Guest guest Posted May 1, 2008 Report Share Posted May 1, 2008 Pam, Thanks for the article. And I must say this, I have been here since '99 and they have been saying " in 6 years maybe a cure or something. " Wonder where they get that number from? Hugs, Donna R Caregave for Mom (after I brought her from WI to MI) for 3 years and 4th year in a nh. She was almost 89 when she died in '02. No dx other than mine. Check out Alzheimer's Disease - Expert Q & A - Tracing the Path from DNA to D Here is another link, although I know it's no LBD. But I can't help thinking that, because this decease is so much more widely known they will find a cure sooner and that has GOT to be helpful for people with LBD, right? Pammie, proud daughter of the " Little Queen " , 76 years old, Diagnosed with LBD in the fall of 2007, currently taking Avapro, Aricept, Risperdal, Foltrin, Verapamil ER, Nexium, Prednisone, Ketoprofen and Boneva. _Click here: Alzheimer's Disease - Expert Q & A - Tracing the Path from DNA to Dementia - NY Times Health_ (http://health.nytimes.com/ref/health/healthguide/esn-alzheimers-qa.html?WT.mc_i\ d=HL-D-I-NYT-MOD-MOD-M039-EM-0408-HDR & WT.mc_e v=click & mkt=HL-D-I-NYT-MOD-MOD-M039-EM-0408-HDR) Tracing the Path from DNA to Dementia By IRENE M. WIELAWSKI Bill Crandall for The New York Times Dr. Marcelle on-Bogorad is director of the neuroscience and neuropsychology of aging program at the National Institute on Aging. In collaboration with the Alzheimer's Association, the institute runs the Alzheimer's Disease Genetics Initiative, which is collecting and banking genetic and cellular material from families in which multiple relatives have late-onset Alzheimer's, the most common form of the disease. Q. How do researchers today differentiate between the brain effects of normal aging and Alzheimer's disease? A. This is really fundamental to one of our major problems in Alzheimer's research. We're used to saying that there is memory loss and a decline in brain function as we age. Things get a bit slower. You don't remember quite as readily. But laid on these are changes in cognition that aren't part of normal aging and that indicate that at some point later in time, the person is going to develop Alzheimer's disease. As the brain ages, inflammation and oxidative damage caused by free radicals increase. Free radicals are very unstable molecules that attack different c omponents of cells, like DNA and protein and lipids, and transform them into oxidized products that do not work as well. It is a sort of brain rusting, to give you an analogy. There are also age-related changes in the activity of particular genes. When we are young, we have in every cell of our body a rate of production which is very specific for every single one of the 30,000 proteins that we need to keep life going. As aging progresses, the levels of certain of these proteins change, with biological consequences. Specifically, in the brain there are changes in the production of neurotransmitters, which are the molecules responsible for connecting neuronal circuits — the basis for memory. The connections between neurons, called synapses, get weaker in certain areas of the brain. It turns out to be very tricky to differentiate between changes that are normal aging and changes that are due to Alzheimer's disease. Normal aging makes you even more susceptible to developing the pathology of Alzheimer's disease, such as amyloid plaques and neurofibrillary tangles, and dementia. Q. What do we know about the genetic risk of Alzheimer's disease? A. We know most about early-onset Alzheimer's disease, which you can get as early as age 30, ranging up to age 65. That's because about 10 percent of early-onset disease is inherited in an autosomal dominant fashion, which means that if your mother or father has the disease, you have a 50 percent chance of getting it, too. The rest of early-onset disease is not inherited in such an all-or-nothing fashion, but certainly the disease tends to run in families. As for late-onset disease, it looks like quite a large percentage runs in families as well. It therefore has a genetic component, but it is more like having a risk factor gene for heart disease. Having a family where Alzheimer's occurs certainly increases your chances of developing it, perhaps about threefold in some estimates, although that is a very soft number. But it certainly doesn't mean that you yourself will get it. Q. What gene mutations are involved in Alzheimer's disease? A. Three autosomal dominant genes have been identified for early-onset disease. The first one is the amyloid precursor protein (APP) gene, located on chromosome 21. Mutations in the APP gene lead to an increase in the production of amyloid, which is the major component of the plaques that develop in the brains of Alzheimer's patients. The mutation also results in a more sticky form of amyloid. The other two genes in early-onset disease are called presenilin 1 (PS1) and presenilin 2 (PS2). Mutations in these genes cause them to act as molecular scissors that help cut the amyloid out of the precursor protein. They cut it more rapidly, and they cut it in a form which is more toxic. These mutations account for only perhaps 1 percent of the total number of Alzheimer's cases, but they gave us very important clues as to where to focus our research. For late-onset Alzheimer's, the only risk factor gene known right now is ApoE-4. You can have one or two copies, or no copies, of the gene. According to how many copies you have, your risk of getting Alzheimer's increases. If you have one copy, you usually get the disease earlier. If you have two copies, then perhaps much earlier. Q. Is it useful for someone who, say, has older relatives with late-onset Alzheimer's to seek genetic testing? A. There is a great difference in the value of genetic testing between early-onset and late-onset disease. In genetic tests of people with a family history of early-onset disease, testing can determine pretty much for sure that they will or will not get it. In terms of late-onset disease, it is much trickier. All the genetic tests can tell patients is that their risk of getting Alzheimer's is increased, nothing more. Perhaps when we find a few more late-onset genes and you can do a mix of them, then the predictive value might be higher, but we are not at that stage yet. We don't know for sure any other late-onset genes, although there are several promising candidates. That's why we have the Alzheimer's Disease Genetics Initiative: to try to find other late-onset genes that are risk factors for Alzheimer's. Q. Why are biological markers, whether gene mutations or pathological brain changes, important to the development of effective treatments for Alzheimer's disease? A. At the moment, all that we have to measure efficacy in clinical trials are psychological tests: how well you are doing compared to how well you did a year ago. There is quite a lot of variability in Alzheimer's patients as to how they are doing mentally. You can do a test one day and get one result, and the next day you might get a different result. In order to account for these differences, you have to do the trial for quite a long period — years. We're hoping that one or two of the biomarkers, whether through imaging or biochemical studies, will give better, more accurate indications whether a drug has an effect or not. Q. What do scientists hope to learn from the Alzheimer's Disease Genetics Initiative? A. Just as the genes for early-onset disease gave us clues about how important amyloid is, identifying those for late-onset Alzheimer's will give us clues about other pathways which are important. That will give us new avenues for potential therapies, so that when a patient comes to a doctor's office, the doctor can do a test and say, " Well, you've got the ApoE-4 gene, so you are at risk. But you don't have any of the other risk factor genes, so you aren't very much at risk. " The ApoE-4 gene turns out to be a very strong risk factor for late-onset Alzheimer's. Other risk factor genes that we don't know about yet probably have much smaller effects, but there might be quite a few of them. In order to find genes with much smaller effects, we have to analyze many thousands of cases. Our genetics initiative in large part is a way of collecting enough DNA samples from controls and diseased individuals that geneticists can find the remaining risk factor genes. Q. How close are scientists to finding effective treatments for Alzheimer's disease? A. Not as far along as we would like. Unfortunately, there are no clinical trials whose results say this drug stops the disease or this drug will prevent it. But there are drugs which are being tested in the preclinical phases, some being developed from basic science findings and some being tested in humans right now. These include drugs that attack different parts of the process of plaque formation, including blunting the scissors that cut the amyloid and preventing amyloid aggregation. Another approach currently being tested is immunotherapy, which is like giving a vaccine to protect against infection. The idea is to induce the body to develop antibodies against amyloid. Clinical trials are underway, but there are no results yet. If we're lucky we could have something in five years. If we're unlucky, who knows? One of the reasons it is hard to develop drugs for Alzheimer's is that the brain is the most complicated organ in the body by many, many fold. Because Alzheimer's pathology begins to develop before the patient shows any signs, drugs for prevention would need to be taken for many years. So these drugs need to be targeted very specifically, and they need to be very safe with minimal side effects. It's going to take a lot of work to get it just right. 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