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Eleven new Alzheimer's Risk Gense

A study by the International Genomics Project, published in Nature Genetics, identified eleven previously unknown genes that increase risk of developing Alzheimer’s. The research, which brought together leading Alzheimer’s researchers, was comprised of four teams from one hundred and forty-five global academic centers working toward the common goal of determining new information surrounding the genetics of Alzheimer’s disease.

One of the most significant findings of the study, which involved the genome data of 74,076 people from fifteen different countries, relates to the HLA-DRB5/DRB1 major histocompatibility complex region of the brain. The research shows that this same region, associated with multiple sclerosis and Parkinson’s, is involved somehow in Alzheimer’s disease.

The discovered genes revolved mostly around late onset Alzheimer’s, the most common type of the disease. Professor Julie Williams, head of neurodegeneration at Cardiff School of Medicine’s Medical Research Council, says that the teams can now shift their focus to early on-set Alzheimer’s, the most severe form that usually begins around ages 40-50. The Professor says that indentified genetic architecture may make finding new genes easier, and that the genes yield clues for scientists to seek out during research.

These eleven genes bring the total of indentified risk genes to twenty-one, and scientists hope that such findings will help improve knowledge about the mechanisms behind the neurodegenerative disease. The four groups used genome-wide association analysis work that previously identified the first ten risk genes. Professor Williams cautions that although twenty-one of these genes are now uncovered, a large section of genetic risk for Alzheimer’s remains unknown. Williams ends by saying that the identification of more risk genes is imperative to the continued research and development of these findings.

Sources:
1) Meta-analysis of 74,046 individuals identifies 11 new susceptibility loci for Alzheimer's disease; Jean-Charles Lambert, Carla A Ibrahim-Verbaas, Denise Harold, Adam C Naj, Rebecca Sims, Céline Bellenguez, Gyungah Jun, Anita L DeStefano, et al.; Nature Genetics Published online 27 October 2013; DOI:10.1038/ng.2802.
2) Medical News Today (Published 10/28/13). Scientists Discover Eleven New Alzheimer’s Risk Genes. Retrieved 10/30/13 from http://www.medicalnewstoday.com/articles/267998.php

By Emma Henson

The Roskamp Institute is a 501(c)3 research facility dedicated to translating the efforts of its qualified research staff into real-world results for those suffering from neurological diseases. To learn more about our programs and to get information about donating, visit www.rfdn.org.

Genetic deletion of TNF receptor suppresses excitatory synaptic transmission via reducing AMPA receptor synaptic localization in cortical neurons.

The distribution of postsynaptic glutamate receptors has been shown to be regulated by proimmunocytokine tumor necrosis factor α (TNF-α) signaling. The role of TNF-α receptor subtypes in mediating glutamate receptor expression, trafficking, and function still remains unclear. Here, we report that TNF receptor subtypes (TNFR1 and TNFR2) differentially modulate α-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid receptor (AMPAR) clustering and function in cultured cortical neurons. We find that genetic deletion of TNFR1 decreases surface expression and synaptic localization of the AMPAR GluA1 subunit, reduces the frequency of miniature excitatory postsynaptic current (mEPSC), and reduces AMPA-induced maximal whole-cell current. In addition, these results are not observed in TNFR2-deleted neurons. The decreased AMPAR expression and function in TNFR1-deleted cells are not significantly restored by short (2 h) or long (24 h) term exposure to TNF-α. In TNFR2-deleted cells, TNF-α promotes AMPAR trafficking to the synapse and increases mEPSC frequency. In the present study, we find no significant change in the GluN1 subunit of NMDAR clusters, location, and mEPSC. This includes applying or withholding the TNF-α treatment in both TNFR1- and TNFR2-deleted neurons. Our results indicate that TNF receptor subtype 1 but not 2 plays a critical role in modulating AMPAR clustering, suggesting that targeting TNFR1 gene might be a novel approach to preventing neuronal AMPAR-mediated excitotoxicity.-He, P., Liu, Q., Wu, J., Shen, Y. Genetic deletion of TNF receptor suppresses excitatory synaptic transmission via reducing AMPA receptor synaptic localization in cortical neurons.

for more information on the Roskamp Institute and Alzheimer’s please visit:

http://www.mullanalzheimer.com

http://www.mullanalzheimer.info

www.rfdn.org

Family History of Alzheimer's disease - what does it mean?

Frequently in the Roskamp institute Memory Clinic we are asked what a family history of Alzheimer’s disease means for the children and other blood relatives of sufferers. Although this question is always handled on an individual basis there are some general guidelines that can be offered to access risk for the disease to children and other family members related to a sufferer. Naturally, family members who perceive they are at risk for developing the disease themselves may suffer from a great degree of anxiety it is therefore important to ask the staff at the Roskamp Institute what the individual risk is for developing the disease. In general the genetic risk for Alzheimer’s disease can be divided into two categories; early onset familial disease which is highly genetic and occurs in families which may have onsets of the disease in the 40s,50s or 60s; late onset disease which is frequently familial but where the disease onsets in the seventh decade onwards. We shall consider these two scenarios separately.

Early onset Alzheimer’s disease.

The term “early onset Alzheimer’s” is frequently misunderstood or used in a confusing way. What we generally mean by early onset Alzheimer’s is Alzheimer’s that onsets before the age to 60 years. This is in contrast to the term early onset as referencing the early stage of the disease. This is a confusing way to use the term and is discouraged. Early stage disease is a better term to describe the early phases of the disease. Early onset familial disease occurs in families that are affected in multiple generations by mutations in genes that can trigger the disease. Families of early onset disease thankfully are very rare but they have provided great insight into the disease process probably in all cases of the disease (early and late onset). Sadly, frequently in these families the disease is inherited in what is known as an autosomal dominant fashion. Autosomal dominant inheritance means that 50% of the offspring of each generation on average are impacted by the disease. Some generations may be very fortunate and although they may be at risk for inheriting the diseased gene from one or the other parent none of the siblings in a sibship may be affected. On the contrary sibships can be very unlucky in which case more than 50% are impacted with the disease. For each child of an affected parent there is a 50% chance of inheriting the disease and this chance is not influenced by whether other siblings have already inherited the disease or not.

Unfortunately the inheritance of these rare genetic variance means that individuals at risk are highly likely to develop the disease if they live long enough. One of the important characteristics of these familial mutations is that the disease tends to onset around approximately the same time of life. Thus if a family has a mean (average) age of onset of 52 and one inherits one of these rare generic errors then one is unlikely to live to 60 without developing signs or symptoms of the disease. By contrast if one does not carry the mutation then there is no more risk for the disease than the general population.

Again it is most important to emphasize that such families are extremely rare and early onset Alzheimer’s is not the most likely reason for patients or their families to visit the Roskamp Institute Clinic. In fact, approximately 1% or less of cases of Alzheimer’s Disease have what can be described as early onset disease. In the past, individuals who come from such families have sought genetic counseling including genetic testing for these genetic errors. It is relatively straightforward to detect such errors but clearly the genetic information is highly sensitive. Family members should therefore think very carefully before seeking such information however initially finding out more about early onset disease is a recommended step.

Clinicians at the Roskamp Institute are happy to discuss early onset disease with patients and their families as they wish. Finally it should be noted that many cases of early onset disease occur without a family history. Thus individuals can manifest the disease before the age of 60 but have no other known family members either in the prior generations or in subsequent generations that develop the disease the cause of early onset Alzheimer’s that is not familial is not well understood but importantly there is no risk to subsequent family members for development of the disease.

Late onset (common) Alzheimer’s disease. Much more commonly patients and their families come to the clinic at the Roskamp Institute and seek advice on the inheritance of Alzheimer’s when one or more members of the family has late onset disease. This is defined as disease which onsets over the age of 60 and this is by far in a way the most common cause of the disease. It is estimated that approximately 4 million Americans presently either have the disease or are in the early or pre clinical stages - most of these cases are late onset Alzheimer’s Disease. The predicted numbers for future disease prevalence are very high. For instance it is estimated that by mid century there could be as many as two hundred million individuals afflicted with the disease.

Most late onset Alzheimer’s disease does not exhibit a clear autosomal dominant pattern meaning that the risk to offspring of individuals suffering with the disease is usually considerably less than 50%. Certain genetic risk factors for late onset disease have been identified - the most important of which is apolipoprotein E (APOE). There are 3 common forms of APOE: E2, E3 and E4. The discovery by Allen Roses and his colleagues at Duke University showed that Alzheimer’s disease sufferers were much more likely to carry one or two copies of the E4 allele (genetic form) of APOE than the normal population. Carrying one copy of APOE 4 increases ones risk for the disease by approximately three times and carrying two copies can increase the risk for the disease by up to fifteen times compared to individuals who do not carry an APOE 4 allele.

Many family members express interest in being genetically tested for their risk for the disease. Such tests are commercially available but most centers discourage the use of testing prior to symptoms because many individuals who carry an APOE 4 allele do not necessarily develop the disease at least until late old age. Conversely it’s very possible to develop Alzheimer’s disease without carrying an APOE 4 allele. Therefore on an individual basis the test is not overly helpful in specifying who may or may not develop the disease. However on a group basis APOE genetic testing is very helpful to give an average estimate of the numbers of individuals who will subsequently develop Alzheimer’s.

It is anticipated that as better treatments are available for Alzheimer’s disease there will be greater interest in genetic testing. For instance it is expected that as treatments are used earlier and earlier in the stages of the disease that individuals in the very early stage or maybe with no symptoms at all might seek medical treatment once such treatment has been established as effective in stopping the rate of progression or disease onset.

Despite the fact that genetic testing is not used frequently in clinical practice it is a tremendous tool in assisting researchers in understanding when and why the diseases develops and in planning clinical trials to take into account who is most likely to develop the disease. Already there is evidence from several clinical trials that individuals that carry the APOE 4 allele may be more refractory to certain treatments. As drug development progresses it will be important to develop medications that are able to tackle the severest form of the disease i.e. those patients who are carrying and APOE 4 allele.

Summary: The two types of familial Alzheimer’s disease differ in the risk for offspring of developing the disease. The early onset cases as noted have children that are highly at risk for developing the disease if there is a family history. By contrast late onset disease or low clustering in families is much less genetically predisposed. In both cases genetic tests are available but are generally discouraged particularly for late onset disease. Roskamp Institute researchers and clinicians are well versed in the genetic aspects of the disease and can advise on an individual or family basis as required.

The Roskamp Institute is a not-for-profit research Institute located in Sarasota and Tampa, Florida, that is dedicated to understanding the causes of, and finding cures for, neuropsychiatric and neurodegenerative disorders and addictions with an emphasis on Alzheimer’s disease. The Institute’s Memory Clinics also offer comprehensive cognitive and medical assessment toward differential diagnosis of Alzheimer’s disease and offers treatments and disease management options once the diagnostic evaluation is complete

By Dr. Michael Mullan, Director of Alzheimer Research Institute, The Roskamp Institute

for more information on Alzheimer’s please visit:

http://www.mullanalzheimer.com

http://www.mullanalzheimer.info

ß-amyloid exchage in the blood-brain barrier

Why work with Alzheimer's disease patients?

Walking into the Memory Disorder Clinic at the Roskamp Institute one might ask “Why work with Alzheimer’s patients and their families?” The answers are manyfold. One of the most rewarding aspects of working with Alzheimer’s patients is that they are most commonly our oldest citizens who have 60, 70 or 80 years of life experience behind them many of them have served their country in one form or another - frequently in the military but often times in businesses working for others or their own companies. Many of those serving in the armed forces have captivating stories. One visitor to the clinic had parachuted into three war zones Normandy, the “boot” of Italy, and Germany. Remembering this tale this gentleman was most afraid of being shot by the Russians! Of course being able to recall these old memories is not unusual for Alzheimer disease suffers. In fact the tendency to reminisce sometimes becomes a prominent feature of the disorder. Most caregivers are initially concerned by another aspect of the disorder namely the forgetfulness for recently acquired or presented information. Such things as recent visits recent phone calls or recent conversations and events may not be remembered either in part or in full. This distressing symptom interferes with social activities and is a progressive aspect of the disease. Therefore one of the most rewarding aspect of working with Alzheimer’s sufferers and their families is being able to convey to them the several treatment options that are available. This includes, as well as those drugs approved by the FDA, new and experimental treatments including those that are being developed by the Roskamp Institute itself.

Providing hope for patients and their families is a critical part of interfacing with them. In addition helping families to come to terms with a disorder that can impact many aspects of their love ones’ lives (including social interactions, pastimes and sports, financial transactions and medical legal issues) enables families to make the necessary adjustments to deal with the condition. Naturally a particularly satisfying interaction can occur when certain elements of a patient’s health can be altered to improve the outcome once a diagnosis of Alzheimer’s has been made. For instance we know that cardio-vascular health interacts critically with Alzheimer’s disease and aversion of cerebrovascular events (such as small strokes or transient ischemic attacks) has a highly beneficial effect on the outcome of Alzheimer’s patients. In addition other conditions such as diabetes or thyroid disease can interact negatively with the disease. These and many other treatable causes of cognitive dysfunction appear at the Roskamp Memory Clinic and are regularly amenable to intervention. Sometimes previous diagnoses are found to be incorrect and memory loss may be completely reversible. For instance people suffering from normal pressure hydrocephalus have a condition that is completely amenable to surgical correction.

Another gratifying aspect of working with Alzheimer’s patients is being able to give their families and loved ones a clear indication of what the treatment options are and what the outcomes are likely to be. In addition family members are often concerned about their own risk for developing the disease it now being common knowledge that the disease has a familial aspect.

All in all there is much to recommend a profession working and caring for Alzheimer’s patients. Our elderly are frequently amongst our most valued citizens who have contributed to the prosperity and safety of subsequent generations. Continuing to work for their immediate care and finding new treatments to improve their long term prognosis are the premier interests of the Roskamp Institute’s researchers, physicians and clinicians.

Alzheimer's disease drug developed at Roskamp Institute approved for key clinical trial funding in Europe

Nilvadipine, an Alzheimer’s drug developed at the Roskamp Institute in Sarasota announced earlier this year was selected for funding or a large-scale European clinical trial. An international research consortium led by Trinity College Dublin (Ireland) announced more than 500 patients will participate in the multicenter Phase III clinical trial designed to study the effectiveness of Nilvadipine.
Michael Mullan, M.D., Ph.D., Roskamp Institute director who, with associate director Fiona Crawford, Ph.D and lead scientist Daniel Paris, Ph.D., led the research team that developed the drug. Mullan said, “We need many more medicines to move forward into advanced clinical trials in the fight against Alzheimer’s Disease and we are pleased the Roskamp institute has played such a major role in the development of this drug.” Before a drug can move into clinical practice, Phase III is usually the last step in the regulatory process.
The clinical trials will take place in Europe, where Brian Lawlor, M.D., Connolly Norman Professor of Old Age Psychiatry at Trinity College Dublin, Ireland, will be principal investigator and coordinator. The study will be funded by the European Commission Seventh Framework Programme and more than 20 European clinical sites will participate. Nilvadipine is already approved for the use in mild cases of hypertension (high blood pressure) and Mullan says, “The process can move more quickly in Europe, and the study findings may help accelerate the process with the U.S food and Drug Administration (FDA).
Mullan and Crawford have been studying Alzheimer’s disease for more than 20 years, moving from the UK to Florida in 1991 and to Sarasota in 2003 to establish the Roskamp Institute. “Some of our recent studies have involved Sarasota area residents, who have contributed to our understanding of Alzheimer’s disease and helped move the development process forward,” said Crawford. Now, the Roskamp Institute will provide research support for the Phase III clinical trial, such as assessing genetic and other markers for Alzheimer’s disease in study participants.
For more information on Alzheimer’s Disease please visit www.mullanalzheimer.com
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Roskamp institute studies may lead to better diagnosis

Researchers at the Roskamp Institute have new studies that could lead to better diagnosis and eventual treatment for U.S. military personnel as well as other patients with TBI, commonly known as traumatic brain injuries.
Fiona Crawford, Ph.D., associate director of the Institute, a leading research facility for Alzheimer’s disease and other neurological disorders says, “We have found that there are changes in blood proteins that occur after a head injury, and that these are dependent on the severity of the injury, the time since the injury and genetic factors influencing outcomes after head injury.” Crawford’s research indicates that TBI can affect cellular mechanisms in the brain long after the original trauma, and that blood biomarkers reflect these ongoing processes. She also stated, “Translating these finding from the laboratory to human patients may help clinicians determine the extent of the brain injury, how long ago the injury occurred and the patient’s prognosis for a favorable or a poor outcome.”
Traumatic brain injury has multiple consequences at the cellular level and so molecular changes can persist for weeks and months after the initial brain swelling and other immediate issues have resolved. Crawford says, “Identifying blood biomarkers of mild TBI would improve medical management by enabling us to identify patients who need treatment or intervention, even if they do not have obvious signs of a brain injury.” The U.S. Department of Defense, and the Veterans Administration supports all of Crawford’s work because it could lead to better diagnosis of military personnel with mild brain injuries and better long-term care of our veterans.
For more information on Alzheimer’s Disease please visit www.mullanalzheimer.com
Or http://mullanalzheimer.info
Or www.rfdn.org

Dr. Mullan’s Alzheimer Research Involved Studying Brain Proteins

The Roskamp Institute has surfaced as a leading and reputable non-for-profit biomedical research organization. It has successfully experimented to find cures for several neurodegenerative disorders and conditions like Alzheimer’s disease. Through the clinical trials division and outpatient clinic, at the institute, thousands of Alzheimer’s patients get superior services and therapeutic treatments. Dr. Michael Mullan is the Director of Roskamp Institute. Dr. Mullan is an experienced and a competent individual. His research efforts led to the identification of Swiss Mutation.
Along with Dr. Mullan, the institute has helped in contributing to provide insights on the treatments of neuropsychiatric disorders such as Alzheimer, traumatic brain injury, substance abuse, etc. through unparalleled research. Under the supervision and guidance of Dr. Michael Mullan, several causes and cures related to Alzheimer’s disease have been found. Dr. Mullan’s Alzheimer research identified various types of genetic variations which may be the cause of predispose humans to this disease. His research and study identified that the central reason to the disease process is a small protein known as ß (beta)-amyloid. The excess and abnormal accumulation of ß-amyloid in the brain results in Alzheimer’s disease. With Dr. Mullan’s Alzheimer research, cutting edge cures, medications, and therapeutic treatments are tested and developed to help slow down the process of ß-amyloid’s toxic accumulation.
As per the research on Dr Mullan’s Alzheimer, Aβ peptide is responsible for preventing blood vessel growth and inhibiting tumor growth. He studied several particular sequences within the Alzheimer’s Aβ peptide to identify if Aβ can have the same effect with short derivatives as well. The research proved that the peptide has potential therapeutic relevance to prevent the growth of tumor. The research involved conducting clinical trials which are specifically conducted to developing superior treatments for neurodegenerative diseases. In order to understand the diseases and finding its causes and prevention, Dr. Mullan’s Alzheimer research work has contributed extraordinarily in the field. Furthermore, with his constant efforts and guidance, the Roskamp Institute was also able to carry out research in neuropsychiatric disorders such as Traumatic Brain Research, Gulf War Illness, and Alzheimer’s. Find out more about his Alzheimer research works, by browsing through www.rfdn.org or www.mullanalzheimer.com or www.mullanalzheimer.info.

The Direct Causes Related To The Disease

Alzheimer’s disease affects patients over 65 years of age and is classified as a type of dementia. However, the less prevalent early-onset Alzheimer’s can also occur earlier than 65 years of age as shown by several researches. As per the 2006 statistics, there were 26.6 million patients of Alzheimer’s and it is estimated that the disease will affect 1 in 85 people globally by 2050. Presently, there are no cures available for the disease and it is estimated to get worse with age gradually leading to death. Alzheimer’s is calculated to affect a person’s memory, affects the ability to learn and also types of behavioral changes.
Dr. Michael Mullan is a highly accredited biomedical professional and has contributed vastly to the field of research on neurodegenerative disorders conditions such as Alzheimer’s disease. He is chaired as the Director at Roskamp Institute. He is based in Sarasota, Florida, and is exceptionally qualified in finding cures for neuropsychiatric and neurodegenerative disorders and addictions. The Roskamp Institute utilizes superior scientific approaches along with Dr. Mullan to understand the root causes and potential therapies of disorders such as Alzheimer’s disease. Aside researching on Alzheimer’s, the institute has successfully studied other illnesses and disorders such as Gulf War Illness, Brain Research, etc.
With Dr. Mullan’s Alzheimer research, science has come to a better understanding of the disease and of developing its prospective cures. Dr. Mullan’s Alzheimer research proves that one of the direct causes related to the disease is the excess accumulation of beta-amyloid which is a type of protein in the brain. It is noticed that the protein is produced in every human, but its excess accumulation can result in Alzheimer’s. Along with the team, Dr. Mullan’s Alzheimer research has tested many medications and therapeutic treatments to help slowing down the accumulation of beta-amyloid and associated inflammation.
About Dr Michael Mullan
Dr Michael Mullan has been working in the biomedical field for many years. He is a leading researcher with special expertise in assessment of the earliest cognitive symptoms and stages of Alzheimer’s disease. Mullan’s Alzheimer research works are also published in various articles which help students and researchers for making new discoveries. Find out more about his Alzheimer research works, by browsing through www.rfdn.org or www.mullanalzheimer.com or www.mullanalzheimer.info.

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