The Mount Sinai ADRC is excited to announce our participation in a new nationwide study examining the effect of resveratrol in patients with mild to moderate Alzheimer’s disease (AD).  What makes this trial unique is that in addition to the traditional paper and pencil tests, the effects of this medication will be evaluated using MRIs (to assess the size of various areas of the brain), as well as biological markers found in the cerebro-spinal fluid (CSF) that are thought to correlate with AD. CSF is a fluid that surrounds the brain and spinal cord; one function of the CSF is to protect these areas from injury. CSF is collected using a procedure called a lumbar puncture (or “spinal tap”) — in which a needle is inserted into the lower back and a small amount of the fluid is removed for testing. CSF collection is quickly becoming a standard part of research, as it is the most reliable source for measuring brain metabolism and function.
Resveratrol is derived from plants and is found in high levels in certain red wines and the skin of red grapes. You may have heard that drinking one glass of red wine a day is beneficial for your memory. There is some evidence to suggest that resveratrol is the reason for this potential benefit.
It appears that resveratrol may have several mechanisms of action related to the development of AD. In the lab, resveratrol protects cells against Abeta/amyloid-induced injury to brain cells. Abeta is a peptide that can clump together to form amyloid plaques in the brain, which is one of the hallmarks of AD.  Furthermore, in the lab, resveratrol lowers the levels of Abeta produced from different types of cells. It also appears to help in the breakdown of Abeta.  In mice, resveratrol decreased the amount of amyloid plaque in the brain.  Resveratrol is also involved in genetic regulation of the aging process, such that it mimics a protein that is known to prolong the lifespan of an organism. Together, these results are promising; however, a large scale clinical trial examining resveratrol’s potential benefits in people with AD is critically important.
The drug has been tested in healthy men using a single oral dose of up to 1000mg.  It is commercially available in doses up to 700mg, although the actual amount of resveratrol in commercial formulations is unknown, as it is not regulated.  In general, it is categorized as “generally recognized as safe” by the U.S. FDA and the FDA is currently reviewing the study protocol to evaluate the proposed doses. 
There was a pilot study examining the effects of
resveratrol at Mount Sinai. However, the pilot study used a much lower dose of resveratrol than what is planned for the new study. Results of the pilot study are almost ready to be analyzed.
The upcoming Resveratrol study will take place over one year, and will require 10 visits, including two lumbar punctures and three MRIs. This study will evaluate resveratrol’s effect on biomarkers of AD, as well as resveratrol’s effect on brain atrophy. We are excited to be taking part in this study. For more information, please contact Helene Geramian at 212-659-8885.

Caregiver’s Corner

Support Groups For information about our Spanish Groups, please see page
Early-stage-dementia support group— This is a bimonthly support group for caregivers of individuals with early stage dementia. The group meets on Wednesdays at the Martha Stewart Center for Living at Mount Sinai and is lead by Elizabeth Fine, M.S.W. For more information, please call 212-659-9230.
The Memory Tree by DOROT— This is a unique program that offers programs for individuals with mild Alzheimer’s disease, as well as their family and caregivers. For more information, please visit http://www.thememorytree.org or contact Elizabeth Fine, M.S.W at 917-656-0558.

Resources for Patients and Caregivers
Safe Return Bracelet — The MedicAlert + Safe Return program work in tandem to ensure that lost or separated individuals are reunited with their families. To register a loved one call 800-272-3900.
Jitterbug cell phone—This is a simple and affordable cell phone especially made for seniors. For more information call 888-824-1895.
This Caring Home — An interactive website with information and tips to make the home safer for individuals with Alzheimer’s disease. http://www.thiscaringhome.org/
Medical Alert Service — Lifeline is a service that with the push of a button can alert appropriate individuals in case of a medical emergency. Some models automatically call for help when it detects that the person has fallen. To register for their services or obtain more information, call 800-566-6218.
Meals on Wheels — An organization comprised of local and community-based nutritional programs which provides meals to seniors. There are several participating centers in the NYC area. To find a local program, visit http://www.mowaa.org.
Alzheimer’s Disease Education and Referral (ADEAR) — A comprehensive website with AD information and resources from the National Institute on Aging. http://www.nia.nih.gov/Alzheimers/
Mount Sinai ADRC — Our website is an all encompassing tool containing information about AD, our research programs, as well as resources for caregivers. You can also find previous editions of our newsletter here. www.mssm.edu/adrc

Memory Enhancement Tip…
By Margaret Sewell, Ph.D.

Although it may seem simple, a major memory culprit in healthy elders is a failure to pay attention. As individuals living in the 21st century, we are continuously bombarded by a slew of information- what some may call information overload. However, there are simple techniques that can be employed in order to best attend to (and remember!) the details of our daily lives.
Some suggestions:
Slow Down: By slowing down, the mind has more time to process what you are experiencing, which makes for a better “memory imprint”.
Focus: Concentration is key to memory enhancement.
Rehearse the information out loud: By vocalizing what you wish to remember, you allow yourself another opportunity to encode information.
So next time you need to remember a book club book, try summarizing a chapter out loud. Need to remember where you parked your car? Take a moment to repeat the level or number to yourself. Learn the name of a new friend? Pause and match the name to the face. You’d be surprised what a difference focus can make!

Results: Home-Based Assessment Study
By Mary Sano, Ph.D.
The Mount Sinai ADRC community, under the leadership of Jane Martin, Ph.D., is a strong participator in the Home-Based Assessment (HBA) Study, in which healthy seniors complete evaluations in their home. This is the first study of its kind, comparing traditional testing with automated telephone testing or computerized testing. It is also unique in that it will continue for four years. The results of the initial participant selection and evaluation were presented at the Alzheimer Association International Congress by Mary Sano, Ph.D., which was held in Paris this past June; Dr. Sano is the national director for the study. Several interesting results were reported. Overall, individuals were generally willing to participate in all arms (i.e., telephone, traditional, or computerized testing) regardless of age, education or general health. This suggests that many people are open to trying new technologies. However, there seems to be a preference for less frequent assessment and for technologies that used more traditional equipment, such as telephones. We want to thank all of our volunteers and ask them to “stay the course” to finish this important four year project.

Participant Appreciation Day
The Alzheimer’s Disease Research Center (ADRC) hosted its fourth annual Participant Appreciation Day on May 11, 2011. Our staff was joined by 58 participants and caregivers. Following a warm welcome by Margaret Sewell, Ph.D., presentations included information about genetics, new treatment approaches, and the experience of participating in a clinical research trial. Sam Gandy, M.D., Ph.D., the Associate Director of the ADRC, discussed the process of developing new medications. Gregory Elder, M.D., reviewed what genetic studies have told us about Alzheimer’s disease. Mary Sano, Ph.D., the Director of the ADRC, delved into the benefits of participating in research. Information about our current clinical research trials was presented by Hillel Grossman, M.D., and Judith Neugroschl, M.D. In addition, Laurel Humble, from the Museum of Modern Art (MoMA), joined us for a presentation about the Art and Dementia Program at the MoMA. She also conducted a break-out session where participants created personal masterpieces from paper cut-outs. Meanwhile, Elizabeth Fine, MSW, informed caregivers on various sources of support.

In the news…

Does moderate drinking help prevent Alzheimer’s disease? A recent review of research regarding alcohol consumption and dementia indicates that drinking moderate amounts of alcohol, especially wine, may lower the risk of dementia. The review of 143 studies demonstrated that individuals who drank moderately were in fact 23% less likely to develop dementia, including Alzheimer’s disease and other forms of cognitive impairment; wine may be slightly more beneficial than beer. On the other hand, heavy drinking, which constitutes more than three to five drinks per day, was found to be associated with an increased risk of cognitive impairment and dementia. Although there are several reports of the beneficial effects of alcohol, Sam Gandy, M.D., Ph.D, associate director of the ADRC, cautions against individuals using alcohol as an approach to prevent cognitive decline, as there have been no clinical trials examining the relationship between moderate alcohol consumption and cognitive health.

Doctors Debate Effectiveness of Alzheimer’s “Milkshake”. Axona is a controversial new alternative treatment for Alzheimer’s disease. Axona is considered to be “medical food,” not a drug, that supplies the brain with fats and ketones, which are to be used as fuel. Although some people are hopeful about alternative treatments, such as Axona, many researchers, including Sam Gandy, M.D., Ph.D, are less optimistic about these products. “It’s fairly outrageous that little can be done to impede the exploitative marketing of unproven and unlikely substances to vulnerable Alzheimer’s patients and their desperate caregivers,” says Dr. Gandy. A major concern among critics is the lack of data showing that the “medical food” is beneficial.

FAQ: Lumbar punctures (LP)
How long does it take? The LP takes approximately 20 to 30 minutes, with an additional 30 minutes to rest after the procedure.
Does it hurt? You can expect pressure when the needle is inserted and may experience brief leg pain while the needle is positioned.
Can I be paralyzed if the needle hits the spinal cord? No. The needle is inserted below the spinal cord. There is no risk of paralysis.
What are the side effects of a LP? During the procedure, you may have temporary back pain and/or discomfort. After the procedure, you may have a headache. There are other side-effects that are uncommon, which our physician can discuss with you.
How is the lumbar puncture performed? You will either lie on your side, with your knees drawn up or you will sit on the edge of the exam table. A local anesthetic may be given at the puncture site. A needle is inserted into your back to collect the spinal fluid.

For more information about lumbar punctures, please contact us at 212-241-8329. We can arrange an appointment with one of our physicians. We also have informational videos about the procedure that you may borrow or you can visit http://www.adcs.org/Research/LPVideo.aspx.

Mount Sinai Clinical Research Day
On Wednesday September 21st, members of the ADRC participated in “Clinical Research Day”, hosted by the Mount Sinai School of Medicine. Situated in the bustling first floor of the hospital, investigators and coordinators from various departments of Mount Sinai had the opportunity to showcase their research projects, engage with potential participants and meet other members of the Mount Sinai research community. The ADRC proudly displayed results from closed clinical trials as well as information related to new programs. The event provided a unique opportunity to share a love of science with peers and passerbys alike.

Mount Sinai joined forces with other ADRCs in NYC as part of NYCARE for the
23rd Annual Memory Walk
on
Sunday, October 23, 2011
Riverside Park

Through generous donations from our family, friends, and supporters, we were able to reach our
fundraising goal! So far, we have raised over $10,000!!

Haven’t made a contribution? It’s never too late!
Visit our team page at: http://walktoendalz.kintera.org/nyc/mountsinai

We hope you join our team next year.

Nuevo proyecto de investigación evalúa un derivado del vino tinto para combatir la Enfermedad de Alzheimer
By Judith Neugroschl, M.D.

El Centro de Investigación de la Enfermedad de Alzheimer’s o ADRC, por sus siglas en ingles, del “Mount Sinai School of Medicine,” se complace en anunciar que formará parte de un estudio a nivel nacional con el objetivo de examinar el efecto de “resveratrol” en las etapas leves o moderadas de esta enfermedad. El estudio evaluará los efectos del “resveratrol” en los marcadores biológicos y en las áreas del cerebro con evidencia de atrofio. Además examinará si esta sustancia es segura y tolerable en pacientes mayores de 50 años en las etapas moderadas o leves de la EA.
El ensayo clínico se distingue de manera singular ya que además de utilizar instrumentos de investigación tradicionales, tales como exámenes en papel y lápiz, utilizará pruebas de resonancia magnética para explorar el efecto de “resveratrol” en el cerebro. A través de pruebas de resonancia magnética, o MRI , se podrá observar el tamaño de áreas en el cerebro. Pruebas adicionales se utilizarán para determinar la presencia de marcadores biológicos correlacionados con la EA en el líquido cefalorraquídeo (LCR).
El LCR es el líquido que rodea y protege el cerebro y la médula espinal. El LCR se obtiene a través de una prueba conocida como “punción lumbar” que consiste en introducir una aguja en la parta baja de la espalda para extraer una pequeña cantidad de líquido. El LCR se observa y evalúa en el laboratorio y es una fuente de información confiable para medir el metabolismo y funcionamiento del cerebro. Es por esta razón que el uso del LCR en la investigación médica se ha convertido en una práctica de rutina.
El “resveratrol” es una sustancia derivada de plantas que se encuentra en algunas clases de vino tinto y en la piel o cáscara de la uva roja. Se piensa que el “resveratrol” posee varios mecanismos de acción relacionados al desarrollo de la EA y es por esto que puede que usted haya escuchado decir que el consumir una copa o un vaso de vino tinto al día es de beneficio para la memoria.
En exámenes de laboratorio se ha encontrado que el “resveratrol” protege las células cerebrales contra los daños causados por el “Abeta/amyloid.” El Abeta es un péptido que tiene la capacidad de agruparse para formar placas amiloideas en las células del cerebro, uno de los mecanismos que se piensa que puede ser la causa de la EA. En el laboratorio el “resveratrol” disminuye los niveles de Abeta producidos por diferentes tipos de células, y facilita su desintegración. En pruebas de laboratorio, llevadas a cabo con ratones, el “resveratrol” también disminuye la cantidad de placas amiloideas en el cerebro. El “resveratrol” además está asociado a la regulación genética del proceso de envejecimiento, tanto así que mimetiza una proteína que se distingue por alargar las expectativas de vida de un organismo. En conjunto estos resultados son prometedores, pero es de gran importancia el desarrollar un ensayo clínico a gran escala para determinar el beneficio de esta sustancia en las personas con EA.
El “resveratrol” esta disponible comercialmente en dosis de hasta 700 mg. y se ha evaluado en hombres saludables en dosis de hasta 1000 mg. El contenido específico en las formulaciones comerciales no se conoce ya que todavía no existen políticas de control. Hasta ahora el “FDA” o Administración de Alimentos y Drogas de los EEUU, ha determinado que es una sustancia segura. Actualmente esta agencia federal lleva a cabo una evaluación con el fin de emitir recomendaciones acerca de las dosis propuestas para uso. En un estudio piloto, que se llevo a cabo en el “Mount Sinai School of Medicine” se utilizaron dosis mucho menores y los resultados están en proceso de análisis.
El proyecto de investigación que describimos actualmente se llevará acabo durante un periodo de 52 semanas. Los participantes realizarán10 visitas a la clínica y se someterán a 2 exámenes de punción lumbar y a 3 exámenes de resonancia magnética.
El proyecto de investigación, como dijimos anteriormente, tiene el objetivo de evaluar los efectos del “resveratrol” en los marcadores biológicos y en las áreas del cerebro con evidencia de atrofio. Además este proyecto tiene el objetivo de examinar con mas precisión si esta sustancia es segura y tolerable en pacientes mayores de 50 años durante las etapas moderada o leve de la enfermedad.
Para más información sobre este estudio por favor contacte a Helene Geramian al 212-659-8885.


Mark P. Mattson, Ph.D., chief of NIA’s Laboratory of Neurosciences in Baltimore, directed the research, in collaboration with colleagues at Konkuk University College of Veterinary Medicine, Seoul, South Korea, and the Indiana University School of Medicine, Indianapolis.

Mattson’s team found that diazoxide stabilized nerve cells in the brain and prevented a biological cascade in the mice that can result in the destruction of these cells. The drug also improved blood flow in the brain and prevented the harmful accumulation of two proteins, beta-amyloid and tau, which are hallmarks of Alzheimer’s. Widely used in the 1970s and ‘80s to treat patients with severe hypertension, diazoxide is currently used to treat hypoglycemia, or low blood sugar.

“These intriguing findings open new avenues of basic research that may increase our understanding of how modulating theelectrical activity of nerve cells may slow the damage wrought by Alzheimer’s disease pathology,” said NIA Director Richard J. Hodes, M.D. “More research will be needed before we can determine whether this may be a potential therapy for Alzheimer’s.”

NIA scientists studied two groups of Alzheimer’s mice, one given diazoxide in drinking water and one given a placebo. After eight months, the diazoxide group outperformed the placebo group on a standard test of learning and memory. The brain tissue of the treated group showed fewer deposits of amyloid and tau proteins, less damage due to oxidative stress, and better blood flow—all indications that diazoxide may have suppressed some of the harmful cellular changes associated with Alzheimer’s disease. “To better understand the complex biological mechanisms by which diazoxide may exert a positive effect on nerve cells, we then studied the effects of diazoxide on cultured nerve cells,” Mattson said.

The scientists found the drug activates and opens channels in the cell that enhance the movement of potassium, which then calms the electrical activity of nerve cells in parts of the brain involved in learning and memory. Diazoxide also lowered the excessive calcium often found in nerve cells in brains affected by Alzheimer’s. These beneficial effects were seen with a dose of diazoxide low enough to avoid a major decrease in blood pressure, Mattson noted.

Comment by Dr. Sam Gandy: “Many groups are looking to re-purpose existing drugs with known safety profiles, evaluating them anew in mouse models of Alzheimer’s. Diazoxide has a number of clinical applications, but its benefit in the mouse model is believed to be associated with its ability to promote nerve cell communication. Work from many labs shows that more communication often translates to improved plasticity, which, in turn, helps nerve cells fight off the poisonous environment of amyloid clumps called oligomers. Moreover, as MSSM colleague Joe Buxbaum and I showed over 20 years ago, nerve cell communication reduces generation of amyloid, so these two actions of diazoxide might be predicted to synergize in the AD brain. Of course, the true test will come in a randomized clinical trial, and I look forward to seeing Samuel Gandy, Ph.D., M.D. the Mount Sinai ADRC participate in a diazoxide trial when that time arrives.”

The NIH recently sponsored a panel made up of 15 specialists in a variety of fields of medicine and public health, along with 20 expert presenters, in order to assess the current research on Alzheimer’s disease prevention. They came up with a consensus statement with a couple of major points – the most general being that given the difficulty in diagnosing the “pre-clinical” stages of Alzheimer’s disease, firm conclusions cannot be drawn about the association of any modifiable risk factor with Alzheimer’s disease. They did, however, conclude that “the evidence is insufficient to support the use of pharmaceutical agents or dietary supplements to prevent cognitivedecline or AD.”

Many possible factors have been studied ranging from cognitive stimulation, and physical activity to blood pressure medications, vitamins, omega 3 fatty acids, red wine, and eating a Mediterranean diet, among others. There are studies that are ongoing, and hopefully will augment our understanding, but so far the jury is still out as to whether they can alter an individuals risk for developing a memory problem.

The bottom line is that researchers need to continue to look for early diagnostic markers and identify people at significant risk, so that further large randomized trials can help sort out these answers. One example of how researchers are approaching this is through the AD neuro-imaging initiative (ADNI) – a study looking at imaging and other markers in blood or spinal fluid and following people over time to better understand and define who will go on to develop a dementia.

In the meantime doing “healthy” things – getting exercise, staying mentally active, eating a healthy and balanced diet may help and certainly won’t hurt!

Researchers are one step closer to discovering the genetic precursors to lateonset Alzheimer’s disease, the most common type of the disease. Investigators from four institutions, including Dr. Joseph Buxbaum of Mount Sinai Medical Center, collaborated to discover the role of variations in a gene named MTHFD1L. The presence of this altered gene appears to result in a nearly twofold increase in an individual’s risk of developing Alzheimer’s.

The research was conducted by a team of researchers led by Margaret Pericak-Vance, Ph.D., director of the John P. Hussman Institute for Human Genomics (HIHG) at the University of Miami Miller School of Medicine (details appear September 23 in the open-access journal PLoS Genetics). According to Dr. Pericak-Vance, identification of this gene “is important because the gene is known to be involved in influencing the body’s levels of homocysteine, and high levels of homocysteine are a strong risk factor for late-onset Alzheimer’s disease.” In a previous study conducted at Queen’s University Belfast and published in Stroke, it was reported that even moderate elevations of homocysteine were associated with a nearly threefold increased risk for Alzheimer’s disease. Homocysteine is an amino acid believed to be toxic to blood vessels. “We are hopeful our identification of MTHFD1L as a risk gene for Alzheimer’s disease will help us to better understand how this disease develops and potentially serve as a marker for people who may be at increased risk,” said co- author Dr. Adam Naj.

“This finding gives us unique insight into possible interactions between genetic and environmental risk factors that contribute to AD,” said Dr. Buxbaum. “We know of environmental and lifestyle factors that can impact homocysteine levels and it will be important to understand whether variations of the MTHFD1L gene can modulate these effects.”

This latest discovery of a gene variation that appears to increase the risk of this devastating disease “will lead to a better understanding of what’s happening in Alzheimer’s disease, and how we can improve treatment,” added Dr. Jonathan L. Haines of Vanderbilt Center for Human Genetics Research. This discovery comes at a time when new insights into the prevention and treatment of Alzheimer’s disease are desperately needed. The latest statistics released by the Alzheimer’s Association show that about 5.3 million Americans have this form of dementia, with a nearly threefold increase anticipated by 2050.

New criteria have been proposed to integrate the biological and epidemiological information we now have. The diagnosis of “all cause dementia” is similar to the current diagnosis in that it focuses on problems in social or occupational function (i.e. every day activities), that are a clear decline from a previous level and are due to cognitive loss. However, unlike current criteria for dementia, memory impairment may be apparent, but is not required. The criteria for the clinical diagnosis of the specific condition of Alzheimer disease also includes gradual onset of problems. Probable AD would be defined by evidence of clinical decline which means worsening noticeable by families or doctors. However, if this type of information is not available, (such as when there is no way to be sure about the previous ability), biomarkers including genetic markers could provide support for the diagnosis. This approach suggests that we have growing confidence in biomarkers (such as brain scans) as an indicator of specific disease.

Diagnostic criteria were also proposed for symptomatic predementia known as Mild Cognitive Impairment (MCI), consisting of 4 basic elements: 1) Concern about any cognitive change, not just memory; 2) poor performance in any cognitive area including but not exclusively memory; 3) relatively normal day to day function and 4) the absence of dementia. MCI cases could be evaluated for the etiology (cause) of the problem and the likelihood of AD might be determined by the type of cognitive problem (such as memory loss), or by genetic (such as Apolipoprotein E4 ) and biomarker data that are strongly associated with AD diagnosis.

Perhaps most controversial is the attempt to define a “pre-clinical” Alzheimer disease. This asymptomatic (normal) condition would be defined by biomarkers associated with AD pathology in the absence of any clinical features. While this may be a step toward earlier detection of AD, more information is needed before we can confirm that biomarkers in AD are really predictive of specific conditions when there are no symptoms present. Currently, markers thought to indicate AD have been present in about a third of the elderly asymptomatic individuals and right now we have no evidence that these people get worse. This highlights the importance of following normal volunteer elders to determine if we can accurately predict the onset of AD.

Mount Sinai School of Medicine researchers have found that a gene associated with the onset of Type 2 diabetes also is found at lower-than-normal levels in people with Alzheimer’s disease. The research, led by Giulio Maria Pasinetti, MD, PhD, The Saunder Family Professor in Neurology, and Professor of Psychiatry and Geriatrics and Adult Development at Mount Sinai School of Medicine, was published this month in Aging Cell.

The new study provides insight into a potential mechanism that might explain the relationship between Type 2 diabetes and the onset and progression of Alzheimer’s disease. Recent evidence indicates that healthy elderly subjects affected by Type 2 diabetes are twice as likely to develop Alzheimer’s disease, but researchers have been unable to explain how. “The relationship between Type 2 diabetes and Alzheimer’s disease has been elusive,” said Dr. Pasinetti. “This new evidence is of extreme interest, especially since approximately 60 percent of Alzheimer’s disease cases have at least one serious medical condition primarily associated with Type 2 diabetes.”

Using mice that were genetically engineered to have Alzheimer’s disease comparable to that seen in humans, Dr. Pasinetti and colleagues found that a gene known as proliferator-activated receptor coactivator 1 (PGC-1), a key regulator of glucose currently investigated as a potential therapeutic target for Type 2 diabetes, is decreased in Alzheimer’s disease. The team reports that this decrease might be causally linked to promotion of Alzheimer’s disease. They found that PGC-1 promotes degradation of a specific enzyme known as beta-secretase (BACE). BACE is directly involved in the processing and eventual generation of β-amyloid, an abnormal protein highly linked to Alzheimer’s disease and brain degeneration.

Dr. Pasinetti and his colleagues are optimistic that if they find that PGC-1 can be manipulated pharmacologically to prevent BACE accumulation in the brain, these studies will provide important insights for the formulation of novel treatments and possible preventative strategies in Alzheimer’s disease.

Sam Gandy, MD, PhD

Since 2004, scientists have been discovering mice that had no build of up amyloid plaque in the brain, but nevertheless showed the typical symptoms of dementia. At the same time, other researchers were beginning to show that if rats were injected with oligomers, memory loss, the symptom so well associated with Alzheimer’s, was undeniably discovered. These findings led to yet another recent study in which scientists, knowing that the two elements are made up of the same protein, amyloid, attempted to convert oligomers into plaque, which Dr. Gandy stated, “when they did this gene trick, the mice got better, [and] their memory improved.”

With this research behind them, Dr. Gandy, along with his study team at Mount Sinai, genetically engineered mice whose brains only produced oligomers, but never plaques. At six and twelfth months of age, these mice were exposed to the Morris water maze task, a test of spatial learning and memory. At the latter time period, the mice with readily detectable levels of considerable oligomer build-up displayed a significant delay in acquisition of the task, especially when compared to non-transgenic mice, or mice who did not develop Alzheimer’s disease. Moreover, when a gene that converted oligomers into plaques was added to the mice, the mice were no more impaired than they had been previously.

The potential implications for these findings are insurmountable in light of the recent upsurge in the development of Alzheimer’s medications by pharmaceutical companies worldwide. Over the past few years, many of these medications, including the failed Alzhemed, have focused their lines of attack on breaking up amyloid plaque in the brain, which may altogether be a futile attempt to find a treatment to the disease. Further, in following the line of thought of Dr. Gandy’s study, it may even be argued that these medications may actually cause more harm that benefit. In an interview for the AARP Bulletin, Andrew Dillin of the Salk Institute of California and the Howard Hughes Medical Institute, stated, “I think the plaques are a sign that your brain was trying to do something very beneficial for itself in the last stages of the disease. If you go in and take these plaques apart, you’re going to make oligomers, and that could actually be worse.”

In reviewing this research, Dr. Gandy states, “These findings may enable the development of neuroimaging agents and drugs that visualize or detoxify oligomers. New neuroimaging agents that could monitor changes in Abeta oligomer presence would be a major advance. Innovative neuroimaging agents that will allow visualization of brain oligomer accumulation, in tandem with careful clinical observations, could lead to breakthroughs in managing, slowing, stopping or even preventing Alzheimer’s.”

Despite the excitement of this research, William Theis, Chief Medical Officer of the Alzheimer’s Association, warns that it’s still too early to make the jump from mice models to the human brain. For the AARP Bulletin, he warns that it’s still too soon to eliminate plaques as a target for Alzheimer’s medications. However, he still sees the importance of this research—research that nonetheless will help researchers closer to finding a cure to this disease.

There are several biological explanations for the possible increased risk of AD after head injury. First we know that the ApoE4 allele increases both the risk of AD and the risk of cognitive deficit after a head injury. Also, we know the brains of people with AD and those who have suf- fered a head injury have amyloid plaques and neurofibrillary tangles. However, while the brains of boxers diagnosed with dementia pugilis- tica have a significant number of tangles in some of the same areas where tangles are found in AD patients, tangles are also found in these boxers in brain regions that are involved with emotions. This has lead to the idea that head injury results in a type of dementia called chronic traumatic encephalopathy, or CTE, rather than AD.

The traditional view of head injury, more accurately referred to as trau- matic brain injury (TBI), suggested that there was an initial period of recovery followed by life-long stable cognitive functioning. Recently, we have become aware of individuals with TBI who were stable for some years, but then began to demonstrate cognitive, functional and behavioral deterioration resulting in an earlier onset of dementia.

Stories of former boxers who are diagnosed with dementia pugilistica and more recently, former NFL players who are diagnosed with dementia at younger ages, suggest that even mild head injuries may cause early onset AD. The findings in former boxers and football players lead us to wonder about players of other types of sports that are associated with concussion. Will those players be at risk, too?

Mild TBI (MTBI) is the most common form of head injury and is often the result of a concussion from motor vehicle accidents, falls or sports-related activities, or repeated bumps to the head. Concussion can result in temporary loss of awareness, dizziness, nau- sea, vomiting or brief loss of consciousness. All age groups are at risk for these injuries. While younger people may be at risk of an MTBI from a sports-related incident, older adults are at risk of concussion from falls. While there is overlap in cognitive symptoms between AD and MTBI such as memory loss (more profound in AD versus MTBI) and attention problems, there are differences as well. For example, the memory problems in AD are characterized as a profound difficulty in learning and retention of new informa- tion. In MTBI, memory can often be aided by cuing. In addition, executive function (thinking abilities required for planning, problem solving, self-regulation of behavior, and judgment) may be impaired early in MTBI while in AD, executive dysfunction becomes more prominent later, as the disease progresses. Complicating the diagnostic scenario is the fact that depression is frequently found in both AD and MTBI patients.

To this day, how and whether MTBI triggers progressive brain changes leading to AD remains controversial but there is a growing body of research trying to understand this important issue. Brain imaging techniques offer a glimpse into the living human brain, allowing us to identify and track the disease process. Current studies are using a relatively new brain imaging technique called diffu- sion tensor imaging (DTI) to examine the integrity of nerve cell connections in the brain, which are sheared and torn following TBI, which may shed light on the underlying disease process. Imaging in combination with neuropsychological assessment, which is the use of objective measures (i.e., paper/pencil tests) to assess brain activity, will hopefully clarify the diagnostic picture.

While researchers are working to better understand the link between head injury and AD, it is important for people both young and old to follow some safety precautions to avoid head injuries. When riding a bicycle a helmet should always be worn. Because motor vehicle accidents occur so frequently and increase the risk of a head injury, people of all ages should wear a seat belt. Some simple precautions for older adults to take to avoid falling include using a steady step ladder and wearing sensible shoes. Do not trust your eyes to see in dark places if you know you have vision problems. You could easily trip over that lost shoe, fall, and hit your head on a piece of furniture. Be sure to obey signs about wet floors. Caution leading to prevention is the best way to avoid falls and may reduce your risk of dementia.

A vaccination can be “active” like AN-1792 (vaccination with amyloid plaque material so the body produces its own anti-amyloid antibodies) or it can be “passive” (where anti-amyloid antibodies are created in a lab and infused into patients). Because some patients developed that allergic inflammation of the brain during the AN-1792 study, many researchers have turned to immuno- therapies that rely on passive immunity against amyloid plaques. Recent estimates indicate that there are 10-15 amyloid immunotherapy trials ongoing worldwide at this time, and most of those focus on passive immunity because of the problems with AN- 1792. One such synthetic antibody, “Bapineuzumab”, is currently in Phase III trials, and the Mount Sinai ADRC is one of its sites.

In July, 2008, the results of a Phase II study of Bapineuzumab was reported to the public, and the benefit was marginal. Further, some subjects had a significantly increased risk of mild brain swelling (usually only detectable on brain scan), known as “vasogenic edema” (V.E.). Since the V.E. was often unnoticed clinically and since the overall results were interpreted as en- couraging, a larger “Phase III” trial, of Bapineuzumab is now in progress nationwide. Other studies using infusion of synthetic antibodies are being conducted by Lilly (under the drug name “LY2062430”) and Pfizer (under the drug name “RN1219”). The Lilly antibody has completed Phase II trials, while the Pfizer anti- body is in Phase I.

In addition to the infusion of synthetic antibodies, there are Phase III trials ongoing using the antibody-rich drug, Intravenous Immunoglobulin “IVIg”. In contrast to synthetic antibodies IVIg is prepared from donor human blood. Studies of IVIg have shown that there are, in normal human donor blood, naturally occuring circulating antibodies against amyloid clumps. Though theoretically promising there have not yet been sufficiently large, randomized clinical trials of IVIg that permit us to draw any conclusions about efficacy. However, small single-site studies have been sufficiently encouraging to warrant a larger controlled study. As of this writing (mid-January, 2009), this study has begun and will be recruiting subjects at 38 centers around the US, including the Mount Sinai ADRC.