurate, the patient may very well have the “early-onset” and, therefore, a rare, virulent form of the disease. That would be odd, though, with no family history, but not unprecedented.
A man in his mid-70s with no obvious Alzheimer’s symptoms. If, in 10 years, he starts to show obvious symptoms of the disease, would the hoped-for cure be able to arrest or reverse his symptoms, or would it have to be identified at an earlier point in the disease’s progression?
Ideally, anyone with a genetic predilection to the disease would understand that early in life and do whatever it takes to retard progression. However, we believe that within 10 years, there will be therapies available to retard or stop progression. It is not impossible to believe that some symptoms could be reversed or that, at least, effective rehabilitation programs would be available once the disease’s progression is halted.
I understand that exercise offers some protection against Alzheimer’s. Why?
Sangram Sisodia, Ph.D, a member of the Cure Alzheimer’s Fund Research Consortium and the Thomas Reynolds, Sr., Family Professor of Neurosciences at the University of Chicago has written:
Specifically, studies have revealed a possible protective role of exercise, particularly if it starts early and is maintained. In one study, over 1,700 people aged 65 and older, none showing any signs of dementia at the start were examined over a six-year period. These studies revealed that older people who had increased physical activities when they were middle-aged had significantly decreased risk of dementia and Alzheimer’s. The authors believe that exercise may improve brain function by boosting blood flow to areas of the brain used for memory. In another study, over 3,000 men and women aged 65 years or older who participated in the Cardiovascular Health Cognition Study from 1992 to 2000 and who did not have dementia at the onset of the study were assessed 5.4 years later. The most significant finding was that dementia occurred less frequently in those participating in more activities relative to those who participated in fewer activities.
How much physical activity must an individual do to have a recognizable effect on deterring the disease? Would basketball once a week work?
There are too many factors at play in individual physiology to generalize, but movement that stimulates blood flow daily would be a good start.
Is there any correlation between sleep deprivation and Alzheimer’s?
David Holtzman, M.D., a member of the Cure Alzheimer’s Fund Research Consortium and the Andrew and Gretchen Jones Professor and Chair of the Department of Neurology at Washington University School of Medicine notes that not only does the risk of Alzheimer’s increase with age, the sleep/wake cycle also starts to break down, with older adults progressively getting less and less sleep. Investigators are considering epidemiological studies of whether chronic sleep loss in young and middle-aged adults increases risk of Alzheimer’s disease later in life. David has an article about this work in the Cure Alzheimer’s Fund Quarterly Report, Fourth Quarter of 2009.
Does stress play a role in Alzheimer’s?
There is no published research data indicating a connection between stress and Alzheimer’s disease in patients. However, if an animal model (mouse) for Alzheimer’s is subjected to emotional stress, e.g., by being sequestered in a small, dark box, it will accumulate more Abeta in the brain as has been shown by David Holtzman’s ( of the Cure Alzheimer’s Fund Research Consortium) laboratory.
Do dietary considerations help–herbals, green tea, eating vegetarian, Mediterranean diet?
To the extent that “eating right” is good for anyone, the answer is “yes.” Again, there is no reliable published data that suggests that any one diet is better than another in slowing the onset of Alzheimer’s or ameliorating symptoms once begun.
If “social engagement” is one of the lifestyle elements that may be helpful in staving off Alzheimer’s, does the increased use of computers and other technologies that keep us from traditional social engagement impact the onset of Alzheimer’s?
While we know of no research addressing this question with regard to Alzheimer’s, one could logically conclude that any activity that enhanced isolation and lack of social contact might affect the onset of the disease. On the other hand, and there is no data about this either, it might be that intellectual activity exerted in computer or other solitary electronic activities could actually stimulate the brain. But again, no data on this so we are reluctant to express an opinion.
I understand that the peptide (small protein) Abeta is a major player in Alzheimer’s disease. How can it be identified, measured and tracked in the body? The analog is cholesterol for heart disease, which can be monitored through simple blood tests.
See “Testing for Predisposition to the Disease” above. Unfortunately, Abeta is not as clear a marker as cholesterol. The changes with disease are more subtle, and clear trends are much harder to identify in individuals.
How do you monitor the effectiveness of drugs–brain scanning, biopsies, autopsy?
A range of biochemical parameters are followed, but the most prominent for AD is Abeta deposition in the brain. A range of techniques are used to measure these parameters, including those mentioned above. However, at some point a drug must demonstrate efficacy in treating the disease–for AD it must slow, stop or reverse cognitive decline. Researchers follow the specific parameter that the drug targets but also general indicators for AD. For example, if a drug binds and removes Abeta from the blood, then circulating levels of the peptide are closely followed. Before a potential new drug is even assessed for efficacy, however, it must pass several major hurdles. Firstly the drug must show efficacy in treating the disease in laboratory animals. Next the drug must be shown to be safe in animals and then humans. Only then is the drug tested for efficacy in humans. A promising drug compound may fail at any of these points. This long and intensive process is why established drugs that already have been proven safe for humans are attractive as potential candidates for testing for efficacy in new diseases. But if starting from scratch, the compound must work its way through these steps.
One of the limiting factors for testing drugs for Alzheimer’s in animals has been the length of time it takes in the laboratory observe the interaction of a compound in an animal carrying Alzheimer’s. David Holtzman, of the Cure Alzheimer’s Research Consortium, and colleagues at Washington University School of Medicine in St. Louis have developed an innovative way to radically reduce the time it takes to determine whether an Alzheimer’s drug is effective in mice. They have developed a facility to measure the concentration of Amyloid-beta in real time in the brain of living, behaving mouse models that develop features of AD. The model enables screening for drugs that lower Amyloid-beta directly in the brain in relatively high throughput.
Brain scanning in humans by various emerging technologies is also promising, but has not progressed to the point of widespread use for research in humans and is certainly not ready for clinical use.
The use of “biomarkers” or the change of physical elements in the blood and/or spinal fluid is another way to track the effectiveness of a drug. If the drug either lowers or raises certain proteins in either of those media, it may indicate that the drug is effective in reducing or clearing the protein from the brain. However, researchers have not yet identified consistently reliable, broadly acknowledged biomarkers for Alzheimer’s.
Do persons who take psychoactive medications, such as anti-depressants, earlier in life have an increased risk for Alzheimer’s?
Depression and social isolation are risk factors for AD. However, there is no evidence to suggest that antidepressants, which reduce these conditions, have a positive effect on AD.
Why don’t the drugs in recent failed drug trials for Alzheimer’s work?
Developing a drug for any disease, let alone one that is as complex and complicated as Alzheimer’s is a delicate and very expensive proposition. There are several reasons why a drug doesn’t work, and usually are found to be acting in concert:
Emerging Alzheimer’s drugs have suffered from all three of these difficulties. However, a failed drug does not mean that the drug target is wrong. More probably, it means that the particular drug just wasn’t potent enough, safe enough, or was too cumbersome and/or expensive to be useful in the population at large.
Finally, even though a drug fails to slow or stop the disease, it is not a total loss. The results of that drug can teach us valuable lessons about how to build the next generation of drugs. With the cost of bringing a drug to market of over $1 billion, this is an expensive, but necessary learning exercise.
Are there any promising drugs currently under development?
Yes. Several drugs, including a few of which Cure Alzheimer’s Fund-funded research has helped to develop, are very promising and almost ready for human trials. A cautious estimate is that within the next five years, the Alzheimer’s research field should have at least one drug in development that will retard significantly or stop the disease. It may take longer to develop drugs that will prevent the disease from occurring, or at least delay onset until very old age.
Are researchers aiming for one cure-all drug or some mix or cocktail as is true with AIDS?
There is probably not going to be one “blockbuster” drug for Alzheimer’s. The disease’s genetic complexity, and the number of ways onset canbe initiated through stroke, headinjury and other life factors, suggest that there is no one way to prevent or counter the disease. Most likely, therapies will vary according to the patient’s genetic makeup and life factor influences.
The research pursued by the Cure Alzheimer’sFund focuses on drug solutions. How do you feel about the results of the ACTIVE study? How about Yaakov Stern’s Cognitive Reserve strategy? What about hopes for neuroplasticity of the brain to rehabilitate executive function?
The deposition of Abeta is an extremely useful marker for AD. However, the relationship is not straightforward and classifying the severity of AD from plaque load can be misleading. Loss of synapses is the “bottom line” for AD. The progressive loss of synapses best correlates with the degree of dementia or Alzheimer’s disease and this leads inevitably to cognitive decline. Genetic, or even environmental factors, are likely to lead to variation between individuals in the resistance of their neuronal cells to plaques and the AD process. While there may be individuals with high plaque loads that maintain relatively high cognitive function, this is usually due to the fact they have low tangle counts and thus less extensive synapse and neuronal loss. At the present time, limited data supports Cognitive Reserve (number of synapses) as the cause of variation in AD progression. Without halting the AD process first, there is little hope of rehabilitation of executive function–through neuroplasticity or any other methods.
Do you endorse brain fitness exercises?
There is no data to suggest such mental exercise works. The important thing is to build new synapses to back up the ones you already have. This is best achieved by learning novel things more than playing mental games.
How does Abeta get into the cells to interact with the tangles and tau?
Abeta is made normally by cells and already is present. In AD, Abeta generation is either increased or shifts from “good” to “bad” forms. The important disease–causing form of Abeta is now thought to be soluble oligomers, small assemblies of Abeta molecules, which are still soluble and able to diffuse throughout the brain. The insoluble plaques come later, after these assemblies aggregate into bigger and bigger forms. One of the biggest questions is how Abeta oligomers drive tangles. The most likely possibilities are through amyloid-induced inflammation, calcium imbalances and altered cell-signaling events beginning at the cell surface where Abeta interacts with nerve cells.
To what extent might leaking blood vessels (increasing in older people) be a culprit? If so, how might we better seal blood vessels in the brain?
They may indeed be a contributor and this has been a line of investigation for many years. However, at present it is still unclear. Among the complicating factors is that while AD pathology may be made worse by leaky blood vessels, it is also known that the disease decreases vessel integrity. At present there is no clear strategy for improving leaky blood vessels.
Could bacteria leaking across the blood-brain barrier cause an uptick in Abeta response, Abeta being partly a good thing identified as an anti-microbial agent?
This may indeed be the case. Several researchers have claimed Alzheimer’s disease occurs with brain infections. Notably 20 percent (and rising) of long-term HIV patients develop dementia that appears to include extensive Abeta deposition. However, the antimicrobial function of Abeta is a very recent finding and a lot more research will be needed to confirm a microbial role in AD pathology.
Please comment on the association between Alzheimer’s and anesthesia.
Animal studies suggest that the general anesthetic isoflurane can induce Alzheimer’s-like changes in the brain. This finding was pioneered in Dr. Tanzi’s lab. Please note that to date these are animal studies only, and are only now being tested in humans who undergo surgery. These effects have not yet been confirmed in human studies. Dr. Tanzi personally recommends to family members and friends that they choose the anesthetic desflurane instead of isoflurane in consultation with their doctor prior to general surgery.
Is there a correlation between Alzheimer’s and Parkinson’s disease? Lewy Body disease?
Lewy body disease involves the abnormal accumulation of a different protein in the brain called alpha-synuclein, which also accumulates in the brains of Parkinson’s patients. Often the alpha-synuclein lesions called Lewy bodies are observed along with Abeta deposits, e.g., plaques and tangles in Alzheimer’s disease.
What is the link between diabetes and Alzheimer’s?
Type 2 diabetes and AD share a broad array of disease features and a large body of evidence accrued over the last 60 years suggests the pathologies of these two disorders are strongly linked. However, as of yet no common molecular mechanism has been identified that can explain the epidemiological commonalities between diabetes and AD. The link between the two diseases was made even stronger when in 1987 the death of pancreatic islet cells (the cells that make insulin) was associated with amyloid deposition. Thus, both diabetes and AD are amyloid diseases. However, the amyloid in a diabetic pancreas is not made from Abeta, but another peptide called amylin. There are striking similarities between amylin and Abeta. Despite the discovery of amylin, the specific disease mechanisms common to these two epidemic diseases remain elusive.
Given the link between Alzheimer’s and diabetes, should this connection become better known as we work to reduce Type 2 Diabetes? Isn’t this a major public health issue?
We know that factors affecting the onset of diabetes are increasing the prevalence of the disease, and to the extent that this exacerbates or accelerates any relationship to Alzheimer’s disease, the implications are truly frightening on a societal basis. As we learn more about the inter-relationship of these diseases and how behavior can affect their onset, public health/awareness campaigns on the level of the “Stop Smoking” effort are certainly warranted.
Given the link between diabetes and Alzheimer’s, is there a higher prevalence of Alzheimer’s in certain populations? E.g., African Americans have a higher incidence of diabetes; does that population therefore have a higher incidence of Alzheimer’s disease?
This suggested link had not been established in published data.
Can you comment on how Alzheimer’s disease correlates with Down Syndrome? Do individuals with Down Syndrome have more Abeta coding genes because of the triplicate copy of the 21st chromosome?
Down’s syndrome involves an extra copy of the APP gene. As would be predicted if Abeta is the culprit in AD, a dose response is observed for Down’s patients, with all showing early AD pathology–with the exception of a rare form in which the part of chromosome 21 containing the APP gene is not duplicated. These Down Syndrome patients do not show AD pathology. This is good evidence of the key role of Abeta in AD.
Funding for AD research by the federal government
How could proposed cuts to the National Institutes of Health (NIH) impact Alzheimer’s research?
They would be devastating. Not only is there not enough money available now to fuel the research that will get us to effective therapies in time to head off the entrance of baby boomers into the age range where Alzheimer’s is most prevalent, but the lack of research funding is driving away the next generation of medical researchers as well. There are too few people to make the discoveries and do the complicated, important work to end this disease and others. This is a classic case of “pay me now, or pay me later”. If we do not as a society make the investment we need to make in medical research, we will be paying far more for the care of those immediately affected. In the case of Alzheimer’s, right now we spend $180 billion on care for Alzheimer’s through Medicare, Medicaid and private insurance; and $450 million through the National Institutes of Health for the research that would obviate much of the care. This situation cannot continue or the disease will overwhelm us.
Is the NIH spending research dollars effectively?
The NIH has a huge mission with very limited resources. Under its new director, Dr. Francis Collins, who was a co-discoverer of the human genome, NIH is looking hard at how best to use the resources it has. One example of that is the new series of NIH “Blueprint” grants for the fast-track development of promising drug therapies. Cure Alzheimer’s Fund is proud to say a researcher it has supported, Steve Wagner of the University of California at San Diego, is one of seven first-time recipients of this grant to pursue the development of certain compounds into effective Alzheimer’s drugs.
Are Cure Alzheimer’s Fund and The Alzheimer’s Association cooperating? If so, how?
The Alzheimer’s Association has a very broad portfolio from awareness to caretaker support to research funding. The Cure Alzheimer’s Fund focuses only on the funding of research along a very specific road map. Both organizations are working hard to serve the Alzheimer’s community, but we approach it in different ways. We have collaborated on a research prize for mid-career researchers, and we have collaborated together and with other Alzheimer’s organizations to lobby for passage of the National Alzheimer’s Project Act, co-sponsored by Congressman Markey of Massachusetts and others, to coordinate the efforts of the federal government with regard to a better and more strategic focus on Alzheimer’s disease and to develop a national plan to end the disease.
Do researchers in the U.S. collaborate with those abroad?
Yes. Researchers worldwide are in touch with each other through published papers, conference and seminars and by working collaboratively on research projects. Cure Alzheimer’s Fund supports research done at the Max Planck Institute in Berlin through the website www.AlzGene.org.
Does the U.S. lead the world in the race to find a cure for Alzheimer’s?
Even though the funds for Alzheimer’s research are too scarce in the U.S., there is more money being spent here than abroad. However, there are important discoveries being made every day from around the world that contribute to a better understanding of the disease and therefore a faster development of effective therapies. Researchers tend to think less about nationalities and more about who is doing the best work on specific aspects of the disease.
Do all countries share all their new findings with the rest of the scientists working to find a cure?
Yes, through published papers, conference and seminars and by working collaboratively on research projects.
Why don’t we follow the Rotary model used to eradicate polio for the children of the world? Let’s eradicate Alzheimer’s disease for the adults of the world with support for research through better marketing and fundraising.
Rotary International has created a powerful template for attacking a worldwide problem in its dedication to ending polio in the world, an objective largely achieved with the help of various international health agencies around the world. The organization has made a tremendous contribution in that regard, and it and other similar organizations can certainly advance the cause of ending Alzheimer’s in similar ways.
