Down syndrome: The key to Alzheimer’s?

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San Diego (Ivanhoe Newswire) — More than five million Americans are living with Alzheimer’s. More than 400,000 of them also have Down syndrome. What does a condition seen at birth have in common with a disease typically diagnosed in the elderly? Quite a bit!

Jonathan Shirley has Down syndrome, but he’s never let what he can’t do hold him back. “I don’t look at disabilities at all. I look at what I can do.” Shirley told Ivanhoe.

Jerry Shirley, his dad, says Jonathan’s always finding ways to help others. “Jonathan is an amazing guy. He’s been an inspiration.” He said.

Shirley is now helping doctors at the University of California San Diego not only learn more about his condition but also about Alzheimer’s disease.

“These individuals, when they hit the age of 40, 100 percent of them have the pathological changes of Alzheimer’s disease in their brain.” Dr. Michael Rafii, MD, PhD, neurologist at UCSD told Ivanhoe.

As part of a clinical trial, Dr. Rafii has found Down syndrome brains look very much like Alzheimer’s brains. Both have higher levels of the protein beta amyloid. In fact, Down syndrome patients develop the protein at double the rate.

“We may be able to translate those discoveries into therapies for the general population… People with Down syndrome represent the world’s largest population of predetermined Alzheimer’s disease from a genetic perspective.” Rafii said.

61 year old Lisa Goldberg has Down syndrome and her sister says she is now showing some signs of dementia also.

“Something that happened five minutes ago, it’s hit or miss whether she recalls.” April Hinson, Goldberg’s sister told Ivanhoe.

Goldberg still works and doesn’t let her disability get in her way.

And Shirley agrees…“We are all special in our own way.”

It just may be that Down patients like Shirley and Goldberg hold the key to finding the answer to Alzheimer’s.

Dr. Raffi’s research is now focusing on how somebody can have amyloid plaques in their brain and have full dementia, whereas someone else has the same amyloid plaque but no dementia. Rafii believes there is something some patients have in their brains that makes them resilient to it.

BACKGROUND: Down syndrome is caused when the nucleus of a cell has either a part of or a full extra copy of chromosome 21. The syndrome affects one in every 691 babies born in the U.S. which makes it the most common of all genetic defects. Approximately 400,000 Americans currently suffer from Down syndrome and 6,000 American babies are born with it each year. People with Down syndrome live on average 55 to 60 years, putting them at increased risk of developing early Alzheimer’s. By the age of 40, people with Down syndrome have higher levels of plaques and tangles in the brain, which are commonly linked with Alzheimer’s. (Sources:,

SYMPTOMS: Early symptoms of Alzheimer’s in Down syndrome adults may include:

• Seizures that begin in adulthood

• Changes in coordination and walking

• Decline in ability to pay attention

If you’d like to share the facts of Alzheimer’s disease, please visit to watch the Facts and Figures video, send information about the disease to a friend and learn more. The Alzheimer’s Association also offers a 24/7 helpline that has helped millions. Since 2007, the helpline has received nearly two million calls, with a 48 percent increase in calls over the last four years and 300,000 coming in 2013 alone. The helpline can be reached at 1.800.272.3900. (Source:

MORE FROM DR. MICHAEL RAFFI: 50 percent of Down syndrome adults will go on to develop Alzheimer’s disease in their 50’s. By understanding more about beta amyloid, a precursor protein formed in the brain, doctors may be able to determine more effective treatments for Alzheimer’s in patients with Down syndrome. The syndrome causes an overproduction of beta amyloid; therefore treatments that reduce this protein may help patients suffering from both Alzheimer’s and Down syndrome. (Source: Dr. Michael Raffi)

Michael Rafii, MD, PhD, neurologist at UCSD talks about how Down syndrome patients may hold the key to finding the answer to Alzheimer’s.

So we’re here to talk about Alzheimer’s and Downs and I’m a little confused. Do all Downs kids get Alzheimer’s and dementia at a certain time?

Dr. Rafii: They can. Down syndrome is one of the most common causes of developmental disability in our country and is due to a chromosomal abnormally. When individuals with Down syndrome reach the age of 40, 100 percent of them have the pathological changes of Alzheimer’s disease in their brain.

Is that the plaque?

Dr. Rafii: Right, the amyloid plaques and neurofibrillary tangles. However, not all people show the symptoms of dementia and the question is why. Some people with Down syndrome develop signs of dementia in their 50’s while others in their 60’s. We’re trying to understand why that is even though everyone has plaques and tangles by age 40. People with Down syndrome represent the world’s largest population of predetermined Alzheimer’s disease from a genetic perspective and we’re trying to understand why that is.

Let’s go back to that stat I was reading. It said, all people all Downs kids or people, will have the plaque when they’re 40 that 50 percent will then go on to get Alzheimer’s by the time they’re 50. Is that true?

Dr. Rafii: That’s true. Alzheimer’s disease is the most common cause of dementia. Dementia is the clinical syndrome that they will show, such as progressive difficulty with memory and problem solving. In our country the most common cause of dementia is Alzheimer’s disease. Alzheimer’s disease is thought to be due to the buildup of amyloid plaques and neurofibrillary tangles in the brain. It turns out that everyone with Downs syndrome develops those plaques and tangles around the age of 40. However not all of them show the symptoms of dementia.

Can you tie this together with a protein that makes the plaques that downs kids may have more of?

Dr. Rafii: That’s right. We know that Alzheimer’s disease is associated with the buildup of an abnormal protein in the brain called beta amyloid. We think this beta amyloid is toxic to the brain and over decades it deposits into plaques. The brain cells around these plaques contain neurofibrillary tangles which are an abnormal accumulation inside of neurons. Together these form the basis of Alzheimer’s disease pathology. There are certain forms of Alzheimer’s disease that are genetically inherited, where people overproduce that beta amyloid. People with Down syndrome have trisomy 21. They have an extra copy of the 21st chromosome. On the 21st chromosome is the gene for this beta amyloid protein, which is cleaved to produce beta-amyloid. So they are producing 50% more amyloid precursor protein and therefore an extra amount of beta amyloid deposits in the brain.

So how do kids with this extra 21st chromosome hold the key to Alzheimer’s?

Dr. Rafii: We think that by understanding how beta-amyloid develops in the brain of people with Down syndrome over time, and how it exerts its effects on the brain, we can better understand and develop treatments for Alzheimer’s in people with Down syndrome, perhaps even in the larger population as well. They’re overproducing beta-amyloid and there are therapies being developed that are reducing beta-amyloid which may help people with Down syndrome who are at a very high risk of developing Alzheimer’s disease.

Are all of these people getting early onset dementia because isn’t that very aggressive?

Dr. Rafii: Early onset Alzheimer’s disease occurs when somebody develops dementia due to Alzheimer’s disease typically under the age of 65. Early onset Alzheimer’s disease in some cases is due to a genetic cause, an autosomal dominant mutation that’s inherited from a parent and can be more aggressive. People with Down syndrome represent another population of early onset Alzheimer’s disease.

So you can have therapies that help reduce this protein buildup, the amount of protein that is being made with this extra chromosome. What’s this mean for people who do not have Downs but have Alzheimer’s?

Dr. Rafii: The genetic forms of Alzheimer’s disease are due to an overproduction of beta-amyloid. That’s about five percent of all cases of Alzheimer’s dementia. In fact, 95 percent are people who develop Alzheimer’s in their 70’s and 80’s in the general population. Why do they develop Alzheimer’s disease? It turns out it’s not an over production of beta amyloid, but rather an under excretion of beta amyloid out of the brain. By understanding how beta amyloid is produced but also cleared is critical in developing therapies. If we can understand the biology of beta amyloid in Down syndrome we may be able to translate those discoveries into therapies for the general population as well.

It sounds like too much or too little of this protein has damaging effects.

Dr. Rafii: Well too much in terms of overproduction of beta-amyloid or too little of its removal. Both of those lead to a buildup or an accumulation of beta amyloid in the brain. In the genetic forms, it’s overproduction. In the sporadic form it’s an under excretion of beta amyloid out of the brain. Most of the therapies that are being developed right now for Alzheimer’s disease are aimed at either reducing the production of beta amyloid or accelerating its removal out of the brain.

So tell me about your study with this.

Dr. Rafii: We have different studies in the general population at risk for developing Alzheimer’s disease, but also in older adults with Down syndrome. One study is called the Down syndrome biomarker initiative or DSBI. This study essentially is a study of natural aging in older adults with Down syndrome to understand where the plaques come from, how soon they develop and what the effects of those plaques are on the person’s thinking. What we do in this study is image the brain with MRI and amyloid PET scans. We also utilize retinal amyloid imaging to look at the buildup of amyloid plaques in the retina. We administer memory tests and cognitive thinking tests to see what effect the presence of those plaques have on the person’s thinking. We do that in individuals who are in their 30’s, 40’s, 50’s and even in their 60’s again to try to understand the natural progression of Alzheimer’s disease in this population.

How long do they study is this?

Dr. Rafii It’s a three year pilot study, with annual visits right now but we’re making plans for a much larger study that would have hundreds of participants. This study is modeled after already existing studies including a study called ADNI which stands for Alzheimer’s disease neuroimaging initiative. That study has been going on for eight years and is a study of these same biomarkers of Alzheimer’s disease in the general population. There is also another study called the DIAN study which is dominantly inherited Alzheimer’s network and these are people who have an early onset genetic form of Alzheimer’s disease. Again trying to understand, what the changes are that are occurring in the brain even before the patient develops symptoms of dementia. Can we find a biomarker of the Alzheimer’s pathology before the person shows symptoms? We believe that in order to treat Alzheimer’s you really need to prevent it. The question is, how early do you need to intervene to prevent the dementia from occurring.

Do you use CAT scan or blood tests or how do you do this?

Dr. Rafii: We use different kinds of tests. We use MRIs, a particular kind of MRI called the volumetric MRI, which allows us to measure the volume of different areas of the brain including the memory centers of the brain, looking for shrinkage, which occurs in Alzheimer’s disease. We also use amyloid PET scans where we can actually see those amyloid plaques in the brain of our participants. We can quantify or measure how much amyloid is in the brain and how that relates to any shrinkage in the brain seen on MRI.

How far into the study are you and have you seen that with let’s say, Jonathan and Lisa?

Dr. Rafii: We’ve done baseline imaging of all of our participants in this pilot study. Some of our participants, especially the older ones, are already showing the plaques in the brain. We also do genetic testing and blood levels of amyloid to see if we can correlate all of these changes together.

So for example, say a 90 year old has just as many plaques and tangles in her brain as another 90 year old, but one is full Alzheimer’s and the other is active and healthy. How could you tell? How do you know those plaques are going to cause Alzheimer’s?

Dr. Rafii: We know that the accumulation of beta amyloid is critical for showing the symptoms of dementia, but how is it that somebody can have amyloid plaques in their brain and be fully demented, whereas someone else with just as much plaque and has very little dementia? There was a well-known study called The Religious Order Study which demonstrated that there can be individuals where the brain has a lot of pathology but they’re doing just fine. The concept has been that of cognitive reserve. We think that there is some feature in those individuals that even though they have Alzheimer’s disease pathology in their brain, they’re resilient to it. Just last week there was a paper published in the journal called Nature where one of the biochemical mechanisms that provide this protection was discovered. It was studied in animal models but also in human brain studies including participants in the Religious Order study. We think that there are certain genetic, but also environmental features that promote someone in being healthy.

Although it’s increased immensely over the years, Down’s patients seem to have a very short lifespan.

Dr. Rafii: Alzheimer’s disease affects five and a half million Americans in the general population. One out of every three individuals over the age of 85 has Alzheimer’s dementia. The fastest-growing segment of our population in the United States is those over 85. Alzheimer’s disease is an age-related disease; it’s a neurodegenerative disease that seems to be age related. The biggest risk factor for developing Alzheimer’s disease is age. As people are living longer we’re seeing that the incidence of Alzheimer’s dementia is increasing. The same is true with people with Down syndrome, they are living longer and because they’re living longer and also at risk for developing Alzheimer’s disease. It’s just that in Down syndrome there is this genetic predisposition for developing Alzheimer’s disease at a higher rate.

Is it making this protein double the rate of normal?

Dr. Rafii: It’s making 50 percent more amyloid precursor protein and because of that excess production of amyloid precursor protein there’s an excess production of beta amyloid.

So tell me a little bit about Jonathan.

Dr. Rafii: Jonathan is a younger individual with Down syndrome. He’s very active, very well spoken, he does not have dementia and he does not have any Alzheimer’s disease. He’s an individual who is at high risk for developing Alzheimer’s disease but again he’s years away from that happening. At UCSD we have an adult Down’s syndrome clinic. In this clinic we evaluate patients who come in with memory concerns and in addition we have research studies. If someone with Down syndrome was interested in participating we can offer the clinical study to understand healthy brain aging in adults with Down’s syndrome. We’re also conducting clinical studies of new compounds that are being developed again to reduce the risk of Alzheimer’s disease in Down syndrome.

So with Lisa, tell me a little bit about her, she’s part of other studies as well right?

Dr. Rafii: Lisa is an older individual with Down syndrome and she has some of the cognitive impairments that we see in older adults with Down syndrome that we think may be attributable to Alzheimer’s disease pathology. She is participating in the Down syndrome Biomarker Initiative Study. Again, what we’re trying to do is correlate what we see in an individual’s cognition with the changes that we see in the brain both from an MRI standpoint, a structural standpoint, and the presence of amyloid with amyloid PET imaging. We’re just trying to understand the trajectory of how these biomarkers develop in the brain and how they may relate to new symptoms of dementia.

Is Lisa also taking part of an investigational drug?

Dr. Rafii: No.

Is there anything else we should be talking about?

Dr. Rafii: The most important thing to keep in mind when you’re talking about studying Alzheimer’s disease in people with Down syndrome is that people with Down syndrome have an opportunity to benefit from all of the research that’s taking place in Alzheimer’s disease in the general population. Since they are a highly enriched group that’s at very high risk for developing Alzheimer’s, our understanding of Alzheimer’s disease in the general population should be translated into this population as well. They should benefit from all of those efforts. At the same time, people with Down syndrome who are at such high risk for developing Alzheimer’s disease may actually teach us the best way to intervene with regards to Alzheimer’s disease in the general population. I think it’s a bidirectional type of approach where not only people with Down syndrome benefit from the research discoveries in the general population, but by understanding Alzheimer’s disease in people with Down syndrome, we may be able to translate new information that could guide therapeutic development for the general population as well.

Since their rate of production is twice as fast, does that mean that your study can go twice as fast because you’re kind of seeing what would happen in a normal 30 year span in 15?

Dr. Rafii: The rate of production is 50% more. It allows us to know that these individuals will develop the pathology of Alzheimer’s and knowing that, we can look for the earliest changes in anticipation of that happening. In the general population, we believe that the amyloid plaques develop in the brain about 15 years before the patient shows any symptoms, so there appears to be is a 15 year lag between the pathology and the symptoms showing up in the general population. We’re trying to understand if that’s also the case in Down syndrome which hasn’t been answered. In addition, we want to understand how you can have pathology in the brain in some individuals that show symptoms, but others have the same amount of pathology and don’t show the symptoms. What is that key factor that provides that resilience?

This information is intended for additional research purposes only. It is not to be used as a prescription or advice from Ivanhoe Broadcast News, Inc. or any medical professional interviewed. Ivanhoe Broadcast News, Inc. assumes no responsibility for the depth or accuracy of physician statements. Procedures or medicines apply to different people and medical factors; always consult your physician on medical matters.