My friend Chuck Jackson, who along with many family members has early onset Alzheimer’s disease, will testify at a U.S. Senate hearing on Alzheimer’s tomorrow (Wednesday May 14th). The hearing starts at 10:30 AM eastern time. A link to the live webcast will be available at http://aging.senate.gov/.
Note: you can now watch the webcast of the full hearing at any time, or read a transcript of Chuck's testimony.
Summary: CADASIL is a type of stroke disorder that can cause young onset dementia. Two web sites have been developed by women whose families are affected by the disease.
Billie Duncan-Smith’s husband Steve’s first symptom came when he was 38. He woke up with an excruciating headache, and started vomiting because the pain was so bad. Over the next few years, he would suffer many such migraines, some lasting for several weeks. An MRI of his brain showed a high number of white matter lesions, but Steve’s doctors weren’t sure what was causing his headaches.
Billie and Steve in 2004
While Steve suffered, Billie searched the internet and contacted medical experts all over the world. She sent his records and test results to those who offered to help. Finally, someone at the U.S. National Institutes of Health called her to suggest Steve might have CADASIL (Cerebral Autosomal Dominant Arteriopathy with Sub-cortical Infarcts and Leukoencephalopathy), a type of stroke disorder.
Continue reading "CADASIL: Young Onset Dementia Caused by a Stroke Disorder" »
Summary: Genetic variations linked with Alzheimer’s provide clues on potential treatments. Many drugs currently in trials are based on these clues.
With advances in technology, software and the Human Genome Database, Dr. Rudolph Tanzi is optimistic about the future for personalized medicine, where prevention and treatments could be tailored to a person’s specific genetic profile.
Because an estimated 70 percent of Alzheimer’s genetics is still unknown, researchers have a lot of work to do before this vision can be realized.
Scientists study genetic variations and how they are linked with pathologies and symptoms to determine who is at risk for developing diseases. But there’s another important reason they study genetic variations: to look for clues about potential treatments.
To understand why genes might hold clues about treatments, it helps to know that genes contain the blueprints for making proteins, which carry out most of the functions of a cell. If one or more of the thousands of proteins working in a cell is missing or malfunctioning, disease can result. So studying the genes associated with Alzheimer’s disease may lead to a better understanding of the proteins those genes encode, and how they might go awry. These proteins are then “targets” for potential treatments – by manipulating them, we may be able to treat or even prevent Alzheimer’s.
This search for potential Alzheimer’s treatments through the study of genes was the focus of Dr. Rudolph Tanzi’s keynote speech at the Alzheimer’s Association Wisconsin Annual State Conference in May. Dr. Tanzi is Professor of Neurology at Harvard University, and the author of Decoding Darkness. He also runs the Genetics and Aging Research Unit at Massachusetts General Hospital.
Rudolph Tanzi, Ph.D. (center) with conference attendees Cambria Anderson and Chuck Jackson
Dr. Tanzi’s Brief History of Alzheimer’s Gene Research
In the early 1980’s, Dr. Tanzi says, he was working with Dr. James Gusella who discovered the Huntington Disease gene. Dr. Tanzi was inspired to try to accomplish the same thing with Alzheimer’s; eventually his lab would be involved with the discovery of all three of the early onset familial Alzheimer’s genes.
In the mid-1980’s, two different teams of researchers found that the plaques in Alzheimer’s brains are made up of a protein called beta amyloid. One of the researchers, George Glenner, found that the plaques in Alzheimer’s are similar to those in Down Syndrome. “Because people with Down Syndrome have three (instead of the usual two) copies of Chromosome 21, Glenner predicted that beta amyloid was made from a gene found on Chromosome 21,” says Dr. Tanzi.
A few years later, researchers did in fact find a gene called amyloid precursor protein (APP) on Chromosome 21. “APP is a long protein, and when it gets cut apart, it results in beta amyloid,” Dr. Tanzi explains. Later research linked variants of APP to early onset Alzheimer’s disease.
By the mid-1990’s, two more gene variants, called presenilin 1 (PSEN1) and presenilin 2 (PSEN2) had also been linked to early onset Alzheimer’s disease. The PSEN genes are related to the presenilin enzymes [proteins] that cut APP to make beta amyloid.
With these discoveries, scientists knew that variations in three genes were linked to inherited or familial early onset Alzheimer’s disease. But even these genes don’t account for all familial early onset Alzheimer’s. Twenty-one mutations have been identified in the APP gene, accounting for seven percent of familial Alzheimer’s. One hundred sixty-five mutations in PSEN1 account for about 40%, and eleven mutations in PSEN2 account for three percent. This means that rare variations in these three genes account for only about 50 percent of familial early onset Alzheimer’s.
For late onset Alzheimer’s, variations in one gene is a confirmed risk factor. “As you probably know, the APOE4 variant increases the risk of developing Alzheimer’s,” Dr. Tanzi says. “About ten percent of the population carries two alleles or copies, which is associated with a tenfold increase in risk. Another 20 percent carry one allele, which brings threefold increase. About 75 percent of us carry the APOE3 variant, which is neutral with regards to risk of Alzheimer’s, and about two percent have the APOE2 variant, which in combination with APOE3 decreases the risk.”
What Alzheimer’s Genes Tell Us About Treatments
“All four genes point to excessive accumulation of beta amyloid peptides [proteins] in the brain as a common event,” Dr. Tanzi says. “Either you produce too much, and this may be early onset, or you clear too little, which may be the case with late onset. Normally, beta amyloid is produced by the brain and eight minutes later, cleared out. APOE variants affect how rapidly you can clear it out.”
But does this accumulation of beta amyloid really cause Alzheimer’s? “You will have heard that the amyloid hypothesis might not be correct,” says Dr. Tanzi. “The problem is that plaques are end-game stuff. You have to back up to where a single beta amyloid peptide is made. At that point, it’s neutral. But if it binds with zinc or copper, it forms assemblies called oligomers. These assemblies lodge in the synapses, and cause short-circuits in synaptic function. It looks more and more like this is what causes the problem. If the oligomers clump together, you get plaques. Maybe way before the plaques, oligomers cause cognitive problems. In the end, Alzheimer’s is a disease of the synapses. It’s really the loss of connections between nerve cells that causes problems.” This view is the basis for drugs under development by his company, Prana Biotechnology.
According to Dr. Tanzi, most drugs currently in trials are based on newer discoveries linked to APP, PSEN1 and PSEN2. Here’s his rundown of some of the treatments being tested:
Vaccines - This approach traps beta amyloid in the blood using antibodies. A new approach, passive immunization, involves making antibodies in lab. Vaccines are being tested in Phase 2 trials.
M1 Muscarinic Agonists - “First, you need to know that you can’t remove beta amyloid intact, but a ‘good’ enzyme – alpha secretase – cuts beta amyloid in half.” Dr. Tanzi says. M1 muscarinic agonists work to activate alpha secretase.
Gamma and Beta Secretase Inhibitors - “There are also ‘bad’ enzymes – beta and gamma secretases – that release beta amyloid. Developing gamma and beta secretase inhibitors is a huge industry. The problem is that both of these enzymes have to clip other proteins too. Gamma secretase can make two forms of beta amyloid – either AB40, which may have a normal role, or AB42, which is more likely to form oligomers. Now there are gamma secretase modulators that instead of eliminating the enzyme, tweak it to produce more AB40 than AB42. But a great concern is that in trials, this has caused problems with microhemorrhages.”
Substances That Reduce the Trace Metals [Zinc and Copper] Needed to Form Oligomers - Dr. Tanzi’s company is working to develop a Metal-Protein Attenuating Compound (MPAC) based on this approach. “It’s not a chelator, because you need metals for other things,” he says. “It just prevents oligomers from forming. One candidate, Clioquinol, showed a 50 percent reduction in beta amyloid in mice, but there were problems with a contaminant,” he says. “PBT2, a second generation MPAC, reduces beta amyloid levels, rescues communication among nerve cells, and improves mouse cognition after five days of treatment. It’s now being tested in Alzheimer’s patients in Sweden”
According to Dr. Tanzi, other possible approaches include:
*increasing blood flow to the brain which turns on the gene for an enzyme called neprolysin, which degrades beta amyloid. It’s not clear whether this can be done safely.
*preventing hypoxia, or lack of oxygen, to regulate beta secretase activity.
*ACAT inhibitors (his wife’s research) – these cardiovascular drugs lower beta amyloid levels, and can be administered nasally.
There’s a lot of work to do. Dr. Tanzi estimates 80 percent of all cases of Alzheimer’s are inherited, but 70 percent of Alzheimer’s disease genetics are unknown. He heads up an initiative called the Alzheimer’s Genome Project, which is working towards identifying that elusive 70 percent.
“We’re seeing the next wave of genetics,” he says. “There have been huge advances the last two years in technology, software and the Human Genome Database. The ultimate goal is to target drugs to your specific genes that put you at risk. This is called pharmakinetics, pharmagenetics or personalized medicine.”
One obstacle to progress, at least in the U.S., is the fear that genetic information could be used to deny employment or insurance. Because of this, an important first step towards preventative medicine in the U.S. is to pass the Genetic Information Nondiscrimination Act, and to add long term care insurance to the bill.
“By 2050,” says Dr. Tanzi, “we will not wait for life-threatening illness to strike.” That seems like a long way off. In the meantime, let’s hope he and other researchers identify new genetic variations linked to Alzheimer’s, and that these discoveries lead to effective treatments.
Summary: Infection with a common bacterium called Chlamydia pneumoniae may increase the risk of developing Alzheimer’s. The bacterium has already been linked to heart disease and hardening of the arteries. Work to investigate the role of viruses and bacteria such as Chlamydia pneumoniae in chronic diseases is in the early stages, but researchers hope it will help identify and treat the underlying causes of Alzheimer’s.
More study is needed to confirm the bacterium’s relationship with dementia, and rigorous clinical trials would be necessary before any treatments based on this research could be recommended.
I’ve written before about how viruses and bacteria can contribute to chronic diseases not previously linked to infections. It is now accepted that a type of bacteria contributes to ulcers, and that human papillomaviruses are the major cause of cervical cancer. A common bacterium called Chlamydia pneumoniae (also called Chlamydophila pneumoniae and C. pneumoniae) has been linked to atherosclerosis (hardening of the arteries) and other chronic diseases.
Dr. Brian Balin, a professor at the Philadelphia College of Osteopathic Medicine and Basic Science Director of the school’s Center for Chronic Disorders of Aging thinks that same bacterium may also contribute to many cases of Alzheimer’s. As the name indicates, the bacterium causes a type of pneumonia - it’s not the same as the sexually transmitted type of Chlamydia.
Although the link between C. pneumoniae and Alzheimer’s is not well-accepted, Dr. Balin has been researching the relationship for years. At a 1995 meeting he attended, talk turned to the possible link between the bacterium, hardening of the arteries and heart disease.
“I asked whether anyone had ever looked for the organism in brain tissue,” he remembers. “My background in neuropathology dealt with the blood brain barrier, and I had for some time believed that damage to the blood vessels in the brain could be involved in Alzheimer’s disease. My beliefs were not widely held….”
“Anyway, after asking the question, I performed a search of the literature and found that no one had ever looked in brain tissues for the presence of this infection.... So, I went to our -80 C freezers and pulled out frozen brain tissues from both AD [Alzheimer’s disease] and non-AD brains. I sent these samples in a coded or blinded fashion to Dr. Alan Hudson for analysis by polymerase chain reaction (PCR), which is a way of testing whether the DNA of the organism was in the tissue samples.” [Dr. Hudson is a Wayne State University School of Medicine professor whose lab focuses on Chlamydia research.]
It turned out that the AD tissue samples contained the DNA from the bacterium, while the non-AD tissues did not. The two researchers repeated the experiment with different samples, and got the same results.
“This then led to our expanded experiments to determine whether C. pneumoniae could be detected using a variety of methods,” says Dr. Balin. “All in all, we used six different techniques which gave consistent results. The first publication of our work was in 1998 in Medical Microbiology and Immunology.”
Chlamydia Pneumoniae - An Elusive Bacterium
All these different testing methods were necessary because Chlamydia pneumoniae is the Loch Ness Monster of the bacteria world – hard to categorize, and even harder to find.
“Because of the nature of this organism, one cannot take a ‘quick and dirty’ approach to this problem,” says Dr. Balin. The bacterium is hard to categorize because it acts more like a virus than a bacterium, growing inside cells and using the resources of the cell to reproduce. Even worse, he says, it keeps changing form. “C. pneumoniae has multiple developmental phases in its life cycle and expresses genes and proteins variably depending on things such as life cycle, environment, and tissue in which it is located.”
This may be why some labs report they have not found C pneumoniae in Alzheimer’s brains. But Dr. Balin thinks the extensive testing he and his colleagues have done is accurate. “There are a number of techniques used to detect C. pneumoniae in clinical samples… What we do, and which is not consistently done in other labs, is use multiple techniques with many different types of probes to detect the presence or not of C. pneumoniae in a clinical sample. We have used at least 15 different antibodies specific either to Chlamydia genus or Chlamydophila pneumoniae on our brain samples to determine if antigens from the bacterium can be detected in the tissues. In addition, multiple PCR primer sets have been used to detect different genetic sequences of C. pneumoniae. We also have used biochemical techniques, electron microscopy, and tissue culturing to demonstrate C. pneumoniae in brain samples. We believe the most thorough sampling is required to truly rule in or rule out presence of the organism in brain tissues.”
He received some confirmation of his findings this year, when scientists at the Wroclaw Medical University in Poland reported finding Chlamydia pneumoniae in the spinal fluid of 44 percent of the Alzheimer’s patients they tested, but only 11 percent of a control group. The Polish researchers suggested that testing for the bacterium in spinal fluid could be useful in the diagnosis of Alzheimer’s.
How Chlamydia Pneumoniae May Trigger Alzheimer’s
How could a type of pneumonia affect the brain? “My group has found that C. pneumoniae, once inhaled, infects white blood cells, in particular the monocytes that circulate throughout the blood stream,” Dr. Balin explains. “These cells can enter through the walls of the blood vessels and can carry the organism into different tissues, including the brain.”
“We also have evidence that the cells in our upper noses known as the olfactory neuroepithelial cells (those cells controlling our sense of smell) are infected by C. pneumoniae.” The olfactory neuroepithelial cells are close to the olfactory bulb region of the brain and to the hippocampus, where short term memory is formed. These areas of the brain are among the first to be affected by Alzheimer’s. This suggests there may be a link between infection with C. pneumoniae and the reported association between the loss of sense of smell and the onset of Alzheimer’s.
Finally, there is some tantalizing evidence that the bacterium may actually trigger the formation of the amyloid plaques characteristic of Alzheimer’s brains. When mice in Dr. Balin’s lab were infected with C. pneumoniae, they developed amyloid plaques in their brains. Adding to the evidence of the link between the bacterium and Alzheimer’s pathology, the bacterium was found near plaques and tangles in human Alzheimer’s brains studied in his lab.
C. Pneumoniae – Another Piece of the Dementia Puzzle?
Dr. Balin points out that the connection between C. pneumoniae and Alzheimer’s is consistent with other research on the disease. Some scientists think inflammation causes the brain damage seen in Alzheimer’s. “Quite possibly the inflammatory response due to a chronic persistent infection with C. pneumoniae and/or other infectants causes much of the cellular damage in the brain,” he says. “Also, genetic risk factors such as having the ApoE 4 variant which has been correlated with Alzheimer’s disease may actually increase one’s risk for being infected with C. pneumoniae and other infectants such as Herpes Simplex Virus 1. The interrelationship of ApoE with infectants may be how this variation confers greater risk for getting both infections and Alzheimer’s disease. Our data have shown that Alzheimer’s brains that express the ApoE4 variation actually have greater concentrations of C. pneumoniae than Alzheimer’s brains not expressing the variant.”
He thinks the connection between C. pneumoniae and hardening of the arteries may also be relevant to dementia. Of course, arteries are a type of blood vessel. Once white blood cells infected with C. pneumoniae reach the brain, Dr. Balin theorizes, they may damage the blood vessel walls there. This would contribute to vascular dementia and brain tissue damage.
But if exposure to Chlamydia pneumoniae is common, as indicated by the antibodies in many people’s blood, why don’t we all develop Alzheimer’s? “Exposure to an infectious agent does not necessarily translate into a specific disease,” says Dr. Balin. “There are many other factors, both genetic and environmental, that would dictate why some get a disease and others do not, even when you have a large percentage of the population exposed to the infectious agent. One example is exposure to the common cold viruses, which are very ubiquitous. Not everyone exposed gets a cold. …so, not everyone exposed to C. pneumoniae would develop Alzheimer’s, but the potential for the disease would be ever-present.”
Potential Treatments for Alzheimer’s and Dementia
Dr. Balin cautions against rushing to treat Alzheimer’s based on the possibility that C. pneumoniae could trigger the disease. “The dilemma that we face is that without current long-term effective treatments for AD, many people may want to try, even experimentally, other types of drug regimens based on the work that we and others are doing with infection,” he says. “Obviously, without clinical trials first, we cannot know for sure who would be most likely to benefit. We have to determine who is infected with which organism(s) and try to treat appropriately. This is why we really need a concerted effort to develop controlled clinical trials.”
He’s done some thinking about what types of therapies a clinical trial could test. “We know that Herpes Simplex Virus 1 may be involved in a significant number of AD cases and this may also have to be considered in a therapeutic regimen. All in all, I think that infection data (even at this point in time), suggests that using combination therapy of an anti-inflammatory, anti-chlamydial and an anti-viral for Herpes could be beneficial."
The “cocktail” he is proposing for trials includes anti-inflammatory medicines or NSAIDs (non-steroidal anti-inflammatory drugs such as aspirin and ibuprofen). Although some population studies have shown a link between NSAID use and decreased risk of Alzheimer’s, evidence from clinical trials using NSAIDs to slow progression of the disease is not very encouraging. If inflammation is caused by infection with C. pneumoniae, Dr. Balin says, it’s unlikely that it could be controlled in the long run by NSAIDs alone.
Antibiotics targeted to Chlamydia bacteria are also part of the proposed cocktail. At least one study has shown antibiotics may slow progression of mild to moderate Alzheimer’s, but more research is needed. “Our research suggests that treating individuals who have Mild Cognitive Impairment, and those who have newly diagnosed and/or existing Mild AD, with anti-chlamydial antibiotics may have a positive effect by either stopping a trigger for the disease or preventing disease onset in the case of MCI,” Dr. Balin says.
But antibiotics don’t always wipe out C. pneumoniae, and as with other infectious disease, there are worries that the bacterium will become resistant to treatment. These worries have scientists searching for alternative therapies, Dr. Balin says. “The use of more novel anti-infection compounds, and potentially the development of a vaccine for these infectants could result in combating dementia-causing organisms.”
Hopes For Finding And Treating The Causes Of Alzheimer’s
“I believe that we have uncovered a non-conventional infectious agent that likely is
increasing the risk for the development of Alzheimer’s,” Dr. Balin says. “We don’t yet have all the answers. However, there is hope because we are still discovering and studying how this actually works. Similar to how the discovery of a bacterium is the cause of gastric ulcers and some types of gastric cancers, we are hopeful that our findings result in expanded efforts by others to consider how infection may be causing many diseases in the nervous system not currently considered to be infectious. This understanding is vital to proceeding in a rational fashion to treat the problem based on the evidence. This will take us from simply trying to treat the symptoms of disease to actually treating the causes. This is why I have great hope that we will defeat this and other neurodegenerative diseases in our lifetimes.”
“I don’t know why I can’t remember words lately,” my maternal grandmother said to my mother. Grandma Ben (shown here at her college graduation in 1924) was then in her early 80’s, brisk and competent. 
Around the same time, my paternal grandmother (right) started getting lost while driving around our small town. “Kilo,” as we called her, was in her early 70’s. And when my father (below, on the Pamlico River with his dog Beau) was in his late 60’s, he too had trouble finding words. They all went on to develop dementia. So it isn’t surprising I had a personal interest in a presentation called “Family History as a Risk Factor for Alzheimer’s” at the Wisconsin State Conference on Alzheimer’s Disease and Related Disorders earlier this month. The talk was given by Dr. Mark Sager, Director of the Wisconsin Alzheimer’s Institute at the University of Wisconsin. For early onset Alzheimer’s disease, family history is a huge risk factor. But the majority of people who develop dementia do so later in life, and it’s not clear what role family history plays in these cases. One genetic variant (APOE4) is associated with increased risk of late onset Alzheimer’s, and researchers are working to confirm the risk associated with another gene, SORL1. But these weakly associated genes don’t allow us to predict with any accuracy who will develop Alzheimer’s. Are there other inherited or family risk factors? This isn’t clear, says Dr. Sager. “We know nothing about the adult children of Alzheimer’s disease - we don’t really understand the risk.” 
By tracking these adult children through a program called WRAP (Wisconsin Registry for Alzheimer’s Prevention), Dr. Sager and his colleagues hope to address this knowledge gap. The average age at enrollment of the more than 1000 WRAP volunteers is 53, much younger than when the first symptoms of Alzheimer’s typically appear. Why study people before they develop dementia? “Alzheimer’s is labeled an old person’s disease because the brain is so resilient that the disease manifests when people are in their 60’s, 70’s and 80’s,” says Dr. Sager. “But actually, the brain begins to fail much earlier.” Scientists hope that within a few years, Alzheimer’s will be more like heart disease in that we will be able to identify who is at risk, and begin treatment before symptoms appear. “The presence of symptoms means the disease is at an advanced stage,” Dr. Sager says. “We want to intervene before that.” What does data from the first wave of testing in the WRAP program show? On average, the neuropsychological test scores of the adult children of Alzheimer’s are the same as those of volunteers whose parents didn’t have the disease. But even though they have no apparent cognitive problems, the brains of volunteers whose parents had Alzheimer’s seem to work differently. During functional MRIs, participants with a family history of Alzheimer’s show less activity in the part of the brain called the hippocampus when viewing new items. A second wave of testing, funded by a grant from the U.S. National Institutes of Health, will determine if the Alzheimer’s children’s thinking and memory has declined over the four year interval between evaluations. These tests will include PET scans using the new Pittsburgh Compound B imaging to map amyloid deposits in the volunteers’ brains. WRAP data is also being used to study risk factors besides family history, including: - previous surgeries (often associated with post-operative memory problems) - high cholesterol (and the use of statins) - hormonal status (along with the use of hormone therapy). Even before we understand how to prevent or delay Alzheimer’s, the staff at WRAP is developing a pilot study of interventions based on the available research. Study volunteers who develop Mild Cognitive Impairment will be offered these interventions in an attempt to slow or prevent further decline. Interventions will probably involve the lifestyle factors that research has shown may lower the risk for Alzheimer’s, such as cognitive and leisure activities, moderate alcohol consumption and physical exercise, as well as reducing psychological stress or untreated depression. Dr. Sager and his colleagues are also following the research on substances that may delay onset or slow progression of Alzheimer’s. It’s too early to recommend them for prevention, and some have bad side effects. You should check with your doctor before considering any of these treatments on Dr. Sager’s watch list: - estrogen - ginkgo [but many formulations contain contaminants – I’ll write more about this soon] - medicines that lower blood pressure - folic acid - non-steroidal anti-inflammatory drugs - Dr. Sager notes side effects including kidney damage have caused trials of these medicines for Alzheimer’s to be discontinued. - statins - trials are ongoing - selegiline [I plan to write more about this over the summer] - vitamin E - supplements are controversial, so it’s best to try to get this vitamin from foods, Dr. Sager says. - cholinesterase inhibitors [but there’s not enough evidence that these help before symptoms appear]. Want to help? You don’t have to live in Wisconsin to volunteer for WRAP, but you must be able to travel to Madison for testing every four years. People whose parents did not have Alzheimer’s are also needed for comparison. If you’re interested, contact Janet Rowley at 608-829-3306 or jsrowley@wisc.edu. If all of us with family histories of dementia can work with researchers in programs like WRAP, maybe our children and grandchildren will never experience the first symptoms of a failing brain.
Summary: A British scientist, Dr. Ruth Itzhaki, has shown that the combination of latent Herpes Simplex Virus Type 1 (HSV1) in the brain and the type 4 form of the APOE gene could account for 60 percent of all cases of late onset Alzheimer’s disease. Almost all elderly brains are infected with HSV1, which often causes no symptoms. Dr. Itzhaki’s lab found the virus in areas of the brain most damaged by Alzheimer’s, and has data relating HSV1 to plaques and tangles.
The idea that a viral infection could underlie Alzheimer’s is part of an emerging understanding of the role of bacteria and viruses in chronic diseases. This kind of research is neither well-accepted nor well-funded, so don’t expect any Alzheimer’s treatments targeting HSV1 to be on the market anytime soon.
I have only a vague understanding of viruses and bacteria. Most of what I know is based on personal experience and on what little I remember from high school biology class. I know that viruses and bacteria are infectious, and that illnesses caused by them are often short-lived. Until recently, I thought scientists understood and could control most harmful viruses and bacteria.
The leading causes of death in the U.S. seem to be in a different category: the top ten list is dominated by chronic diseases like heart disease and stroke, cancer, and diabetes. Alzheimer’s has moved up to number seven on the list. These illnesses are not infectious, not short-lived, not well-understood and not well-controlled.
But it looks like the two categories might overlap more than I knew - the idea that viral or bacterial infections might contribute to chronic diseases not previously linked to infections is gaining ground. One bacterium called helicobacter pylori has been found to cause ulcers, and another called Chlamydophila pneumoniae (Cp), is linked to coronary artery disease. Human papillomaviruses are now recognized as the major cause of cervical cancer.
These discoveries hint at the possibility of a fundamental shift in the way we view diseases, including Alzheimer’s. In his book Plague Time: The New Germ Theory of Disease, Dr. Paul Ewald, Professor of Biology at University of Louisville in Kentucky, argues that bacteria and viruses are behind many chronic diseases, including Alzheimer’s, cancer and some forms of mental illness.
Herpes Simplex Virus Type 1 Linked to Alzheimer’s
For almost twenty years, Dr. Ruth Itzhaki, Professor of Molecular Neurobiology at the University of Manchester in England, has been exploring possible links between viruses and Alzheimer’s. Viruses are tiny infectious particles that attach themselves to and penetrate cells, then use the capabilities of those cells to reproduce. They can cause diseases like colds, flu and AIDS, or they can just sit there, remaining dormant or latent for long periods of time. A latent virus can become active when triggered by stress, other infections or environmental factors.
Ruth Itzhaki, Ph.D.
For a virus to contribute to the development of Alzheimer’s, Dr. Itzhaki reasoned, it would have to be very common in humans. And because Alzheimer’s appears to develop over a long period of time, it would make sense to look for a virus that has long periods of latency, but could periodically be reactivated and cause damage.
One family of viruses fits her criteria: herpes. There are over 100 types of herpes, of which eight infect humans, causing diseases ranging from chickenpox and shingles to cold sores and mononucleosis. Most people have some type of herpes, even though they may have no symptoms.
When Dr. Itzhaki and her colleagues examined the brains of older people, they found signs of latent Herpes Simplex Virus Type 1 (HSV1) in the areas most affected by Alzheimer’s. Traces of the virus were present in both Alzheimer’s and non-Alzheimer’s brains. Because HSV1 is not prevalent in the brains of younger people, the researchers hypothesize that the virus infects the brain in older age, as the immune system declines.
HSV1 is especially common in humans. The virus, which can be transmitted via skin contact and saliva, infects approximately 58% of people between the ages of 14 to 49, and in older people, almost everyone. Often, there are no symptoms.
Even though the presence of the virus in areas of the brain damaged by Alzheimer’s was intriguing, it was clear that not everyone with HSV1 develops Alzheimer’s. “‘Infect’ doesn’t always mean ‘affect,’ Dr. Itzhaki notes. “With many sorts of infection, some people show no symptoms.” As with other viruses, perhaps an unrelated illness or stress could activate latent HSV1. But Dr. Itzhaki wondered if a combination of HSV1 and some other factor could be involved.
The APOE Connection
The APOE4 genetic variant has already been identified as a risk for developing Alzheimer’s, but is “neither necessary nor sufficient to cause Alzheimer’s,” Dr. Itzhaki points out. She wondered if HSV1 and APOE4 could together trigger a series of events leading to brain damage and degeneration. The idea that APOE status could determine the effect of a virus not new. For example, studies in her own lab had determined the risk for cold sores from HSV1 is higher in people with the APOE4 mutation. Also, her lab found that APOE status determines susceptibility to, or severity of, infections in various other diseases.
When Dr. Itzhaki and her colleagues tested for both HSV1 in brain tissue and APOE4, their data indicated that the combination of these two factors could account for 60 percent of all sporadic Alzheimer’s cases (late onset Alzheimer’s that does not run in families).
It’s interesting that a small study of the brains of three people with familial Alzheimer’s disease by scientists at Aichi Medical University School of Medicine, Aichi, Japan showed signs of active HSV1 in areas with beta amyloid deposits. This would suggest that HSV1 is involved with the type of Alzheimer’s that runs in families, not just the sporadic Alzheimer’s Dr. Itzhaki studied.
How Does HSV1 Damage the Brain?
Just how HSV1 might damage the brain is not known. It could be via inflammation and oxidation. Oxidation is when unstable molecules called oxygen free-radicals combine with other molecules. In the same way that rusting damages metal, oxidation can damage brain cells. Dr. Itzhaki says that oxidation has been found in HSV1 infected cells in the lab and in brain cells harboring latent HSV1.
“We think inflammation must be a major factor,” she says. She lays out the hypothesized chain of events: “When HSV1 is latent (i.e. in a dormant state) in the brain, it can be activated by inflammation of the brain. The latter can occur when somebody has an infection, or is stressed, or immunosuppressed. The virus then augments the inflammation there. So other viral or bacterial infections (not necessary in the brain) can cause indirect trouble.”
What About Other Herpes Viruses?
Dr. Itzhaki and her team have investigated whether other types of herpes might be linked to Alzheimer’s. Their research shows HSV2 (genital herpes) and a type of herpes called cytomegalovirus are not as prevalent as HSV1, and not associated with Alzheimer’s disease. However, cytomegalovirus was found to be present in a high percentage of brains of people who had had vascular dementia. More research is needed to understand this connection.
HSV6 (a virus that is common in infants, but often causes little or no illness), was prevalent in the brains the researchers tested, and was associated with Alzheimer’s. Because it overlapped with the presence of HSV1, it’s not clear whether HSV6 could be a cause or a consequence of Alzheimer’s.
A Unifying Theory?
Dr. Itzhaki’s theory that a combination of HSV1 and the APOE4 genetic variant underlies many cases of Alzheimer’s is appealing because it could explain several factors already linked to an increased risk of the disease:
*Age (the older you are, the more chance you have of having HSV1 in your brain)
*APOE4 (see above)
*Cholesterol (HSV1 is associated with increased cholesterol levels)
*Beta amyloid (Dr. Itzhaki has data [not yet published] linking HSV1 to increased levels of beta amyloid. In addition, increased cholesterol levels seem to increase formation of beta amyloid plaques.)
*Tau (Dr. Itzhaki also has unpublished data linking HSV1 with abnormal tau, the protein in Alzheimer’s tangles).
The hypothesis is also appealing to me because it addresses possible underlying causes of the plaques and tangles that have been the focus of Alzheimer’s research for more than 100 years.
Before this theory is widely accepted, more research in Dr. Itzhaki’s lab and in other labs is needed. Money is tight for any Alzheimer’s research now, with only a small percentage of proposed studies funded. For a theory that’s not “mainstream,” funding is even more difficult.
Future Treatment
What if Dr. Itzhaki’s hypothesis about HSV1’s role in Alzheimer’s proves to be true?
“It would have enormous consequences,” she says, “as antiviral agents, which are currently available and which have relatively small side effects and are cheap, could be used to treat patients and should stop further deterioration.”
A good way to test of the role of HSV1 in Alzheimer’s “would probably be to use antiviral treatment for a year,” Dr. Itzhaki says, “and measure cognitive decline during that year and compare the rate with the patient’s rate a year before and a year after treatment. This would take into account the different rates of decline in different people. Scanning too would be very useful in indicating the course of brain damage during each of the three years.”
This type of clinical trial of antiviral drugs sounds good, but “as antiviral agents are off-patent, pharmaceutical companies have little profit motive in using them thus, especially as trials are hugely costly,” she points out.
In addition to antiviral drugs to stop progression of Alzheimer’s, vaccination against HSV1 could potentially prevent the disease. Dr. Itzhaki and colleagues have shown that vaccination of mice can protect against latent HSV1 infections of their brains.
But right now, she says, there’s no interest in developing Alzheimer’s therapies targeting HSV1. It’s a kind of “Catch-22” – more research is needed to confirm HSV1’s role in dementia, but there’s no funding for that research without confirmation of that role. “The trouble again is not just cost, but also the hostility of many people in the field…as a result, neither we nor others who want to repeat our research can get adequate or even any funding. It’s incredibly frustrating and disheartening. But until funds are available to extend the work, resistance to it will continue,” Dr. Itzhaki says.
Summary: a head injury may increase your risk of dementia, or cause dementia to develop at an earlier age. Head injuries also have some of the same pathologies as Alzheimer’s disease. This means that treatments developed to reduce brain damage caused by head trauma may help those whose dementia is not associated with an injury.
Dolly Knowles fell last week while she was walking the dog. She hit her head on the pavement, and has two black eyes and a broken rib. Dolly, 85, is John’s father Bud's girlfriend, and an important part of our family.
Dolly and Bud
She tells me this isn’t the first time she’s bumped her head. When she was living by herself in Wisconsin, she hit her head on the corner of an antique wardrobe. “The next thing I knew, I was on the floor and it was dark outside. Must have knocked me out. I wasn’t sure what had happened,” she says, “so I just went to bed.” Her doctor checked her over and said she was fine.
But Dolly thinks that blow to her head three years ago may have caused her to lose her sense of smell. She’s also starting to have trouble with short term memory and with finding words. “I think that’s just age,” she says. But it may also have something to do with her run-in with the furniture.
Professional Athletes, Head Injuries and Dementia
Researchers have long known that boxers have a high rate of dementia. Playing other sports where head injuries are common may also increase the risk of developing dementia, or perhaps cause it to develop at an earlier age. In an article published in NeuroSurgery in 2005, University of North Carolina scientists tested more than 2500 retired professional football players. They found those with three or more concussions were five times as likely to have Mild Cognitive Impairment and three times as likely to have significant memory problems compared to retirees without a history of concussion.
“Although there was not an association between recurrent concussion and Alzheimer's disease, we observed an earlier onset of Alzheimer's disease in the retirees than in the general American male population,” the researchers wrote. “Our findings suggest that the onset of dementia-related syndromes may be initiated by repetitive cerebral concussions in professional football players.”
Football players who haven’t suffered concussions may still have an increased risk of cognitive problems. In 2006, University of Pittsburgh researchers published case studies of two former football players who didn’t have a record of multiple concussions, but did have cognitive impairment. Both men also had “Major Depressive Disorder.”
The prevalence of dementia among football players was highlighted this year by the retirement of Ted Johnson of the New England Patriots at age 34 due to the memory loss, depression and other problems his doctor says were caused by repeated head injuries. And last week, a New York Times article profiled the efforts of the wives of two retired professional football players to encourage the National Football League to help pay for the care of their husbands and other retired players with dementia. The NFL has now established a fund for this purpose.
Not Just for Professional Athletes
What about those of us who don’t box or play professional football? Recent studies of general populations show that moderate to severe (but maybe not mild) head injuries may increase the risk of dementia:
- "Head injury with loss of consciousness, although uncommon in this sample, was associated with increased risk of Alzheimer's disease. "University of Washington, 1997 study in which 32 of 349 people with probable Alzheimer’s had had head injury, as compared to 16 of 342 control subjects
- “This study suggests that mild head trauma is not a major risk factor for dementia or AD in the elderly.” Erasmus University, The Netherlands, 1999 review of data from The Rotterdam Study of more than 6000 people
- “Moderate and severe head injuries in young men may be associated with increased risk of AD and other dementias in late life. However, the authors cannot exclude the possibility that other unmeasured factors may be influencing this association.” Duke University, 2000 study of the medical records of approximately 1800 retired military personnel, 548 of whom had had head injuries
- “Head injury is a risk factor for AD. The magnitude of the risk is proportional to severity and heightened among first-degree relatives of AD patients.” Boston University, 2000 review of data from over 2000 persons with probable Alzheimer’s and over 14,000 of their family members from the Multi-Institutional Research in Alzheimer Genetic Epidemiology project.
The APOE Connection
Researchers are still working to understand why some people with head injuries don’t develop memory problems. More than twenty years ago, scientists found a possible link between APOE4 (the genetic variation associated with an increased risk of Alzheimer’s) and higher rates of dementia after head injury, as well as a higher risk of increased accumulation of beta amyloid plaques. But the link isn’t clear - none of the population studies above found a significant link between APOE4 and an increased risk of dementia in people with head injuries.
How might APOE status make a difference? Dr. Daniel Laskowitz, Associate Professor of Medicine and Director of the Neurovascular Laboratories at Duke University Medical Center, says he thinks there’s a synergistic relationship between APOE4 and head injury. “I think it’s likely that inflammation (perhaps exacerbated by amyloid deposition) plays an important role in neuronal injury…. APOE4 predisposes to inflammation, which causes neuronal injury and cognitive loss. Head injury associated with inflammation accelerates this process.”
Daniel Laskowitz, MD
In his lab, Dr. Laskowitz is working to understand how the brain is damaged after head injury, and to develop new treatments for both patients with head injuries and those with various types of dementia. In an article published in Neuroscience last month, he and his colleagues describe how a treatment based on a protein similar to the APOE protein [produced according to instructions contained in the APOE gene] reduced inflammation and Alzheimer’s-like pathology in mice following head injury. But in their experiments, mice bred to have the APOE4 variation didn’t have the same physiological and functional improvement after treatment as those with APOE2 and APOE3 did. More work is needed to confirm the role of this gene in determining the effectiveness of treatment.
“The data suggests that there may be a pharmacogenomic interaction between the APOE therapy and E4 - you may, for example, need higher doses of drug if you have E4…the bottom line is that it is too early to tell,” Dr. Laskowitz says. Pharmacogenomics is the study of how your genes affect how you respond to drugs.]
What does this have to do with Alzheimer’s and other types of dementia? “We used head injury as a model to accelerate Alzheimer’s disease pathology,” he explains, “but the results would be relevant to those without injury, as well as those with other forms of injury (bleeds, etc) that may have provoked the inflammatory response, regardless of genotype.”
If my father were still living, treatments based on this research might have been able to reduce the brain damage from microbleeds caused by his cerebral amyloid angiopathy. Drugs might be available for people with head injuries like Dolly’s if brain damage is detected. But these treatments will probably not be available in her lifetime, and maybe not within mine.
As with most Alzheimer’s research, funding is a major obstacle. At this point, Dr. Laskowitz says, “there is not much forward movement on this…. If there were funding, it could be put in preclinical development tomorrow, and be ready for clinical testing within several years.”
I just came back from the Alzheimer’s Association’s Public Policy Forum, during which several hundred of us went to Capitol Hill to ask for increased NIH funding for research on new Alzheimer’s treatments like this. Maybe that will make a difference for the next generation.
Summary: In a small pilot trial, Lipitor (a statin), seemed to improve scores on neuropsychological tests, especially for patients with mild Alzheimer’s, high cholesterol and the APOE4 genetic variation. The results of two large trials of statins for treatment of Alzheimer’s should be published in 2008. Whether or not statins prove to be effective against Alzheimer’s, this research adds to the evidence of a connection between heart disease and some dementias.
In my last post, I wrote how recent research has dampened hopes that the cholesterol-lowering drugs called statins can reduce the risk of dementia. But what about people who’ve already been diagnosed with dementia?
Two large trials of statins to treat Alzheimer’s are underway. Dr. Larry Sparks, Head of the Ralph & Muriel Roberts Laboratory For Neurodegenerative Research at the Sun Health Research Institute in Arizona, is a lead investigator for one of these trials. He’s enthusiastic about exploring the connection between cholesterol and Alzheimer’s.
“Think about it,” Dr. Sparks says. “APOE4 [the genetic variation linked to increased risk of Alzheimer’s] leads to elevated cholesterol. I don’t think cholesterol causes Alzheimer’s, but I believe it negatively influences it, or causes it to progress faster. There’s definitely a vascular influence.”
Earlier in his career, Dr. Sparks was a Medical Examiner in Kentucky. While performing autopsies of non-demented people with coronary artery disease, he noticed they had amyloid plaques similar to those in people who had been diagnosed with Alzheimer’s. Later, working at the Sun Health Research Institute, he found that rabbits fed high cholesterol diets developed amyloid plaques in their brains. This plaque build-up was reversed when the cholesterol was removed from the rabbits’ diet.
Now, in a small pilot trial, Dr. Sparks and his colleagues have shown that a statin called Lipitor may actually improve scores on neuropsychological tests for some people with Alzheimer’s. In an article published last year, they wrote that Lipitor seemed to help the most in patients with mild Alzheimer’s, high cholesterol and the APOE4 genetic variation.
So reducing cholesterol to treat Alzheimer’s seems logical, right? Nothing is that simple with Alzheimer’s and dementia.
First, some scientists think statins might work by reducing inflammation in the brain, rather than by reducing cholesterol. Second, brain cells produce cholesterol because they need it to function. While bringing down cholesterol levels in the blood might prove helpful for Alzheimer’s, decreasing cholesterol in the brain may harm neurons. Three statins, Mevacor (Lovastatin), Zocor (Simvastatin) and Baycol (Cerivastatin – now off the market in the US) appear to work in the brain as well as in the blood. Two trials at the University of Pittsburgh testing the effects of Mevacor and Zocor on cognitive functioning in people with high cholesterol showed the drugs may have caused a small decrease in performance on some neuropsychological tests. While the effect of these statins on the brain is unknown, Dr. Sparks thinks a safer approach is to influence the brain indirectly by using statins that reduce cholesterol in the blood rather than in the brain.
Finally, a new study shows a late-life drop in cholesterol may actually be associated with an increased risk of Alzheimer’s. I’ll talk about that in my next post.
The results of the two large trials of statins for treatment of Alzheimer’s [CLASP (testing simvastatin or Zocor) and LEADe (testing atorvastatin or Lipitor)] should be published in 2008. Whether or not statins prove to be effective against Alzheimer’s, this research adds to the evidence of a connection between heart disease and some dementias. Dr. Sparks puts it this way: “if you’re sufficiently resilient that you don’t succumb to cardiovascular disease, then you’re looking down the barrel of dementia.”
Summary: A new study shows variations in a gene called SORL1 are associated with an increased rate of late onset Alzheimer’s. The effect of this gene on your risk of developing the disease is probably modest, and researchers don’t know which variations of the gene could increase that risk. The results of this study will not lead to a simple genetic test for increased risk of Alzheimer’s, at least not anytime soon. But the discovery, along with related research, may generate new ideas for Alzheimer’s treatments.
I’ve been taking a break from blogging about Alzheimer’s and dementia. But when I picked up the newspaper from our driveway Monday morning, the top headline screamed “Gene linked to Alzheimer’s.” “More than 40 scientists worldwide find an inherited flaw that can lead to the disease,” the subtitle said.
I’m tired of headlines announcing Alzheimer’s breakthroughs, but decided to check it out anyway.
The headline referred to a new study that shows variations in a gene called SORL1 are associated with an increased rate of late onset Alzheimer’s. Results of the study, conducted by researchers from fourteen universities and institutes, were published online in the February edition of Nature Genetics.
Despite my skepticism about the headline, this study is intriguing. But it doesn’t mean a simple genetic test can tell you if you’re at increased risk of developing Alzheimer’s, at least not anytime soon.
To understand why the study is important, you have to look at related research results published in the last few years.
SORL1 in the Alzheimer’s Brain
Some of the early clues that SORL1 might be involved in Alzheimer’s came from physiological, rather than genetic, studies. First, scientists found that the level of the protein SORL1 was lower in the brains of people who had late onset Alzheimer’s than it was in “normal” brains.
How is a protein related to genes? The information stored in our genes is used to make proteins. Variations in genes (either inherited or that happen during a person’s lifetime) change how proteins are made. The theory is that variations in the SORL1 gene change how the corresponding protein (also called SORL1) is made, perhaps by regulating levels of the protein.
With the new study, there is now evidence that SORL1 may contribute to the risk of Alzheimer’s on both a physiological and a genetic level.
SORL1 Affects Levels of Beta Amyloid
Dr. James Lah is Assistant Professor of Neurology at Emory University, and co-author of the study linking SORL1 protein levels to Alzheimer's. Last year, he and his colleagues found that decreasing levels of the SORL1 protein increases the amount of beta amyloid near cells in lab tests. Beta amyloid is the sticky protein that makes up the plaques found in the brains of Alzheimer’s patients.
James J. Lah, M.D., Ph.D.
This finding is exciting for researchers who think beta amyloid causes Alzheimer’s, and are working on treatments targeting that protein.
“The available data support an important role for LR11 [SORL1] in AD pathogenesis and identify this receptor as a potential novel therapeutic target for treatment of late-onset sporadic AD,” Dr. Lah and his colleagues wrote in their paper published last year in the Journal of Neuroscience.
SORL1 Is a Receptor for APOE
In addition to the link between SORL1 and beta amyloid, there’s a connection between SORL1 and the APOE gene already known to influence the risk of developing Alzheimer’s. The protein SORL1 is a receptor, which means when a specific molecule is nearby, SORL1 binds itself to that molecule, and then causes a reaction within a cell. The specific molecule it binds to is APOE.
APOE is a kind of protein involved in processing cholesterol and other fats. A variation in the corresponding APOE gene, APOE4, has been linked to Alzheimer’s disease. Given this link, APOE variations change the effect of SORL1 variations on Alzheimer’s risk, or vice versa?
“When we began studying LR11/SorLA our first efforts were directed at finding a relationship between it and APOE,” says Dr. Lah. “Their interactions have been surprisingly elusive. However, in my opinion, it is difficult to believe the functional links are merely coincidental. I expect that further work will define the nature of their interactions at both genetic and physiological levels. With the added attention that will follow the Nature Genetics paper, I expect this will come out pretty quickly.”
Intriguing, But More Research Needed
So, why won’t these discoveries lead to a simple genetic test for increased Alzheimer’s risk anytime soon?
While it’s too early to tell how much the SORL1 gene affects the chances of developing the disease, the co-authors of the new paper write that they believe the effect will be “modest.” There are several reasons for this.
First, SORL1 and APOE are just two of many genes suspected to affect the risk of developing Alzheimer’s. In an article published in the January issue of Nature Genetics, researchers at Massachusetts General listed 13 other “potential Alzheimer disease susceptibility genes.”
Second, scientists involved in the new genetic study couldn’t identify which variations of the SORL1 gene might increase the risk of Alzheimer’s. “In sharp contrast to APOE (where APOE e4 is associated with Alzheimer disease in most data sets), no single SORL1 SNP [common variation] or haplotype is associated with increased risk for Alzheimer disease in all six data sets,” they wrote in the article published this week.
Third, the study didn’t show an association between variations of the gene and increased rates of Alzheimer’s in two of the sample populations studied: Caucasians from the MIRAGE (Multi-Institutional Research in Alzheimer's Genetic Epidemiology) study and another set from the Mayo Clinic in Rochester.
This does not necessarily mean that SORL1 is not a risk factor for the populations the people studied represent. “One possible explanation for lack of association in these data sets is genetic heterogeneity,” says Dr. Lindsay Farrer, one of the study’s authors and Chief of the Genetics Program and Professor of Medicine, Neurology, Genetics and Genomics, Epidemiology, and Biostatistics at Boston University School of Medicine. The problem is that multiple variations in the SORL1 gene may contribute to increased risk. “Specifically, in these samples representing perhaps many ancestral European populations there is no one SORL1 SNP variant or haplotype sufficiently enriched to show an association,” he says.
Dr. Farrer also says perhaps the groups in which no association was found just weren’t big enough, especially given the conservative statistical approach used in this study. It may also be that other causes of Alzheimer’s (genetic or not) were somehow over-represented in these groups.
Despite these uncertainties, the results from this analysis of the genetic material, family relationships and medical histories of over 6000 study participants “suggest that inherited or acquired changes in SORL1 expression or function are mechanistically involved in causing Alzheimer disease,” wrote Dr. Farrer and his colleagues.
The scientists supplemented their genetic findings with research on the physiological level by testing for levels of SORL1 in the blood of participants. Those diagnosed with Alzheimer’s had blood levels of SORL1 less than half that of non-Alzheimer’s participants. But this finding had its own uncertainties: only about 14 percent of that difference was accounted for by SORL1 variations.
They also showed in lab tests that decreasing SORL1 in cells increased the production of beta amyloid. This confirmed the earlier research described above, and the results of these new tests will add detail to the hypothesis about the mechanism by which SORL1 may affect beta amyloid.
Something Dr. Lah said helps clarify the connection between the genetic and physiological research for me. “I believe we are entering a new period in which we will be identifying genetic influences on the common late-onset forms of Alzheimer's which individually modify risk more modestly than the very, very potent effects associated with APOE,” he says. “However, these new findings are likely to shed light on physiological pathways that will lead to development of new and more effective treatments for Alzheimer's disease.”
More study on both genetic and physiological levels is needed. “My co-investigators and I encourage other researchers to evaluate association with SORL1 in other datasets,” says Dr. Farrer. “We predict that many, perhaps most, but not all data sets of reasonably large sample size will demonstrate association with one or more SNPs [common variations]. While confirmation is certainly important, in light of our results in which we could not identify any of the SNPs showing association with AD to be functionally or biologically relevant, more intensive interrogation of other variants in this gene is warranted.”
Dr. Lah is a bit less cautious. “I am admittedly biased,” he says, “but I believe that the SORL1 genetic association will hold up, and that LR11/SorLA in Alzheimer's disease will emerge as an important aspect of the disease.”
Reading through the study again, I realize it’s a good example of why there’s often a disconnect between optimistic Alzheimer’s headlines (which set our expectations too high) and the realities of research. The study is big, hard for a non-scientist to understand, and full of twists and turns. Nothing is simple in Alzheimer’s research. But that isn’t the researchers’ fault. We need to have realistic expectations, and support those who are willing to work in this difficult area. I guess I’ll get back to blogging.
I was sorry to hear that Paula Martinac’s father died last month. As she writes in Dementia Blues, he had both diabetes and dementia. Gail Rae Hudson’s (The Mom and Me Journals) mom is a Type 2 diabetic, and has had what Gail refers to as “dementia-lite” since suffering a mini-stroke. “I think that her diabetes is definitely linked to her mental acuity,” Gail emailed me. “The better control we have of her blood glucose levels, the better her mental acuity.”
Bad for your memory?
These connections between insulin problems and dementia in real life are reflected in recent scientific theories and study results:
- Diabetes may increase the risk of Alzheimer’s
- Alzheimer’s might be a “type 3 diabetes”
- IDE degrades or decreases both insulin and beta amyloid [the protein thought to cause Alzheimer’s].
Diabetes and insulin resistance are clearly linked to dementia, but no one knows exactly how. Theories about the mechanism by which insulin problems may cause dementia include:
- Insulin affects glucose utilization in the brain [glucose provides the brain’s energy]
- Insulin modulates acetylcholine [a neurotransmitter involved in learning and memory] levels in the brain
- Insulin increases abnormal changes in tau, the protein that makes up the tangles found in neurons in Alzheimer’s brains
- Insulin makes cortisol [a stress hormone, chronically high levels of which are sometimes linked to cognitive impairment] more toxic to neurons
- Insulin increases inflammation in the brain, damaging cells and increasing production of beta-amyloid, which further increases inflammation
- Insulin problems may increase vascular disease, clogging blood vessels, and reducing blood flow to the brain
- Increased insulin uses more IDE, so less IDE is available to degrade the beta amyloid thought to cause Alzheimer’s.
Even before they can understand how insulin problems contribute to dementia, researchers are studying whether diabetes medicines can help treat or prevent Alzheimer’s and dementia. Scientists at the Veterans Affairs Puget Sound Health Care System and the University of Washington found that raising insulin levels in some patients [those without the APOE4 genetic mutation associated with Alzheimer’s] improved their memories. These researchers are also testing nasal insulin in people diagnosed with early Alzheimer’s or Mild Cognitive Impairment. In a small trial, “nasal insulin improved the ability to retain story details about 25 percent,” says Dr. Suzanne Craft, one of the researchers and Professor of Psychiatry and Behavioral Sciences at the University of Washington.
The idea of increasing insulin levels to improve memory seems counterintuitive, since high insulin levels may damage the brain. “In a healthy physiology, optimal levels of insulin that are secreted and cleared quickly are likely beneficial,” Dr. Craft explains. “But excessive or prolonged elevations are likely detrimental because of induction of insulin resistance and inflammation.” So we may need just the right level of insulin to keep our brains humming along.
Scientists are also studying drugs that increase sensitivity to insulin, instead of increasing insulin levels. “It’s too early to tell about the comparative benefits of the two approaches,” says Dr. Craft. Results of one study using this approach were disappointing. A twenty-four week trial of Rosaglitazone, a drug that increases sensitivity to insulin, in people diagnosed with mild to moderate Alzheimer’s disease showed no benefit over placebo. (Trial results did show that the drug may have helped participants who did not have the APOE gene mutation, but this needs further study.)
Even if it’s not clearly effective in treating Alzheimer’s, perhaps this approach will work to prevent mild memory problems from progressing to full-blown dementia. A preliminary study of Rosiglitazone in 30 people diagnosed with Mild Cognitive Impairment showed improvements in memory and attention. Researchers are now recruiting for a larger trial of the drug in people with Mild Cognitive Impairment. The study will measure the drug’s effects on attention and memory in 120 people 55 and older.
Whether or not diabetes drugs are useful in preventing or treating Alzheimer’s, this research shows how important it is to prevent insulin resistance and diabetes. “Our work strongly suggests that preventing insulin resistance by increasing physical activity, optimizing diet and preventing obesity will ameliorate the risk of Alzheimer’s disease, or at least delay onset,” Dr. Craft says.
Our roads flood all the time here in Tampa Bay. We’re close to sea level. When it rains, there’s just no place for the water to go, especially at high tide. Storm drains back up, the water level rises, cars stall and traffic stops. The problem isn’t just too much rain, it’s also too little drainage.
Some Alzheimer’s researchers think the same thing may be happening in the brains of people with dementia. According to this theory, the problem isn’t really just too much production of beta amyloid [the sticky protein that forms plaques and is thought to cause Alzheimer’s], it’s also too little “drainage” of that beta amyloid.
Most of the efforts to find a cure for Alzheimer’s have focused on preventing the over-production of beta amyloid. But over the last few years, some scientists have been exploring the idea that in Alzheimer’s brains, the balance between production and elimination of this protein has gone awry.
One of the researchers working to find treatments based on this “drainage” theory is Dr. Malcolm Leissring at The Scripps Research Institute. He is testing various proteases’ [enzymes that break down proteins] ability to destroy beta amyloid and unplug the drain. Much of his research is focused on one specific protease: Insulin-Degrading Enzyme (IDE).
Malcolm Leissring, Ph.D.
Insulin-Degrading Enzyme
“I am interested in all beta amyloid degrading proteases, but IDE is particularly attractive for a lot of reasons,” Dr. Leissring says. “It is one of the few to be linked genetically to Alzheimer’s disease. It appears to be the main protease involved in the degradation of (extracellular) beta amyloid in neurons, because when you delete IDE from cells, you also reduce the amount of beta amyloid degradation by over ninety percent. And there are a lot of tantalizing and unanswered questions about IDE, such as how it gets secreted from cells, which makes it very attractive for research.”
His research fits well with that of other scientists who have found that IDE levels are low in the hippocampus of the brains of people who have been diagnosed with Mild Cognitive Impairment, and even lower in those diagnosed with Alzheimer’s. Low levels of IDE are associated with high levels of beta amyloid.
Progress So Far
Dr. Leissring and his colleagues have shown that mice bred to have increased IDE (or another protease called neprilysin) have reduced levels of beta amyloid in their brains. The increased level of IDE appeared to slow plaque formation in the brains of these mice.
Focusing on the proteases that might increase beta amyloid drainage gives researchers a lot of new possible therapies to prevent dementia. “I don’t think we are anywhere near [human] trials involving IDE,” Dr. Leissring says, “ but there are some exciting results coming out.” One encouraging finding is that increasing the levels of IDE or other proteases (and thereby reducing beta amyloid levels in the brain) might be done via the bloodstream. This could be much safer than attempting to administer a therapy directly to the brain.
Raising levels of IDE will probably not involve adding the enzyme itself to the bloodstream or the brain. According to Dr. Leissring, logistical problems with purifying IDE make it more probable that potential treatments will take a slightly different approach. “All cells make IDE,” he says, “and we can engineer bacteria or other cells to produce it. So it’s easy to produce, but not so easy to purify. I don’t think it will ever be produced on a scale for use in humans. More likely, a drug will be found that affects IDE or influences its expression levels within cells.”
The Insulin Connection
The promise of IDE-related therapies seems to contradict studies that show increasing insulin levels may improve memory for some Alzheimer’s patients. IDE degrades insulin as well as beta amyloid, so increasing IDE levels would be expected to lower insulin levels.
While increasing insulin levels may help some patients in the short term, Dr. Leissring points out that “accumulating evidence suggests that chronically high levels of insulin are not good, neither for diabetes nor for AD. There is a growing body of evidence that suggests that chronically high levels of insulin cause the body to become desensitized to the hormone’s effects---which is exactly what Type 2 diabetes is.”
”Based on our understanding of the causes of Alzheimer’s disease, and the role of IDE in degrading beta amyloid,” he says, “increasing insulin levels would be predicted to increase beta amyloid levels. We actually know that this is true from human studies. But insulin is a potent hormone that has myriad effects on cells, and it just might work for some other reason.”
Some diabetes drugs work to increase insulin sensitivity, rather than raising insulin levels. Researchers at the University of Washington are studying whether these drugs can improve memory in patients diagnosed with Mild Cognitive Impairment.
So, Dr. Leissring thinks simply increasing insulin may not help Alzheimer’s patients. “The approach of using insulin enhancers, on the other hand, seems sound, and there is emerging evidence from animal studies that it might work,” he says.
The Cerebral Amyloid Angiopathy Challenge
Cerebral amyloid angiopathy (CAA) seems to have been the main cause of my father’s dementia and death. In people with CAA, beta amyloid similar to that in Alzheimer’s plaques is deposited on the walls of the blood vessels in the brain. The protein causes the vessel walls to crack, allowing blood to leak out. Every hemorrhage, large or small, damages brain cells and can cause dementia and major hemorrhagic strokes like the one Dad had.
Unfortunately, some therapies that decrease the beta amyloid in Alzheimer’s plaques seem to increase the beta amyloid deposits on blood vessels. In theory, Dr. Leissring says, increasing the elimination of beta amyloid would be predicted to prevent both Alzheimer’s and CAA. But in some studies, attempts to dissolve beta amyloid via vaccination have increased CAA and hemorrhages in animals.
A large percentage of Alzheimer’s patients also have CAA. For them, using drugs designed to dissolve amyloid may be risky. “I think we can definitely hope for a preventative treatment for CAA, but the chances of a cure are less certain and will require much more study,” he says.
The Funding Challenge
Dr. Leissring reports that his research is currently funded by “start-up” money from Scripps Florida, funds from the National Institute on Aging (NIA), and a grant from the Ellison Medical Foundation. But even with this funding, he says he’s only been able to start ten percent of his planned projects.
“We are living in an incredible age, where we can do things in a day that would have taken many months just a few short years ago,” he says. “But it really does simply boil down to money (and lab space, ultimately). The more money, the more scientists we can hire and the more experiments can get done.”
Other Alzheimer’s researchers are experiencing the same problems - government and large organization funding seems totally inadequate. It may be that the only way to fill the gap is with private donations. The McNally family, whose father Richard died of Alzheimer’s six weeks after my dad’s death, has started a non-profit fund to support the research of Dr. Leissring and his colleagues. If you’d like to help, please go to The Unforgettable Fund, read the McNally family’s blog, and click on How to Donate.
This morning I gave blood and completed the neuropsychological testing for the Wisconsin Registry for Alzheimer's Prevention (WRAP). Nicole Wright, Research Specialist with the Wisconsin Alzheimer's Institute, met me at the University of Wisconsin Hospital in Madison. She introduced me to Sue, a nurse who recorded my vital statistics and drew blood. My blood will be used for genetic testing, and to record levels of substances such as cholesterol that may affect my risk of developing Alzheimer's.
Nurse Sue draws my blood
Then it was off for two and a half hours of neuropsychological testing administered by Nicole. Here's a list of the tests I took:
As Nicole predicted, some tests were easy, but others seemed difficult to impossible. I didn't feel stressed during the testing - it probably helped that we took two breaks. The experience on each test is probably different for every participant, but what's important is how your abilities change over time, not your absolute scores.
These tests will be my baseline tests, and I'll be back to take them again every four or five years. I won't know the results of my blood tests or neuropsychological tests (at least as long as WRAP is ongoing), but at least I feel I'm contributing to the effort to find Alzheimer's treatments.
If you're interested in participating in WRAP, you can contact the Wisconsin Alzheimer's Institute at +1 608-829-3306 or 1-800-417-4169. You can also email Janet Rowley at jsrowley@wisc.edu.
Going through the thick folder containing Dad's medical records, I found the results of a genetic test:
Apolipoprotein E Genotype: 2 and 3. Interpretation: This individual does not possess an apoe 4 allele. This result does not indicate whether this individual's dementia is due to Alzheimer's disease or other cause of dementia.
The APOE or apolipoprotein E, gene makes a protein that carries cholesterol and other fats through the blood to be processed. The three common variations of this gene are called e2, e3 and e4. Everyone has two copies of this gene; Dad had one e2 and one e3 copy. If you have one or two copies of the e4 variation, you may have a somewhat higher risk of developing Alzheimer's disease.
But the connection between the APOE gene and Alzheimer's is not very strong. Some people who don't have the e4 variation have Alzheimer's, and some people with Alzheimer's don't have the e4 variation. My father didn't have the e4 variation, but still developed dementia. The e2 variation he had is actually associated with a lower risk of developing Alzheimer's disease in some studies.
The APOE gene may also influence the age at which people develop Alzheimer's. People with the e4 variant who have Alzheimer's tend to develop it at a much earlier age than those who have Alzheimer's but not the e4 variant. Even this influence is weak - in an article published in The American Journal of Human Genetics in 2000, researchers estimate that only 7 to 9% of the age of onset of Alzheimer's is explained by the e4 variation.
Dad did not have the gene variation associated with higher risk of Alzheimer's
Because the connection between the APOE gene and Alzheimer's or dementia isn't very strong, environmental factors and/or additional genes must play a role in determining whether someone develops dementia, and at what age. The search for other genes involved with dementia is an intimidating task. An overview of presentations at a recent conference on Alzheimer's notes that the AlzGene database of studies on genes and Alzheimer's contains information on over 300 candidate genes and 800 common variations. So far, no one has found another gene that plays as significant a role as APOE.
It could be a combination of genes determines whether or not someone will develop dementia. For example, a study of 180 Alzheimer's patients and 120 non-demented volunteers identified three different gene combinations, each of which appeared to increase the risk of developing Alzheimer's by 800 percent for study participants.
The US National Institute on Aging is sponsoring ongoing research to identify genes involved in Alzheimer's. The study is recruiting siblings, at least one of whom must have been diagnosed with the disease.
If the link between genes and dementia were better understood, genetic tests could be used to predict, diagnose and maybe even treat Alzheimer's and other dementias. In the meantime, the association between the APOE gene and Alzheimer's isn't strong enough to be useful. Testing for the e4 variation of the APOE gene didn't help us understand Dad's dementia at all.
More than two years ago, one of my father’s neurologists determined that Dad had low levels of B-1 in his blood, and said this was the major factor in his dementia. “We think iron overload causes B-1 deficiency,” he told me. “Genetic tests show he is an iron overload carrier – he has one copy of the C282Y mutation in the hemochromatosis gene that causes iron overload when present in two copies. Being a carrier is typically a silent condition, but it is not with your dad – he does have high levels of iron. Iron overload may be a factor causing his dementia.”
Did I inherit Dad's iron overload gene mutation along with his good looks?
This neurologist was not alone in thinking there might be a connection between the genes associated with iron overload or hemochromatosis and Alzheimer’s. The results of a University of Toronto
