Big Think Panel Discussion on Alzheimer's Disease
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: I am Meryl Comer, president of the Geoffrey Beene Foundation Alzheimer’s Initiative. Welcome to Breakthroughs: Alzheimer’s, the first in a three part video series on the major diseases of our time, Alzheimer’s, autism, and cancer. This Breakthrough's series produced by Big Think and made possible by Pfizer focuses on cutting edge medical innovations in our effort to fight disease. In the US alone a new Alzheimer’s case is diagnosed every 70 seconds. 5.3 million people have Alzheimer’s and it is already now the 6th leading cause of death. By 2050, up to 16 million Americans will have this disease and a new case will be diagnosed every 33 seconds.
After years of slow gains, recent research into Alzheimer’s is unlocking its underlying causes and this has brought up the potential for new ways to diagnose, treat and possibly prevent and cure Alzheimer’s, but as of now these remain largely unrealized.
Four of the world’s leading Alzheimer’s researchers have joined me today for our discussion. At the far end of the table Dr. Sam Gandy, associate director of the Mount Sinai Alzheimer’s Disease Research Center in New York City. Next to him, Dr. Juan Troncoso, director of the Brain Resource Center at Johns Hopkins University School of Medicine. He is professor of pathology and neurology. Next, Dr. Octovio Arancio, professor of pathology and cell biology at Columbia University. And, next to me, Dr. Leonard Guarente, director of the Glenn Lab for Science of Aging at MIT.
Before we begin, I want you to know that I have a very personal interest in Alzheimer’s. Sixteen years ago my physician/researcher husband was diagnosed with early-onset Alzheimer’s at age 58 after having been misdiagnosed for over two years. I've been his at-home caregiver throughout and more recently with my 90-year-old mother with late onset dementia who lives with us as well. There are 10 million unpaid caregivers just like me taking care of loved ones, which is why research into disease modifying therapies deserves our support and attention, so let’s get on with the conversation.
What is Alzheimer’s?
Meryl Comer: I'm going to give you a statistic that will be bothersome to most of us: January 1st, 2011, boomers will begin turning 65 every 8 seconds, 10,000 a day, 4 million a year, what does that say to you Dr. Guarente?
Dr. Guarente: Well that says we have a big problem on our hands and the problem is diseases of aging, diseases where aging is a major component of the onset of the disease and I would say Alzheimer’s is number one on the list of diseases of aging and we really have to worry about it.
Meryl Comer: Dr. Gandy, can you put that in perspective of prevalence and what is the risk when you turn 65 and take us forward?
Dr. Gandy: Well the current prevalence is about 6 million in the United States alone. At age 65 the risk becomes about 10%, but by age 85 half of the population at that age and older have Alzheimer’s disease.
Meryl Comer: And the pathology, does it start then? Has it been in our systems? What is the progression? What is the pathology?
Dr. Gandy: Well the pathology is really a couple of things that have been discovered over the past 30 or 40 years. The first pathology that was identified really was a biochemical pathology, a deficit in a transmitter, a chemical that nerve cells use to talk to each other and the currently available drugs all target that sort of molecular pathology. More recently we’ve studied the buildup of proteins, substances that are normally present in the brain and function happily for 50, 60 years... but for reasons that we often don’t understand these proteins change their shape, clump and accumulate and buildup and kill the nerve cells of the brain.
Meryl Comer: Dr. Arancio, you’re an expert in synaptic dysfunction. What is going on in that disconnect?
Dr. Arancio: It’s I think that synaptic disfunction is the key to everything. The concept is more than 100 years old, that memory occurs in normal conditions when we are normal where the synapses become stronger. And really about 100 years ago this nobel Prize winner from Spain. He just wrote down that dementia occurs when the strengthening of synapses no longer works well, so I think it’s the key to understand the mystery of this disease.
Meryl Comer: Dr. Troncoso, the area, your specialty is frontal temporal dementias, Parkinson’s, Huntington. In most of those diseases it goes hand in hand with dementia-related issues. Can you tell us what the connection is?
Dr. Troncoso: Sure. I think that first of all we should have like a definition. Dementia is a clinical term. It means that you lose certain cognitive abilities that you have attained previously and then there are many diseases that can lead to dementia as the ones that you mentioned now—frontal temporal dementia for instance can cause dementia. Some patients with Parkinson’s disease eventually can develop dementia and, more importantly, vascular diseases, strokes also can either cause or contribute to dementia. And I think that when we talk about Alzheimer’s disease in terms of the pathology we should be aware that not everybody has Alzheimer’s disease by itself. In fact, most patients with Alzheimer’s disease do have some what we call co-morbidity, a second disease and the most common of the co-morbidities is vascular diseases, so patients have both Alzheimer’s and strokes and together then they lead to dementia.
Meryl Comer: And from a family perspective the management issues are the same. It’s just complicated because there are two diseases versus one disease.
Dr. Troncoso: Exactly, from the standpoint of the caretaker it is probably the same, but I think from the perspective of a health provider it is not the same, because in the case of vascular disease there is an element of treatment. It is.... you can prevent at least some of the vascular disease. For instance, if you prevent hypertension, which is something that can be done fairly easily, you actually prevent at least in some cases the development of dementia.
Race, Gender and Alzheimer's
Meryl Comer: The Shriver report just came out, Dr. Gandy, and it indicates that women are more at risk for the disease. I mean statistically we outlive men, but we’re more prone to it and researchers don’t seem to know why, but they’ve mentioned post-menopausal. Can you help us out with that?
Dr. Gandy: Well the relationship with hormones has been postulated for many years and part of that has to do with... you asked earlier about when the disease begins and it seems to begin in mid-life. Mid-life risk factors like hypertension, obesity all seem to increase the risk for Alzheimer’s, but the pathology, the buildup of these abnormal proteins, doesn’t occur over the entire lifespan. You can live until 40 or even 50 with absolutely zero pathology in your brain. These structures begin to build up for reasons we don’t understand beginning in the 50s, the 40s and the 50s, and accumulate thereafter. That is very similar to the time when menopause and andropause, the male equivalent, both occur. And so that coincidence has sparked a lot of interest to understand if that is the under... if the hormonal changes underlie are sort of the trigger that determine the midlife turn towards Alzheimer’s disease.
Meryl Comer: What about ethnicity? When you look at diabetes, Dr. Troncoso, is the African-American population more predisposed to Alzheimer’s issues, Hispanic populations.
Dr. Troncoso: There has been a lot of actually misunderstanding. I looked specifically at the issue of African-American Americans because the literature tells us that there... African-Americans have a higher index of dementia. But there is several caveats. The first caveat is the instruments that are being used to test the subject may not be appropriate. People may have a different cultural background. They may have different education, so those tests are, in many ways, suspect and on the other hand African-Americans tend to have more vascular disease, so that may be a contributing factor to dementia and then I decided to look to this issue on my own and we have looked at the Alzheimer’s relations, the work that Dr. Gandy was mentioning at plaques and tangles in African-Americans and whites, and as he was saying these lesions start fairly early on in the late 50s, early 60s, but they’re similar in terms of their incidence and their frequency in African-Americans and whites. We didn’t find any difference.
Why Some People Get Alzheimer’s and Others Don’t
Meryl Comer: Now when you study longevity, Dr. Guarante you’re 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.
Can Head Trauma Cause Alzheimer's?
Meryl Comer: And to this conversation what happens now where we have young men returning from war with concussions and post-traumatic stress syndrome that is accelerating the dementia? How, as scientists, do you look at that phenomena and relate it to this conversation?
Dr. Gandy: Well I think this now gets into the area of head trauma. One of the most robust environmental risk factors ever identified and most consistently identified for Alzheimer’s disease is head injury. And this is now having repercussions for all of the vets returning from OEF and IEF, from Iraq and Afghanistan. Traumatic brain injury is considered the signature injury of these wars. And the TBI, the traumatic brain injury, can be manifest as post-traumatic stress disorder, so there is a very close interaction between the two.
Meryl Comer: Dr. Arancio.
Dr. Arancio: Yeah, for instance, is what is called dementia pugilistica or boxer’s and it is one of the major problems for these people. It’s a big, big problem, so there must be something happening in the brain and since [...] synapses are most likely the synapses that breaks because of this trauma. It could be a big trauma, even in small traumas they can do that and then the synapse, which normally... because, one thing we have to think of this material that we think that we know they are toxic, but they are there in the brain since the time in which we are born and... in small amounts. However, something happens in the disease and this balance, the communication within cells is broken and there is an accumulation of this material.
Meryl Comer: When that communication is broken, is the outward manifestation in people with Alzheimer’s there is a constant repetition. It’s almost like they’re lost in time and the language is repetitive. There is certain elements that become repetitive behaviors.
Dr. Arancio: It’s even more subtle than that. It’s very, very subtle. It’s what you just said before, when people try to overcome, to compensate. That is what they are doing at that stage. It’s just when you are already... have more advanced stages already it’s...
Meryl Comer: Yes, Dr. Gandy.
Dr. Gandy: So one of the really sort of more frightening things that we’re beginning to be confronted with is whether Alzheimer’s might sometimes be a pediatric disease. Head trauma has now been identified to be sort of... occurs in two types. There can be sort of a single severe incident and that leads to Alzheimer’s disease, can increase the risk for Alzheimer’s disease. There is also another entity, another disease called chronic traumatic encephalopathy, which is like boxers, in which they have multiple repetitive head injuries. Within the past six months, the first collegiate football player committed suicide was found to have chronic traumatic encephalopathy. So clearly he began to suffer the ravages of this head injury due to football in high school. Just last week a study from Perdue using magnetic resonance imaging to look at the function of the brain shows that not only are the people who have clinical concussions at risk, but the rest of the team also has subtle deficits in their imaging and in the cognitive function.
Will Everyone Get Alzheimer’s If They Live Long Enough?
Meryl Comer: From a population perspective, 85-plus is the fastest-growing segment of the population. Now can we assume that everyone who lives long enough will get Alzheimer’s, Dr. Guarente?
Dr. Guarente: Well I don’t think we know for sure, but my guess would be that the answer is no and I base that on the fact that there is a population of people now called centenarians, who are people who live to be 100 and longer, and many of these people are in quite good health physically and mentally and have evidently escaped from all of the major diseases, including Alzheimer’s. Now, that said, I think it’s certainly true that many, many people, maybe most people would get Alzheimer’s. So from a societal point of view I think the answer is most people would be vulnerable, but from a scientific point of view I think there might be people who are just so resistant to these diseases, including Alzheimer’s that they would escape it.
Meryl Comer: Dr. Gandy, 85, 1 out of 2 gets the disease. Do you want to comment further on that?
Dr. Gandy: Well there are a handful of people who live to 120, so then they’ve been characterized neuro-psychologically near the time of death and then studied pathologically and it’s possible for some people with the right genes to live to 120 and be cognitively intact and have absolutely clean brains, have no Alzheimer’s pathology.
Meryl Comer: But let’s...
Dr. Arancio: Maybe even live to be 150.
Dr. Gandy: It’s possible if everyone lived to 150 then everyone would get Alzheimer’s disease, but 120 is not the 100%. It may even be 99%, but it’s not 100%.
Meryl Comer: Well let’s help our audience move along a progression from mild cognitive impairment and that trajectory that takes you to Alzheimer’s, which is just the most common form of dementia. Can you help us, take us down that road?
Dr. Gandy: Mild cognitive impairment is really the first sort of syndrome that neurologists will diagnose that might be related to Alzheimer’s disease. Mild cognitive impairment usually means there is a problem with memory and it may be isolated to just memory and if it’s called mild cognitive impairment or MCI, by the abbreviation, it usually implies that the person’s normal function is not impaired, so that they can compensate for it and continue to do their normal tasks in their regular lives. The prognosis of mild cognitive impairment has long been sort of a mystery because it was some people seem to live through MCI and never get Alzheimer’s disease while some actually went on from MCI to progress to dementia, which was usually Alzheimer’s disease. We now we learned just this past summer that there are spinal fluid tests that might be able to help us predict which people with MCI are on their way to Alzheimer’s disease.
Meryl Comer: But the majority of people in assisted living facilities today, 60% have MCI that put them in there in the first place. What's their trajectory onto Alzheimer’s?
Dr. Gandy: Well without this sort of spinal fluid evidence we can’t really predict. That is part of why the Food and Drug Administration hasn’t allowed us to use MCI as a diagnosis because the prognosis of MCI as a group is unknown. Some people stay unchanged. Some get worse. Some get better.
Dr. Arancio: It’s about 18% every 2 years that go from MCI to Alzheimer’s.
Meryl Comer: And what happens with your patients with Parkinson’s plus dementia? Does Alzheimer’s or dementia come at the end of the disease like Parkinson’s or frontal lobe...?
Dr. Troncoso: Well in the case of Parkinson’s disease, from a clinical perspective once that individual has had probably 8, 10 years of the disease is at high risk of having some sort of dementia, which is actually different from the Alzheimer’s disease. It’s not the same type of manifestation. It’s not so problem with memory for instance, but it’s a difficulty in getting tasks performed. Kind of they are very slow in performing tasks. Having said that the substrate, the reason why patients with Parkinson’s disease have dementia is not clear. Furthermore, because these are diseases of aging many patients that have Parkinson’s disease also have Alzheimer’s disease, and probably both disorders add their lesions to render the patient demented. That is why it would be very important perhaps to slow down the aging process. You would kill two birds with one stone. You would actually prevent both Parkinson’s and Alzheimer’s disease.
Dr. Guarente: It would be more than two because we all have vulnerabilities and resistances and if we are resistant to one thing we’re going to be sensitive to something else.
Dr. Troncoso: Exactly.
Dr. Guerente: Aging is going to cause something bad to happen.
The Brain Plaques and Tangles That Cause Alzheimer’s
Meryl Comer: The mainstream research has been focused on beta amyloid. Tau has always been there, but now there is a big controversy about where the progression comes, where does it really lie? Take that debate on Dr. Gandy.
Dr. Gandy: Well certainly people with Alzheimer’s disease have two sorts of lesions in their brains, two sorts of clumps of protein. Some of these clumps are in between nerve cells, and others are inside nerve cells. The ones that are in between the nerve cells are called amyloid plaques. The clumps that are inside the nerve cells, which are twisted, are called tangles or neurofibrillary tangles. Now for many years we didn’t sort of know what the sequence of events was, but it is very clear now that all the genes that cause Alzheimer’s disease point to the buildup of amyloid. So it appears that Alzheimer’s disease amyloid comes first and tangles come next. They may be extremely important in understanding why the nerve cell dies. Now the disease that Dr. Troncoso mentioned, frontal temporal dementia, has also helped us to understand the relationship between plaques and tangles because in that disease the mutations that cause the genetic forms are in the protein called tau that builds up and causes tangles. People with frontal temporal dementia get tangles, but they never get plaques, so in Alzheimer’s disease plagues can cause tangles, but in frontal temporal dementia tangles don’t cause plaques.
Meryl Comer: Well why is it so hard these days to get a grant from NIA around beta amyloid when you can get it for tau?
Dr. Gandy: Well so there is a specific reason for that that’s really evolved a lot in the last year. There is a study that was reported this spring that showed using an antibody, a chemical aimed at the amyloid substance... that if people with mild Alzheimer’s disease received antibody infusions, anti-amyloid infusions, for a year and a half that the amyloid buildup in their brains would go down by about 25%. They didn’t change at all clinically. They didn’t get any better in terms of their cognitive function. Why is that? Because we didn’t start early enough, because we didn’t treat long enough or because it’s actually another form of amyloid, not the plaques, but these floating clumps called oligomers?
Meryl Comer: You wanted to make a point, yes, doctor.
Dr. Troncoso: Yeah well, I think that there is a lot of debate between the amyloid and tau deposition, but I think one should not get stopped at that point of that argument because it’s perfectly possible that one of these abnormalities, let’s say amyloid may trigger the rest and there is more than amyloid and tau. We haven’t spoken, but there is a very significant inflammatory, inflammation in the brain that once you have perhaps amyloid and tau trigger that event it becomes self-sufficient. It actually may even promote more amyloid or more tau deposition, so I think that tau it may be as important as amyloid, but it may be later on in this progression of the disease. And if you could actually target each of these elements it probably would be beneficial. So I don’t see really a tremendous dichotomy, antagonism between looking at amyloid and tau. I think that both are perfectly legitimate targets of research and one more perhaps disgression in terms of the dementia that is being seen in patients who have head trauma. Most of that, the lesions that they have is of the tau type, so I think both of these targets amyloid and tau should be addressed. There is no reason to eliminate one of them.
Dr. Gandy: There is the one experiment to mention that might also explain why the shift sort of toward tau. A lot of what we’ve learned about Alzheimer’s disease is from mouse models. Mice normally never ever get Alzheimer’s disease because their amyloid is different enough that it doesn’t clump and build up. If we then put into a mouse the gene for amyloid and with a mutation that would cause it to build up and the gene for tau so that it will get tangles, then as that animal ages it will get buildup of plaques and tangles just like, similar to humans with Alzheimer’s disease. They will then lose their ability to find their way around their cage or to find their way around a swim maze. If you then treat them with a drug or substance that will decrease the levels of tau, will lower the tau down, the cognitive function comes back, so it’s possible to sort of render the amyloid inert if you can turn down the tau at least in the mouse model.
Is Alzheimer’s Disease Genetic?
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.
Is Alzheimer’s Infectious, and Is a Vaccine Possible?
Meryl Comer: For the general public the other issue is, is Alzheimer’s infectious? What would...
Dr. Arancio: My take on it is that it might be, but wait a second. It’s not that I'm thinking it’s like a flu and you might get infected. However, we were talking before at tau protein. There is common work and showing that actually it could spread within the brain just like prion disease, the same way, so it starts from one area and then it spreads all over the brain, so it’s not infection in the sense that we understand normal get infected, but it could once it is initiated in a certain part of the brain there is the possibility. It’s not 100% sure, but there are people now we’re starting to see that there is this spreading within the brain, because this tau protein comes out of the cells and spreads to the next cells and then from one area and goes all over the brain and so the disease it’s classical normal... these plaques. They start from a part of the brain and what we call the temporal lobe an then goes from the lobe. At very end it just goes to the occipital lobe, which is where we see, so from this point of view there could, although it has not been totally demonstrated, but there are some people that are following along this path.
Meryl Comer: Dr. Gandy?
Dr. Gandy: I think for classical thoughts about infections I mean like epidemics of flu I would not put Alzheimer’s disease in that category. Back in the 80s a neurologist and scientist and NIH, Carlton Gatacheck and colleague Joe Gibbs tried very, very hard to transmit extracts... use extracts from human Alzheimer’s disease to give the disease to monkeys and they never ever saw any evidence that could be the case.
Meryl Comer: To Dr. Arancio. Dr. Arancio, is a vaccination possible?
Dr. Arancio: All the attempts that are done so far have failed, which does not mean that they will not work in the future. Indeed a very good amount of research in terms of treatment research done on this, on finding a vaccine. Then one thing that we should also know is that there are two kinds of vaccines. One kind of vaccine is what we call "active vaccination," which would be just the same thing that we do with the flu, so you take vaccine and you’re protected for a certain number of years in your life... of your life. In this case one would think about prevention of using vaccine to prevent the disease. There is also what they call passive vaccinations, which will be more short time [...] vaccine. Instead of giving, trying to prompt the body to make what you call the antibodies against the for instance beta amyloid, we give just the antibody that they have a short life. We have to say though that so far all the attempts to fix the problem have failed, but like all the others anyway. That’s what we’re facing, but it could be... it is for sure an interesting avenue to pursue. It would be great if at that time of birth or very short afterward if there were a vaccine, an active vaccination and that will protect us at the very end, but we have to be very careful there too because if for instance what do we vaccinate against? If we vaccinate against A-beta, which is this beta amyloid and if it has some normal function through our life it then could be a negative. We could get also negative effect.
Meryl Comer: For those who know the ravages or have watched the ravages of Alzheimer’s disease in a family, the notion that it might be reversible... Dr. Guarente?
Dr. Guarente: Is it possible?
Meryl Comer: Is it possible?
Dr. Guarente: Well I do get asked that question a lot more broadly about aging: "Is it possible?" And my belief in general is to think that almost anything is possible okay, where science is concerned. Now I do think that at the moment all the research effort is focused on slowing down Alzheimer’s, slowing down aging, slowing down the buildup of and the progression of what is happening in the brain and I think that is the way it has to start because I think we have to be able to do that as a prelude to doing anything more. Now if we can get to effective drugs that can slow the progression of Alzheimer’s and maybe even arrest the deterioration, then I think ultimately, yes, it’s possible. You can imagine replacing neurons that have died by stimulating division of stem cell, neuronal stem cells, and things of that sort, so I think, yes, it’s possible, but I think the way I organize my thoughts on this is first we have to think about the disease and how do we stop it. How do we stop the buildup of damage and how do we arrest it and then we can really... that might give us the space to think about can we actually reverse it and I would give the same kind of answer about aging.
Can Broccoli and B-Vitamins Prevent Alzheimer’s?
Meryl Comer: Just slowing the progression for five years for families builds quality of life, but from a societal point of view saves billions and billions of dollars. Let’s look at the notion of maintaining your brain so you don’t get it. Dr. Gandy, a 15-member panel of experts at the National Institute of Health reported: forget the crossword puzzles, forget the exercise, forget learning French, none of it is going to help. How do you respond to that?
Dr. Gandy: Well I don’t think they quite said it that negatively. What they said was that we currently don’t have sufficient evidence to guide therapy, to guide doctors to tell their patients: yes, take six ounces of broccoli, do the crossword puzzle on Wednesday and Friday and then you run four days a week. The challenge with all these lifestyle issues is that they have to be evaluated with what are called randomized clinical trials, the way a drug is evaluated. And the challenge is turning crossword puzzles and broccoli into drugs. And that is really the challenge for all of us. We think that there are benefits there, but we don’t have the evidence yet and getting the evidence is not easy.
Meryl Comer: Let’s go quickly through some of these. B vitamins, large doses are supposed to reduce the rate of brain shrinkage by half.
Dr. Troncoso: Well I think that the case of B vitamins that have many targets. It is possible they may work for Alzheimer’s disease. We don’t know that. But clearly it has probably some very good affect in the protein metabolism preventing vascular disease, so it may be that it is good, but the point is that it’s not... it hasn’t been demonstrated that it effectively prevents Alzheimer’s disease. It may prevent some brain shrinkage as determined by imaging, but... and I think that this committee that you were quoting there they really they were negative just for being negative. One of the important points is to protect actually the patients and caretakers from individuals or systems that may try to start commercializing puzzles for Alzheimer’s disease or this medication. We don’t want people to have false expectations, at the same time spend tremendous amount of monies in useless treatments.
Meryl Comer: Well one good example of that is 110 million dollars spent annually by Americans on ginkgo biloba and a 30-million-dollar study saying it doesn’t work, so that is one of the challenges. How about the latest study that just was released in the Wall Street Journal about smoking in your 50s doubles your rate of acquiring Alzheimer’s?
Dr. Gandy: Yeah, that sort of what the study shows, and I think there were no obvious flaws in the study that anyone has picked out so far, looking to see if it looks authentic. Obviously all studies, like all experiments, must be replicated by someone to prove that they are true. I mean the most important thing about the smoking paper though is that that is a modifiable factor. Head injury is difficult to modify unless you’re going to wear a helmet and never engage in any activities that are risky—basically don’t leave your house. But the smoking is modifiable.
Meryl Comer: You wanted to make a point?
Dr. Troncoso: I think that many of these risk factors that have been implicated like being in good physical shape, smoking, they all may in the long term contribute and are positive, but there is not a clear guarantee. There is other factors that have become... is demonstrated. For instance, education. So, it’s very clear that if individuals that have longer years of education have some degree of protection compared with the ones that don’t. In fact, we have examined that in a particular study, the Nun Study. It’s very clear that in those subjects the issue of environment is really reduced to minimum. We could clearly see that the nuns that had a longer period of education had less risk of Alzheimer’s disease than the ones that were not, so there are many factors that usually apply in early life that can either increase or decrease the risk for Alzheimer’s disease.
Dr. Guarente: I've always been intrigued by the Nun Study and I wonder to what extent does that represent a sort of a reserve that people have who have had a lot of education and use their brains a lot and as opposed to really protecting at the level of individual neurons and the tissue itself?
Dr. Troncoso: What I can tell you is that when we looked at the group of nuns that had asymptomatic AD compared with the ones that had dementia, the number of those nuns that were in... that had graduate education it was significantly higher than the other ones. It was really an amazing difference.
Dr. Gandy: But as compelling as those data are they’ve still not randomized clinical trials, which is what we need to use to recommend to people what they can do. I mean it’s difficult to tell people in their 50s that they should have gone to graduate school.
Meryl Comer: Exercise, exercise, exercise, that is a prophylactic for many diseases, or proposed. Now the study comes out that walking a mile increases your gray matter. Why should I worry about gray matter in the brain?
Dr. Arancio: The philosophy behind it would be that if you exercise you increase the gray matter, the communication between the cells and strengthen the synapse, and build up the brain just like a muscle and that would help the time... during that time when there is damage to the brain, so you have more reserve to the brain. That could be the philosophy behind it, but with all of this what you have said and that is what Sam was saying, we should take everything being very cautious because none of these things vitamin, exercise, wine, et cetera have so far showed to have solved the problem. The fact is that people still get Alzheimer’s. Millions of people have it and we have not solved it. So it’s unlikely that any of these things that we have so far seen alone will have such a striking affect to solve the disease.
Would You Want to Know If You’ll Get Alzheimer’s?
Meryl Comer: We’re in a world of genomics. James Watson who co-discovered the double-helix structure of DNA had his genome mapped and was only the second to have done it. The cost has come down considerably. I think it was a million dollars to have it done when he had it done. But he told Big Think that the one and only thing he didn’t want to know was his risk for Alzheimer’s. Now do you think he made the right choice?
Dr. Troncoso: I think the team might have not found anything. The question is do you want to know whether you are high risk for Alzheimer’s disease. I think it is a very personal decision. Some people may not want to do it. Others who are very practical for planning reasons may want to do it, but with the understanding that unless it is in one of these families, the 3%, you know. In the rest of the population there is not a single marker that can tell you for sure they will have Alzheimer’s disease, even the most important one APOE you can have APOE4 alleles and you can still escape the disease. So it may be important for some people. They want to plan their life, yeah, why not? But if you don’t want to do it I won’t blame you.
Meryl Comer: In terms of full disclosure about whether or not you want to know if you can’t treat for a disease like Alzheimer’s: I had the test. I wanted to know for life planning. Did you want to know? Do you know?
Dr. Guarente: No, my feeling is I would like to know about risk for any disease that can be treated, but for a disease for which there is really no treatment I would rather not know.
Dr. Arancio: I don’t know and I don’t think it is important, partially for the same reason that he has said. And the second thing he has said, what if I find out before I have two copies of APOE4? I also know that doesn’t mean that I have developed necessarily disease and what if I know that I am the good apple and not the [...] or the [...]? It does not mean that I have not developed the disease.
Dr. Troncoso: I haven’t had a full genetic screening, but I do know my APOE, just at serendipity we needed blood when we started doing it in the lab. I gave a sample and that is what I know and it’s okay, but I don’t have you know. I didn’t do it because I wanted to know whether I would get Alzheimer’s disease. Even if I knew that I have the E4 allele, that doesn’t mean high risk, but there is no certainty.
Meryl Comer: Dr. Gandy?
Dr. Gandy: I don’t know. I tend to plan for the worst anyway, so planning I think I'm going to cover anyway. I think the issue is whether one is ready to deal with that information psychologically, and I've never felt that I really wanted to have that thing sort of hanging around.
Dr. Troncoso: There is one more twist to this. It has to do with your children, so the question is if for some reason you’re going to have a child and you may want to know whether you have a gene that will increase the risk in them. That would be the other situation which I would think about it.
Recorded on October 29, 2010
The team caught a glimpse of a process that takes 18,000,000,000,000,000,000,000 years.
- In Italy, a team of scientists is using a highly sophisticated detector to hunt for dark matter.
- The team observed an ultra-rare particle interaction that reveals the half-life of a xenon-124 atom to be 18 sextillion years.
- The half-life of a process is how long it takes for half of the radioactive nuclei present in a sample to decay.
The controversial herbicide is everywhere, apparently.
- U.S. PIRG tested 20 beers and wines, including organics, and found Roundup's active ingredient in almost all of them.
- A jury on August 2018 awarded a non-Hodgkin's lymphoma victim $289 million in Roundup damages.
- Bayer/Monsanto says Roundup is totally safe. Others disagree.
One victim can break our hearts. Remember the image of the young Syrian boy discovered dead on a beach in Turkey in 2015? Donations to relief agencies soared after that image went viral. However, we feel less compassion as the number of victims grows. Are we incapable of feeling compassion for large groups of people who suffer a tragedy, such as an earthquake or the recent Sri Lanka Easter bombings? Of course not, but the truth is we aren't as compassionate as we'd like to believe, because of a paradox of large numbers. Why is this?
Compassion is a product of our sociality as primates. In his book, The Expanding Circle: Ethics, Evolution, and Moral Progress, Peter Singer states, "Human beings are social animals. We were social before we were human." Mr. Singer goes on to say, "We can be sure that we restrained our behavior toward our fellows before we were rational human beings. Social life requires some degree of restraint. A social grouping cannot stay together if its members make frequent and unrestrained attacks on one another."
Attacks on ingroups can come from forces of nature as well. In this light, compassion is a form of expressed empathy to demonstrate camaraderie.
Yet even after hundreds of centuries of evolution, when tragedy strikes beyond our community, our compassion wanes as the number of displaced, injured, and dead mounts.
The drop-off in commiseration has been termed the collapse of compassion. The term has also been defined in The Oxford Handbook of Compassion Science: ". . . people tend to feel and act less compassionately for multiple suffering victims than for a single suffering victim."
That the drop-off happens has been widely documented, but at what point this phenomenon happens remains unclear. One paper, written by Paul Slovic and Daniel Västfjäll, sets out a simple formula, ". . . where the emotion or affective feeling is greatest at N =1 but begins to fade at N = 2 and collapses at some higher value of N that becomes simply 'a statistic.'"
The ambiguity of "some higher value" is curious. That value may relate to Dunbar's Number, a theory developed by British anthropologist, Robin Dunbar. His research centers on communal groups of primates that evolved to support and care for larger and larger groups as their brains (our brains) expanded in capacity. Dunbar's is the number of people with whom we can maintain a stable relationship — approximately 150.
Some back story
Professor Robin Dunbar of the University of Oxford has published considerable research on anthropology and evolutionary psychology. His work is informed by anthropology, sociology and psychology. Dunbar's Number is a cognitive boundary, one we are likely incapable of breaching. The number is based around two notions; that brain size in primates correlates with the size of the social groups they live among and that these groups in human primates are relative to communal numbers set deep in our evolutionary past. In simpler terms, 150 is about the maximum number of people with whom we can identify with, interact with, care about, and work to protect. Dunbar's Number falls along a logorithmic continuum, beginning with the smallest, most emotionally connected group of five, then expanding outward in multiples of three: 5, 15, 50, 150. The numbers in these concentric circles are affected by multiple variables, including the closeness and size of immediate and extended families, along with the greater cognitive capacity of some individuals to maintain stable relationships with larger than normal group sizes. In other words, folks with more cerebral candlepower can engage with larger groups. Those with lesser cognitive powers, smaller groups.
The number that triggers "compassion collapse" might be different for individuals, but I think it may begin to unravel along the continuum of Dunbar's relatable 150. We can commiserate with 5 to 15 to 150 people because upon those numbers, we can overlay names and faces of people we know: our families, friends and coworkers, the members of our clan. In addition, from an evolutionary perspective, that number is important. We needed to care if bands of our clan were being harmed by raids, disaster, or disease, because our survival depended on the group staying intact. Our brains developed the capacity to care for the entirety of the group but not beyond it. Beyond our ingroup was an outgroup that may have competed with us for food and safety and it served us no practical purpose to feel sad that something awful had happened to them, only to learn the lessons so as to apply them for our own survival, e.g., don't swim with hippos.
Imagine losing 10 family members in a house fire. Now instead, lose 10 neighbors, 10 from a nearby town, 10 from Belgium, 10 from Vietnam 10 years ago. One could almost feel the emotion ebbing as the sentence drew to a close.
There are two other important factors which contribute to the softening of our compassion: proximity and time. While enjoying lunch in Santa Fe, we can discuss the death toll in the French revolution with no emotional response but might be nauseated to discuss three children lost in a recent car crash around the corner. Conflict journalists attempt to bridge these geotemporal lapses but have long struggled to ignite compassion in their home audience for far-flung tragedies, Being a witness to carnage is an immense stressor, but the impact diminishes across the airwaves as the kilometers pile up.
A Dunbar Correlation
Where is the inflection point at which people become statistics? Can we find that number? In what way might that inflection point be influenced by the Dunbar 150?
"Yes, the Dunbar number seems relevant here," said Gad Saad, PhD., the evolutionary behavioral scientist from the John Molson School of Business at Concordia University, Montreal, in an email correspondence. Saad also recommended Singer's work.
I also went to the wellspring. I asked Professor Dunbar by email if he thought 150 was a reasonable inflection point for moving from compassion into statistics. He graciously responded, lightly edited for space.
Professor Dunbar's response:
"The short answer is that I have no idea, but what you suggest is perfect sense. . . . One-hundred and fifty is the inflection point between the individuals we can empathize with because we have personal relationships with them and those with whom we don't have personalized relationships. There is, however, also another inflection point at 1,500 (the typical size of tribes in hunter-gatherer societies) which defines the limit set by the number of faces we can put names to. After 1,500, they are all completely anonymous."
I asked Dunbar if he knows of or suspects a neurophysiological aspect to the point where we simply lose the capacity to manage our compassion:
"These limits are underpinned by the size of key bits of the brain (mainly the frontal lobes, but not wholly). There are a number of studies showing this, both across primate species and within humans."
In his literature, Professor Dunbar presents two reasons why his number stands at 150, despite the ubiquity of social networking: the first is time — investing our time in a relationship is limited by the number of hours we have available to us in a given week. The second is our brain capacity measured in primates by our brain volume.
Friendship, kinship and limitations
"We devote around 40 percent of our available social time to our 5 most intimate friends and relations," Dunbar has written, "(the subset of individuals on whom we rely the most) and the remaining 60 percent in progressively decreasing amounts to the other 145."
These brain functions are costly, in terms of time, energy and emotion. Dunbar states, "There is extensive evidence, for example, to suggest that network size has significant effects on health and well-being, including morbidity and mortality, recovery from illness, cognitive function, and even willingness to adopt healthy lifestyles." This suggests that we devote so much energy to our own network that caring about a larger number may be too demanding.
"These differences in functionality may well reflect the role of mentalizing competencies. The optimal group size for a task may depend on the extent to which the group members have to be able to empathize with the beliefs and intentions of other members so as to coordinate closely…" This neocortical-to-community model carries over to compassion for others, whether in or out of our social network. Time constrains all human activity, including time to feel.
As Dunbar writes in The Anatomy of Friendship, "Friendship is the single most important factor influencing our health, well-being, and happiness. Creating and maintaining friendships is, however, extremely costly, in terms of both the time that has to be invested and the cognitive mechanisms that underpin them. Nonetheless, personal social networks exhibit many constancies, notably in their size and their hierarchical structuring." Our mental capacity may be the primary reason we feel less empathy and compassion for larger groups; we simply don't have the cerebral apparatus to manage their plights. "Part of friendship is the act of mentalizing, or mentally envisioning the landscape of another's mind. Cognitively, this process is extraordinarily taxing, and as such, intimate conversations seem to be capped at about four people before they break down and form smaller conversational groups. If the conversation involves speculating about an absent person's mental state (e.g., gossiping), then the cap is three — which is also a number that Shakespeare's plays respect."
We cannot mentalize what is going on in the minds of people in our groups much beyond our inner circle, so it stands to reason we cannot do it for large groups separated from us by geotemporal lapses.
In a paper, C. Daryl Cameron and Keith B. Payne state, "Some researchers have suggested that [compassion collapse] happens because emotions are not triggered by aggregates. We provide evidence for an alternative account. People expect the needs of large groups to be potentially overwhelming, and, as a result, they engage in emotion regulation to prevent themselves from experiencing overwhelming levels of emotion. Because groups are more likely than individuals to elicit emotion regulation, people feel less for groups than for individuals."
This argument seems to imply that we have more control over diminishing compassion than not. To say, "people expect the needs of large groups to be potentially overwhelming" suggests we consciously consider what that caring could entail and back away from it, or that we become aware that we are reaching and an endpoint of compassion and begin to purposely shift the framing of the incident from one that is personal to one that is statistical. The authors offer an alternative hypothesis to the notion that emotions are not triggered by aggregates, by attempting to show that we regulate our emotional response as the number of victims becomes perceived to be overwhelming. However, in the real world, for example, large death tolls are not brought to us one victim at a time. We are told, about a devastating event, then react viscerally.
If we don't begin to express our emotions consciously, then the process must be subconscious, and that number could have evolved to where it is now innate.
Gray matter matters
One of Dunbar's most salient points is that brain capacity influences social networks. In his paper, The Social Brain, he writes: "Path analysis suggests that there is a specific causal relationship in which the volume of a key prefrontal cortex subregion (or subregions) determines an individual's mentalizing skills, and these skills in turn determine the size of his or her social network."
It's not only the size of the brain but in fact, mentalizing recruits different regions for ingroup empathy. The Stanford Center for Compassion and Altruism Research and Education published a study of the brain regions activated when showing empathy for strangers in which the authors stated, "Interestingly, in brain imaging studies of mentalizing, participants recruit more dorsal portions of the medial prefrontal cortex (dMPFC; BA 8/9) when mentalizing about strangers, whereas they recruit more ventral regions of the medial prefrontal cortex (BA 10), similar to the MPFC activation reported in the current study, when mentalizing about close others with whom participants experience self-other overlap."⁷
It's possible the region of the brain that activates to help an ingroup member evolved for good reason, survival of the group. Other regions may have begun to expand as those smaller tribal groups expanded into larger societies.
There is an eclectic list of reasons why compassion may collapse, irrespective of sheer numbers:
(1) Manner: How the news is presented affects viewer framing. In her book, European Foreign Conflict Reporting: A Comparative Analysis of Public News, Emma Heywood explores how tragedies and war are offered to the viewers, which can elicit greater or lesser compassionate responses. "Techniques, which could raise compassion amongst the viewers, and which prevail on New at Ten, are disregarded, allowing the victims to remain unfamiliar and dissociated from the viewer. This approach does not encourage viewers to engage with the sufferers, rather releases them from any responsibility to participate emotionally. Instead compassion values are sidelined and potential opportunities to dwell on victim coverage are replaced by images of fighting and violence."
(2) Ethnicity. How relatable are the victims? Although it can be argued that people in western countries would feel a lesser degree of compassion for victims of a bombing in Karachi, that doesn't mean people in countries near Pakistan wouldn't feel compassion for the Karachi victims at a level comparable to what westerners might feel about a bombing in Toronto. Distance has a role to play in this dynamic as much as in the sound evolutionary data that demonstrate a need for us to both recognize and empathize with people who look like our communal entity. It's not racism; it's tribalism. We are simply not evolved from massive heterogeneous cultures. As evolving humans, we're still working it all out. It's a survival mechanism that developed over millennia that we now struggle with as we fine tune our trust for others.
In the end
Think of compassion collapse on a grid, with compassion represented in the Y axis and the number of victims running along the X. As the number of victims increases beyond one, our level of compassion is expected to rise. Setting aside other variables that may raise compassion (proximity, familiarity etc.), the level continues to rise until, for some reason, it begins to fall precipitously.
Is it because we've become aware of being overwhelmed or because we have reached max-capacity neuron load? Dunbar's Number seems a reasonable place to look for a tipping point.
Professor Dunbar has referred to the limits of friendship as a "budgeting problem." We simply don't have the time to manage a bigger group of friends. Our compassion for the plight of strangers may drop of at a number equivalent to the number of people with who we can be friends, a number to which we unconsciously relate. Whether or not we solve this intellectual question, it remains a curious fact that the larger a tragedy is, the more likely human faces are to become faceless numbers.
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