Why Some People Get Alzheimer’s and Others Don’t

Meryl Comer:  Now when you study longevity, Dr. Guarante, you’re the upside.  When you look at from your studies at a cellular level what are you looking for and what is the conversation between you and perhaps Dr. Arancio?

Dr. Guarente:  Well I think that we come in a from a very simple position of what causes aging and are there any genes that control aging and that and that is how we have tackled this problem in first simple systems—yeast, fruit flies. And we were able to identify genes that we think work in all systems including humans to regulate aging and to give you an example that will tie it directly to what Dr. Gandy was talking about: one of the most important classes of proteins that have come out of these studies in aging are called sirtuins and they affect aging in a broad spectrum of organisms.  Now, we’re studying them in mammalian systems and in particular in diseases because our premise is that diseases that occur late in life have aging itself as the trigger and if we could attack the aging component of the disease we can treat the disease. So this is just the opposite of taking a focused direct approach on the particulars of a disease and saying: let’s attack the aging, the underlying component and thereby ameliorate the disease. So it turns out in studies we’ve carried out in the past few years in my lab on Alzheimer’s disease in mice that one of the mammalian sirtuins called SIRT1 directly affects one of the components that Dr. Gandy was talking about; the plaques. And it reduces the protein that makes these plaques, which is called A-beta amyloid and so that was a very striking finding that we published.  Now unknown to me two weeks later a paper from a different lab occurred that showed just in an independent study that SIRT1, the same sirtuin, also reduces the tangles and the tau protein, so that to me is very striking because we’re coming from a very, very simple point of view of aging and we end up targeting the two components that go awry and are at the basis of the etiology for Alzheimer’s disease, the plaques and the tangles, so I think to my mind that really justifies the idea that studying aging will have direct relevance to these diseases and, in particular, Alzheimer’s. 

Meryl Comer:  All right, well let’s look at that issue of the beta amyloid in the tau because it is very controversial now within the research field. Dr. Gandy?

Dr. Gandy:  Well the strongest clues for Alzheimer’s, for how Alzheimer’s begins comes from the rare form that are entirely genetic.  Out of all of Alzheimer’s, about 3% is entirely genetic.  We know exactly which genes have the mistakes and what the mistakes are and how they exert their actions. And in every case those all point to this material called amyloid.  It’s normally made by all cells all throughout the body, all throughout the lifespan.  For reasons we don’t understand in certain regions of the brain it changes its shape, forms these sort of clumps that are poisonous to nerve cells.

Meryl Comer:  And yet recent research has indicated that people who age well do have the beta amyloid in their systems.  Is that correct?

Dr. Gandy:  Well so the other side of the issue is how susceptible one’s brain is or one’s nerve cells are to amyloid poisoning.  It’s clear that there are people who have all the pathology, all the pathological hallmarks of Alzheimer’s disease on the day that they die, but they are not demented. So it’s clear that they have resisted that poisoning, that toxicity from the amyloid.

Meryl Comer:  Dr. Troncoso.

Dr. Troncoso:  Yeah, I think that is a very good point.  In fact, the work that I've done in the lab in recent years have focused precisely on that issue.  Fortunately I've been able to work with the Baltimore Longitudinal Study of Aging conducting autopsies in patients who some of them are perfectly normal, others ones who have dementia. And in examining the brains of those individuals who were normal has been very surprising to us that a substantial number have a severe amount of the same lesions that Dr. Gandy was mentioning, plaques and tangles. And we have begun to examine and trying to find out what may be the difference.  Why are they resilient to the disease? And we have found already some changes.  For instance, some of these subjects, part of the brain, some of the nerve cells, are larger. So there is an element of compensation that allows some subjects that have the disease, that have these abnormal proteins, to be resilient at least for awhile.  We don’t know if they’re going to be resilient 20 years down the road.

Meryl Comer:  Let me just ask you about that and let’s talk about the human dynamic.  Many people, smart people hide out in this disease a long time, because I understand it the hippocampus goes into overdrive and they fight harder and harder to keep up.  Is that what you’re describing from a human side or...?

Dr. Troncoso:  It’s the equivalent.  This concept that you can resist the disease is being identified from many angles, like different men touching an elephant.  There is information from the imaging, from functional imaging that individuals that as they get older, engage more brain regions to accomplish the same task, but they are able to accomplish the task.  You can find where you put your keys or your checkbook.  You may need to use more brain though for that.  There is imaging studies that show that the hippocampus in these individuals who are able to resist the disease are larger, so there is evidence from many different perspectives that some individuals are able to resist the disease and if we can identify what are the mechanisms to do that it may contribute to prevent or to alleviate the disease.

Meryl Comer:  Dr. Gandy, yes. 

Dr. Gandy:  There is actually conversation in both directions.  The synapses and the signals control how much amyloid is made and in turn, as Dr. Arancio has shown, the amyloid itself can control the excitability of the nerve terminal of the synapse. So there is a very important conversation and the normal physiology of that conversation is very poorly understood.

Amyloid buildup in the brain is a key trigger for Alzheimer’s, but some people with this plaque live their entire lives without developing the disease.

Videos
  • A huge segment of America's population — the Baby Boom generation — is aging and will live longer than any American generation in history.
  • The story we read about in the news? Their drain on social services like Social Security and Medicare.
  • But increased longevity is a cause for celebration, says Ashton Applewhite, not doom and gloom.


After death, you’re aware that you’ve died, say scientists

Some evidence attributes a certain neurological phenomenon to a near death experience.

Credit: Petr Kratochvil. PublicDomainPictures.net.
Surprising Science

Time of death is considered when a person has gone into cardiac arrest. This is the cessation of the electrical impulse that drive the heartbeat. As a result, the heart locks up. The moment the heart stops is considered time of death. But does death overtake our mind immediately afterward or does it slowly creep in?

Keep reading Show less

Yale scientists restore brain function to 32 clinically dead pigs

Researchers hope the technology will further our understanding of the brain, but lawmakers may not be ready for the ethical challenges.

Still from John Stephenson's 1999 rendition of Animal Farm.
Surprising Science
  • 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. Think a dialysis machine for the mind. 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.