Is Alzheimer’s Disease Genetic?
Dr Arancio is a cellular neurobiologist who has contributed to the characterization of the mechanisms of learning in both normal conditions and during neurodegenerative diseases. During the past decade he has pioneered the field of mechanisms of synaptic dysfunction in Alzheimer’s disease. Dr. Arancio’s laboratory has focused primarily on events triggered by amyloid protein. These studies, which have suggested new links between synaptic dysfunction and amyloid protein, are of a general relevance to the field of Alzheimer’s disease both for understanding the etiopathogenesis of the disease and for developing therapies aiming to improve the cognitive symptoms.
Meryl Comer: Dr. Guarente, let’s move to the genetics of Alzheimer’s disease.
Dr. Guarente: Yes. Some genes have been identified by virtue of studying families in which early onset of Alzheimer’s occurs and is inherited. So using regular standard genetic means scientists have identified a few genes that are important. One is a gene called APP and that gene encodes a protein that gets cut up into bits. And one of those bits is the offending substance, the Abeta amyloid peptide that gives rise to plaques and gives rise to toxic species, oligomers, that figure in the disease. Another gene that was identified through genetics is a protein called presenilin, which is the enzyme that cuts the APP protein into pieces that actually makes the last cut to liberate this offending A-beta peptide, so we can learn about the disease... And another locus that has been identified is APOE4, which is a risk factor for Alzheimer’s disease and is sort of less central in a molecular sense then are APP and the presenilin. So what the genetics tells us... First of all, we can’t really do anything about our genes, so our genes are what they are, but genetics clues us in on what the players are that are important in a disease and what we do is we study those players and how they interact in the context of cells and organs, like the brain. And I think that it opens a door for us to develop strategies to tinker with these steps, but not with genes, but with drugs. And I think that drug development in this field there really is nothing right now for people with Alzheimer’s disease. And it’s really where there is an incredible demand, and a growing demand. And based on the biology that I just described really in a skeletal way of the relevant genes and the relevant pathways I think we have to hammer home to get to drugs and that is only going to come from experimentation and funding and a really intense effort because it’s not easy to develop drugs. And we’ve seen sort of a template for this with AIDS. There was a tremendous emphasis put on getting drugs for AIDS, starting maybe 20, 25 years ago and it has led to drugs that don’t cure the disease, but treat it quite well. And I think that illustrates that once a society decides that they want to do something like this it can be done.
Meryl Comer: Let’s put the genetic predisposition into perspective Dr. Gandy. What percent? If you say age is the greatest determinate of getting Alzheimer’s, what percentage of those are early onset or familial?
Dr. Gandy: Well only about 3% of all of Alzheimer’s is early onset and completely familial, but APOE4 before increases the risk for Alzheimer’s and there are probably certainly more people with Alzheimer’s disease, partially because they have an APOE4 gene than with any other genetic risk factor. So it has been very challenging to understand exactly how APOE4 works and in fact that is an important clue for us to continue to follow because more people have APOE4 related Alzheimer’s disease than Alzheimer’s disease related to either APP or presenilin.
Dr. Guarente: If I might just comment on that. These other 90% of AD patients who don’t have a frank mutation in APP or the presenilin that is not to say that that pathway and those proteins, APP and A-beta are not critical in the disease. I believe that very likely they are in all of Alzheimer’s cases, so by leveraging the genetics to get at these players and developing drugs I think we wouldn’t be just treating the 3%. We potentially could treat everybody.
Dr. Gandy: Yeah, but by the part of the power of these early onset genes is that the clinical manifestations and the pathology of the early onset genetic forms and the common later onset forms are indistinguishable except for the age at onset. They look the same in your waiting room. They look the same under the microscope, so Lenny is exactly right that this pathway points the way for all of Alzheimer’s disease.
Meryl Comer: Dr. Arancio, you wanted to make a point.
Dr. Arancio: Yeah, my point is that I definitely agree with my friends here that interfering with this protein tau and A-beta could be beneficial in terms of therapy and to take advantage of that. However, there is one thing that... an area that I think is underdeveloped in all our studies, which is what is behind that, what comes before that. This is an area that when I see... which it’s my belief that there is... we need more attention because it’s totally a dark area because yes, in the 3% of cases there is for sure with a mutation these proteins are affected, but the remaining 97%, we should find out why. It is not them directly. It is something behind them that through them caused the damage and that is the area, a big area that could be very, very useful and I’d like to sort of find... to draw the attention on all of us that perhaps interfering with the protein that some of the protein that regulates the APP like Lenny just said for instance, also tau, we can interfere with physiological normal function of this factor and therefore we’re hoping to get rid of disease and we are causing other trouble and this could be the reason for failure of some of the drugs that even recently have failed.
Meryl Comer: Well let’s look at one of the other challenges and that is the area around finding biomarkers that will help in the early diagnostics and detection of this disease.
Dr. Gandy: So biomarkers are sort of surrogates for the disease that can be measured perhaps before the clinical manifestations begin. And they primarily included things like blood tests, spinal fluid tests and brain scans. And we know now that we can visualize the buildup of amyloid in the brain long before any cognitive changes occur clinically. About half of the people age 65 and older already have significant visualizable amyloid buildup in their brain yet they mostly aren’t demented.
Dr. Troncoso: I would like to add something, just one more point to the genetics. It’s something that it’s very important to recognize that patients with Down Syndrome which have a definite genetic abnormality, all of them will have at least pathological Alzheimer’s diseases, if not necessarily a manifestation of dementia. And since they they have the APP gene is in chromosome 21 in the segment that is extra in patients with Down Syndrome, this also it supports the hypothesis that the APP and the amyloid is a triggering factor in the disease, but it’s also a very important genetic component.
Genes such as ApoE4 may signal a risk factor for Alzheimer’s. But how do we separate risk factor from an unalterable sentence for the disease?
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Researchers hope the technology will further our understanding of the brain, but lawmakers may not be ready for the ethical challenges.
- Researchers at the Yale School of Medicine successfully restored some functions to pig brains that had been dead for hours.
- They hope the technology will advance our understanding of the brain, potentially developing new treatments for debilitating diseases and disorders.
- The research raises many ethical questions and puts to the test our current understanding of death.
The image of an undead brain coming back to live again is the stuff of science fiction. Not just any science fiction, specifically B-grade sci fi. What instantly springs to mind is the black-and-white horrors of films like Fiend Without a Face. Bad acting. Plastic monstrosities. Visible strings. And a spinal cord that, for some reason, is also a tentacle?
But like any good science fiction, it's only a matter of time before some manner of it seeps into our reality. This week's Nature published the findings of researchers who managed to restore function to pigs' brains that were clinically dead. At least, what we once thought of as dead.
What's dead may never die, it seems
The researchers did not hail from House Greyjoy — "What is dead may never die" — but came largely from the Yale School of Medicine. They connected 32 pig brains to a system called BrainEx. BrainEx is an artificial perfusion system — that is, a system that takes over the functions normally regulated by the organ. The pigs had been killed four hours earlier at a U.S. Department of Agriculture slaughterhouse; their brains completely removed from the skulls.
BrainEx pumped an experiment solution into the brain that essentially mimic blood flow. It brought oxygen and nutrients to the tissues, giving brain cells the resources to begin many normal functions. The cells began consuming and metabolizing sugars. The brains' immune systems kicked in. Neuron samples could carry an electrical signal. Some brain cells even responded to drugs.
The researchers have managed to keep some brains alive for up to 36 hours, and currently do not know if BrainEx can have sustained the brains longer. "It is conceivable we are just preventing the inevitable, and the brain won't be able to recover," said Nenad Sestan, Yale neuroscientist and the lead researcher.
As a control, other brains received either a fake solution or no solution at all. None revived brain activity and deteriorated as normal.
The researchers hope the technology can enhance our ability to study the brain and its cellular functions. One of the main avenues of such studies would be brain disorders and diseases. This could point the way to developing new of treatments for the likes of brain injuries, Alzheimer's, Huntington's, and neurodegenerative conditions.
"This is an extraordinary and very promising breakthrough for neuroscience. It immediately offers a much better model for studying the human brain, which is extraordinarily important, given the vast amount of human suffering from diseases of the mind [and] brain," Nita Farahany, the bioethicists at the Duke University School of Law who wrote the study's commentary, told National Geographic.
An ethical gray matter
Before anyone gets an Island of Dr. Moreau vibe, it's worth noting that the brains did not approach neural activity anywhere near consciousness.
The BrainEx solution contained chemicals that prevented neurons from firing. To be extra cautious, the researchers also monitored the brains for any such activity and were prepared to administer an anesthetic should they have seen signs of consciousness.
Even so, the research signals a massive debate to come regarding medical ethics and our definition of death.
Most countries define death, clinically speaking, as the irreversible loss of brain or circulatory function. This definition was already at odds with some folk- and value-centric understandings, but where do we go if it becomes possible to reverse clinical death with artificial perfusion?
"This is wild," Jonathan Moreno, a bioethicist at the University of Pennsylvania, told the New York Times. "If ever there was an issue that merited big public deliberation on the ethics of science and medicine, this is one."
One possible consequence involves organ donations. Some European countries require emergency responders to use a process that preserves organs when they cannot resuscitate a person. They continue to pump blood throughout the body, but use a "thoracic aortic occlusion balloon" to prevent that blood from reaching the brain.
The system is already controversial because it raises concerns about what caused the patient's death. But what happens when brain death becomes readily reversible? Stuart Younger, a bioethicist at Case Western Reserve University, told Nature that if BrainEx were to become widely available, it could shrink the pool of eligible donors.
"There's a potential conflict here between the interests of potential donors — who might not even be donors — and people who are waiting for organs," he said.
It will be a while before such experiments go anywhere near human subjects. A more immediate ethical question relates to how such experiments harm animal subjects.
Ethical review boards evaluate research protocols and can reject any that causes undue pain, suffering, or distress. Since dead animals feel no pain, suffer no trauma, they are typically approved as subjects. But how do such boards make a judgement regarding the suffering of a "cellularly active" brain? The distress of a partially alive brain?
The dilemma is unprecedented.
Setting new boundaries
Another science fiction story that comes to mind when discussing this story is, of course, Frankenstein. As Farahany told National Geographic: "It is definitely has [sic] a good science-fiction element to it, and it is restoring cellular function where we previously thought impossible. But to have Frankenstein, you need some degree of consciousness, some 'there' there. [The researchers] did not recover any form of consciousness in this study, and it is still unclear if we ever could. But we are one step closer to that possibility."
She's right. The researchers undertook their research for the betterment of humanity, and we may one day reap some unimaginable medical benefits from it. The ethical questions, however, remain as unsettling as the stories they remind us of.
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