THURSDAY, June 24, 2004

Session 2: Aging, Dementia, and the Person: Clinical, Neurological, and Existential Perspectives on Alzheimer/Dementia

Dennis J. Selkoe, M.D., Vincent and Stella Coates Professor of Neurologic Diseases, Harvard Medical School, and Director, Center for Neurologic Diseases, Brigham and Women's Hospital

David Shenk, author, "The Forgetting: Alzheimer’s: Portrait of an Epidemic"

CHAIRMAN KASS:  Could we get started, please?

In this second session of the morning we turn from aging and society in general to Alzheimer's Disease, its scientific, clinical and existential aspects.  And just as we had this morning, the attempt to treat aging both as an external phenomena and its societal wide implications and aging as the kind of life-long journey in search of meaning, so in this session we have a kind of dual perspective that we both need and require. On the one hand the recognition of this disease, which Paul McHugh calls the curse for which we need to understand its scientific foundation in the hope that clinically speaking we will be able to do vastly more by way of prevention and remedy.  At the same time we need to understand the people who are afflicted and what it means for them to have this experience and also what it means for all of those around them who interact with them.

And to help take our bearings in this dual project we're really very fortunate to have our two guests this morning.  Dr. Dennis Selkoe who is Professor of Neurologic Diseases at the Harvard Medical School and the Director of the Center for Neurologic Disease at Brigham and Women's Hospital and who is really one of the nation's leading researchers and educators on the medical/scientific side on Alzheimer's Disease.

And second David Shenk, who is a journalist and author whose absolutely magnificent book The Forgetting:  Alzheimer's, A Portrait of an Epidemic is probably, if I may say so, after President Reagan's letter, the single piece of writing that is done more to publicize and to put this particular subject and problem, on the national agenda.  The film for television that was made from this book, perhaps even more than the book itself.

Thank you both for taking time out of your busy lives to come and join us this morning.

I think as before if the Council won't mind, we can have the presentations back-to-back, though if there are technical things having to do with Dr. Selkoe's presentation, perhaps we should have those clarified before we go on.

Dr. Selkoe, please.

DR. SELKOE:  Thank you. Thank you, Dr. Kass.  I'm delighted to be here. I appreciate being invited to tell you the latest word on a saga that has absorbed me for about a quarter century now. This is my wedding anniversary and my wife reminded me on the way out the door this morning, she was actually up at 6:00, that you've been struggling with this disease, hopefully not personally although sometimes I wonder if she thinks so, for a long time and you still haven't got it licked. At the same time she told me to be home at 6:00 for dinner.  So I'm not sure about that mixed message, but we as a community are pushing ahead to try to prevent Alzheimer's ultimately and to understand it at its root cause.

So I think this is a sophisticated audience, and I will move fairly quickly, but I'll be delighted to have you stop me when things are unclear or something is controversial, which is part of the fun of this.

What I have been asked to do by your colleagues who organized today's meeting is to give you a snapshot of the biology of this disease, also it's clinical aspects in brief. And I'm delighted to share the podium with David Shenk who will tell you so much more than I can even about the human and societal impact of this disorder.  So I am going to stick to its natural history and digress only briefly about its impact on the society.

Now, if you'll look at the screen, I'm going to show you what in many ways I think is the essence of Alzheimer's Disease, sort of the central problem here.  And it's one of my favorite images.  It's a cartoon of a synapse that is firing away, providing electrochemical information from an axon at the bottom there to a large cell body at the top.  And this goes fine during life until you see what happens right in front of your eyes:  That the axon goes cold.  And in this situation we can freeze it, but in our brains we of course cannot. 

And at this moment in time we envisioned that a synapse in the hippocampus of a patient with Alzheimer's Disease no longer is releasing transmitter.  The most famous transmitter we associate with the disease is acetylcholine, but that's not the only one as you'll see in a moment.

And at its essence, I think Alzheimer's Disease is a synaptic failure and that certain synapses, certainly not all, can no longer release information from one neuron to the next.  And over time an axon like this will die and this asystematic synapse will degenerate and, indeed, the soma, the cell body, will ultimately die as well, if enough such axons are lost.

So we'd like to know why that nice bright flash of blue energy no longer is transmitted in this disorder. And if we allow this to continue, we all know what happens; everything goes dark.

Now, in the case of Alzheimer's Disease, we know this is the most common cause of dementia. The numbers are imprecise.  We often hear the term, the number 4 million, 4.5 million I've seen it said now.  I don't think we know precisely, but it's probably in the range of 2 to 4 million.  If that's true, then epidemiological evidence from other nations suggest that there should be 15 to 20 million and perhaps more likely 30 million worldwide that are afflicted not with dementia, but with Alzheimer's Disease.

Americans of African, Asian and European descent have rather closely similar prevalences of Alzheimer's Disease.  And this has been shown by door-to-door surveys; going in rural Mississippi, knocking on doors, not just obviously relying on who comes to the health care practitioner.

The disease is enormously expensive.  Probably I've had 100 billion on my slide for some years, so I'm sure the number is higher. These are imprecise estimates from the Public Health Service, Society for Neuroscience and others.  And I will not, sadly, announce today a cure or effective treatment, but I will point strongly at the end of my remarks to the possibility that we have one virtually in hand.

So quickly, some current concepts for this audience that knows these well.  Senile dementia or senility as we heard in the last session is a term used by the general public that can be defined as progressive mental failure and particularly after age 65.  And that's an arbitrary definition really coming from the Social Security Administration. And before that I understand from Otto Bismark, who understood when it was that he should institute a health care for the elderly, that was the year that they mostly died, age 65.  So ever since that time we've separated pre-senile dementia, which was what Alzheimer was writing about in 1906, from senile dementia, after 65.  But it isn't a bimodal process.  It's a continuum, and so we shouldn't think of Alzheimer's Disease anymore, of course, as a rare pre-senile dementia.

Alzheimer's is the most common of more than 20 causes, it accounts for roughly two-thirds of dementia cases in the U.S.  Again, the numbers are imprecise.  The disease begins very insidiously, usually with decreased memory and a general sense of confusion.  The rest happens slowly over 5 to 20 years. It is fatal. Sometimes that surprises people, but it shortens life expectancy by one- to two-thirds compared to someone of the same age who didn't get Alzheimer's Disease, if other things are taken into account. And, of course, the reason it's fatal is because like neurological disease, there's so much debilitation at the end of the life that the patient cannot move and really take care of their bodily needs, or they aspirate, they get a little bit of pneumonia and they succumb.  And most patients die of pulmonary complications.  Most of my patients, I've been following patients for about a quarter century, some of these patients die primarily at nighttime when they're unattended.

So the cardinal symptoms of the disease, I think, are very familiar.  Progressive loss of memory, recent more than distant, and the most striking early alteration is just not to remember a trivial event of everyday life that happened hours or days earlier; a trip to the store to buy a blouse, a phone call from a grandchild or even something more trivial than that, just doesn't stick.  And you repeat yourself, you don't recall that such a little event occurred.

There's disorientation to date, to time, to place. You just don't know quite where you are in everyday  life.

There's decreased executive function in everyday tasks; making a cup of coffee, shaving and other kinds of tasks.  Usually if we get into more complex tasks, then those examples such as repairing something, etcetera, the spouse will notice that the other member of the couple can no longer do this.

There's a decreased geographic sense.  A number of my patients have gotten lost.  Get into the car. Drive from Dedham to Newton, Massachusetts to get their hair done and end up in Albany, New York. It's a real example of a patient of mine.  And then eventually returned to their home base. They wander.

There is difficulty comprehending and reasoning about especially complex material at first.  There's an emotional ability, a paranoia in some patients and a social inappropriateness that sadly comes into the picture.

And all of these things don't happen necessarily in this area.  They can vary greatly, and they don't all need to happen.

There's impaired language, word finding difficulty in particular and eventually a picture of aphasia or dysphasia.

And all of this occurs in the absence of motor abnormalities until much later in the course.

This is the picture in many sense of Alzheimer's Disease in its early and moderate stages.

Now, the physicians of the audience, and I think many of you otherwise know that there is a complex differential diagnosis of late life dementia.  The first three disorders listed on this slide are the most common we think of in American society; Alzheimer's Disease, vascular or multi-infarct dementia and Parkinson's Disease, which is increasingly recognized as bringing dementia with it but not at the beginning.  Usually it starts with a movement disorder.

The next three disorders are less common but beginning to be known by the general public.  Frontotemporal dementia including a division called Pick's disease.  Diffused Lewy body dementia or just Lewy body dementia.  And the Creutzfeld-Jacob Disease which is, of course, a unusual prion encephalopathy likened to Mad Cow Disease and its variant in humans in Britain.

So there are many other disorders not listed here, but just as a snapshot we try to distinguish these in the clinic, but we don't have an acid test.  We don't have a simple laboratory marker that we can order up and say oh you have Lewy body dementia, it turns out not to be Alzheimer's Disease.  It's a clinical judgment.

Now the defining characteristics of the disease as we move into the biology now and into the pathology, are the following:

The amyloid plaques and neurofibullary tangles that Alzheimer first described, an inflation in the brain represented at the level by microglia activation and reactive astrocytes in the brain. Of course, a selected neuronal degeneration.  But beyond the lost of neurons, per se, there's this synaptic loss that my cartoon attempted to illustrate.  And the synaptic loss must explain the multiple neurotransmitter deficits that I won't read off for you, but only one of which, acetylcholine is addressed by an FDA approved treatment at present.  There is actually a second FDA approved treatment that many of you know, which I'll mention in a moment, a glutamate antagonist called memantine. But ironically, it doesn't actually address the point on this slide which are the deficits in glutamate that occur in the disease.

And the same time that there are deficits, there appear to be some inappropriate release of excess glutamate as a potential toxin, and therefore memantine would block that. But memantine does nothing about the fact that before that the patient has lost glutamaturgic neurons.

This is a patient whom I followed during life. A 69-year-old gentleman when he died. He was a stockbroker, he developed the disease at age 60 with a positive family history.  In the amygdala of the brain, very important for behavioral control, there were these spherical deposits of amyloid beta protein, so called amyloid plaques.  And the plaque on the left is ringed by dystrophic axons and dendrites, so it would be called a neuritic plaque.  On the right there are also dystrophic dendrites quite bulbous and enlarged, but they're not quite symmetrically arranged as they are on the left.  So these are two examples of these so-called amyloid or neuritic plaques.

Adjacent are these neurofibrillary tangles which are silver positive massive of filaments.  And you notice in the lower right hand corner of this section there are cells that are cytologically normal.  Even though my patient had 9 years of clinical disease and very likely had maybe 18 or 27 years of disease in toto.  So even at the end of life some cells are spared. And we do not understand why this selective vulnerability.  But the same could be said for Huntington's Disease, amyotrophic lateral sclerosis, etcetera.

Here's stepping back from the microscope and looking at a lower power view.  There are just enormous numbers of these amyloid plaques and neurofibrillary tangles.  The two that you saw in the last view are somewhere in here. I'm not sure which two they are. But as we step back you see more and more of these.  And they really focus on the areas you'd expect them to, that is important areas for memory for cognition.

Another image, one that has therapeutic implications is that in the amyloid plaque, and it's shown in the brown amyloid staining here, the active angry looking cells I would call them in the foreground are microglial cells.  The macrophage monocyte-derived cells in the brain that produce cytokines, etcetera.  And in this imagine there is a ring of reactive astrocytes, almost appearing to wall of the plaque.  This is inflammation, at least a brain style of inflammation. And it suggests the possibility that folks who take things like Motrin, Advil, ibuprofen and things like that. So it may have a lower likelihood of developing Alzheimer's Disease for this very reason, although we don't know that for sure.  So what I'm telling you is that epidemiologically there is evidence that certain NSAIDS (Non-steroidal anti-inflammatory drugs) taken over the counter nowadays might retard the likelihood of developing Alzheimer's Disease.  We don't know if it's because they help the process you're seeing on the screen.

Now, a few statistics.  I'm a biologist, I think, and a neurologist, but I can't fail to mention that in 1997 the prevalence was estimated at 2.32 million in the United States. In this particular publication the range was large, 68 percent of the patients were estimated to be women, 32 percent estimated to be men. I can't give you a precise answer about exactly why that is, why the gender disparity but I have some thoughts about it if we have time later on.

At age 75 it is said, and these are very precise numbers based on a pretty good study in my opinion, 4.3 percent of folks in the United States have the condition we call Alzheimer's Disease.  At age 80 that rises to 8.5 percent, 85 16 percent, age 90 28.5 percent have the diagnoses that experts call Alzheimer's Disease. Not dementia or not any of the other disorders that we're speaking of.

Incidence, 360,000 new cases per year. The range is very broad.  By 2050 this figure may rise threefold to 1.14 million per cases per year in the U.S. alone.  By 2050 the prevalence may rise 3.7 fold to 8.64 million from the current prevalence that I mentioned above of 2.32 million. But the range is enormous again.  Very hard to estimate.  All of this, of course, predicated on no meaningful treatment beyond what we can prescribe today.

An intervention that delays mean age of onset by five years, which has been likened by the risk calculators to about a 50 percent risk reduction, would reduce expected prevalence by 1.2 million after just ten years if that intervention was on hand, and reduce it by 4 million after 50 years; that is by 2050.

And one that delays onset by two years or so, it slows the course of the disease and makes it a little bit later, that would reduce expected prevalence by 600,000 in the United States after 10 years, 2 million after 50 years.

These are some curves that show the striking rise in prevalence of mild, moderate to severe and total Alzheimer's Disease by one set of data.

Public costs are enormous.  2010 Medicare costs, you know these numbers perhaps, they rise 54 percent from the current figure of 31.9 billion in 2000 to 49.3 billion.   These are Medicare costs.

In Medicaid expenditures, primarily for residential care of dementia.  In fact, this figure is exclusively for residential care of dementia in patients who otherwise do not have physical support for this, may rise 80 percent  to 33 billion.

At present the public sector, from what I read, is estimated to finance a small portion of Alzheimer's Disease care, 13 percent for community outpatient care and 34 percent for institutional care.

And then the remainder is the cost putatively to employers or to the private sector. U.S. businesses are said to bear costs in these ranges.  So for example, business costs for workers or caregivers of people with Alzheimer's putatively costs employers 26 billion going to 36 billion in 2002 according to these earlier data. Business costs for health care and health care research for people with Alzheimer's Disease borne by employers, maybe up to 24 billion.  The total business costs 61 billion.

These numbers then add to the governmental costs to give a figure upwards of 100 billion annually.

And the last statistic I'll bore you with or share with you is this set of graphs comparing the prevalence of mild disease, which is in the darker symbols, and moderate plus severe disease grouped together in the lighter symbols if no treatment becomes available over the next five decades.  So these are the kinds of prevalence numbers going up to 10 billion or maybe 15 billion if nothing intervenes.  The second set of bar graphs is if you had therapeutic that delays onset of the disease by maybe 6 or 7 years.  Then you'd still have the same spread of mild versus moderate to severe, but the total numbers would be done.

This third set of graphs is if you had a treatment that delayed disease progression.  Onset occurred still in the 60s and 70s but it didn't go as quickly. So you had more mild cases as compared to the total. But the total cases would ultimately accrue to similar levels. And this is the case that I think will actually occur.  And the rosiest scenario that you have both delay disease onset and a slower progression so that both mild cases occupy more of the total population and the total numbers are lower.

So let's return to the biology.  Current medications I was asked to speak of briefly.  Symptomatic drugs are the acetylcholine inhibitors.  You see there are brand names here, which is how the public generally speaks of them.  The new glutamate antagonist, just one of these approved by the FDA in January or it came on the market in January, Namenda or memantine.  Behavior modifiers of course, anti-psychoticsm tranquilizers, anti-depressant and a variety of other agents that potentially help with the very difficult behavioral symptoms that my families tell me are the most difficult part of this far beyond the memory impairment.

Potentially disease swelling agents that are currently available include antioxidants.  Most of my patients take vitamin E, 1000 or 2000 units a day. Perhaps anti-inflammatories either because they reduce the inflammatory cells in the brain or perhaps because they actually interfere with the amyloid problem that I'm going to explain to you in a moment.  And maybe cholesterol lowering drugs have some beneficial effect. But we're not ready actually to say this in a more public forum than this one, that is I can't write that anti-inflammatories and cholesterol lowering drugs should be taken by patients in America universally because they have plenty of bad side effects. And I don't know for sure that they slow Alzheimer's Disease.  Sometimes I use them anecdotally in patients whom I think I can follow very closely.

I think this is pretty much it.  This slide summarizes the principle therapies we have available.

So let's talk about the biology.  The diagnostic regions of the disease are those that Alzheimer described.  So this is sort of an operational definition of Alzheimer's Disease.  The condition contains neurofibrillary tangles inside neurons that are composed of altered forms of a particular protein called tau.  Whereas the amyloid plaques, which are really outside cells and between the cells are composed of 40 and 42 amino acid long amyloid beta-protein, so named by George Plenner who I think will be viewed ultimately as a sage in this field.  Sadly he died of another amyloid disease of the heart some time after he discovered the amyloid beta protein in 1984.

Now Alzheimer's Disease is one of a family of diseases potentially, and this isn't a terribly exciting slide for people like myself who study regeneration, it may mean less to this audience. But the point is it looks like diseases like Parkinson's Disease, ALS, Creutzfeld-Jacob Disease and Huntington's disease have a common thread with Alzheimer's in that there is a misfolding of a normally well folded protein and it aggregates in lesions in neurons. And without going into further detail, the details are not really critical here, it looks like things we learn about how amyloid beta protein or tua protein misfolds in Alzheimer's may help us with understanding Parkinson's and ALS.

Now this image is a bit of shocker.  This is a section of frontal cortex from a patient.  And the bottom of the slide, which is devoid of these brown lesions is the white matter of the brain.  Everything above where my cursor is now is the gray matter of the brain.  In simple terms thinking area of the brain.  And these are a zillion amyloid plaques.

This patient was 12 when he died.  So this is remarkable.  It is only one human condition which leads that leads to such an profound Alzheimer's like picture, and I think a number of you know what it is, it is Down's Syndrome.  So it turns out that this has been in an enormously powerful clue to biologists that being born with an extra copy of chromosome number 21, and having three copies instead of two, brings not only the Down's Syndrome, but brings an almost invariant occurrence of Alzheimer's Disease, but already as early at the microscopic level as age 12.

This patient had he lived longer, if he had died from cardiac reasons unrelated to this pathology, would likely have experienced some fall back in his learning ability.  Although he was retarded from birth, he would have certainly been able to learn things. But at 20, 25 I suspect he would have not been able to get on the bus and go to a sheltered workshop and do what he wanted to do as well as he did when he was 15.

Now, what is this telling us?  It's telling us that the beta-amyloid precursor protein which gene is encoded on chromosome 21 almost certainly will turn out to be central to the pathogenesis of the condition we call Alzheimer's.  So I don't want to overwhelm you with a lot of biological gobbledegook but I will tell you that this molecule is the favored therapeutic target of biopharamaceutical companies worldwide right now.  I hope they don't have it wrong. I don't think they do personally.  If they are wrong, then I am big trouble for sure. But it appears that understanding how this molecule is handled by brain cells might lead us to treatments and ultimate prevention.

Why?  Because the amyloid beta-peptide is a small fragment embedded within a 770 amino-acid precursor protein.  It's a receptor like molecule, like the insulin receptor. This is inside a cytoplasmic tail.  This part waves in the breeze and it sticks on the outside of the cell.  There's a single transmembrane domain.  And in 1992 my lab discovered that there is a processing situation that goes on normally in all of us throughout life.  Beta-secretase cuts right at the beginning of the red box here, and that's followed by a enzyme called gamma-secretase in the middle of the transmembrane domain curiously popping out the amyloid beta-peptide.

It is just this peptide, this little red box, that makes up the myriad plaques in the patient's brain.  The rest of the protein is dispensed with, for whatever reason.  Of course this protein has a normal function, and I'm not going to speak about that today. It appears that its involvement in Alzheimer's Disease does not relate to its normal function, but relates to a so-called toxic gain of function when these enzymes make too much A-beta or something else goes wrong.

So I'll ask you to try to recall that beta-secretase and gamma-secretase are two naturally occurring enzymes in everyone's brain that dice up the amyloid precursor protein to release amyloid-beta.  And that happens in in-utero and beyond.

So this has given rise to hypothesis that Alzheimer's is a syndrome caused from a chronic imbalance between A-beta production and A-beta  clearance that leads to cerebral accumulation of A-beta, and particularly a 42 amino-acid form of A-beta called A-beta 42.  The imbalance we thought could be caused by numerous distinct genetic alternations and perhaps by environmental ones.  But if you ask me what you can do to protect yourself environmentally, there's nothing I can recommend with any clarity. 

Head trauma is a known environmental risk factor.  So I'll ask you not to go to go out and beat yourself on the head. But beyond that I can't tell you about a dietary factor or sun exposure. I can only tell you to choose your parents carefully. Beyond that, we really don't know much about environmental alterations.

Now this syndrome has been enormously controversial and it's made it to The Wall Street Journal recently where it's been said that those, like myself, who tout this hypothesis are squelching other areas of research. So we can debate that later on.  I'm not going to digress to talk about that, but Richard Hodes the Director of the NIA I think subsequently wrote an article to The Wall Street Journal saying that he has evidence that a large amount of taxpayers' dollars were spent on other theories besides this one.

So, as Schhopenhauer said, all truth passes through three stages.  First it is ridiculed.  Second it is violently opposed.  Third it is accepted as being self-evident.  We're not yet there with the amyloid hypothesis, but I'm beginning to feel a sense that perhaps this is now being accepted as oh, yes, well that's sort of obvious that this build up would be bad news for memory function.

The basis for saying that is based on this concept.  Studying rare forms of the disease, familial Alzheimer's, and understanding the genotype to phenotype relationships and in very brief summary, there are four chromosomes, four genes that the field agrees are predictive of getting Alzheimer's.  Three of these, the first, the third and the fourth are inherited as very aggressive dominant traits.  If you're born with one of these mutations, it's almost definite that you will develop Alzheimer's, and you will do in your 40s and 50s.

The second trait listed here is a so-called polymorphism.  That is, Apolipoprotein E comes in three variants in the human population, E-2, E-3, E-4 and Allen Roses at Duke University discovered with this colleagues in 1992 that inheriting Apolipo E-4 with one allele from mom, for example, or dad gives you a two to fivefold increased likelihood of Alzheimer's. If you inherit allele from both mom and dad you have a five to 15 fold greater likelihood of Alzheimer's than you do not have the E-4 allele in your genome.

So this became to my knowledge one of the very first examples of a natural polymorphism in our population, in the human population, that you could test for genetically.  But I think everyone in the field recommends against testing for this until we have a treatment. That way we could couple it with the message you have an E-4 allele.

Now, a different example is presenilin, which has been enormously instructive and there are mutations in presenilin, now 146 of them.  You see a few of them scattered in this diagram of presenilin, which winds its way in and out of a membrane eight times.

This mutation here, this cartoon mutation, represents a mutation that causes the most aggressive form of Alzheimer's known in the literature.  A young woman developed this at age 18 and died at age 33. So that is absolutely remarkable.

So mutations in this gene are extremely malignant in terms of causing Alzheimer's.  How do they do it?  My lab and several others have we think figured this out.  If you look closely at the sequence, amino-acid sequence of the presenilin molecule which winds its way in and out of the membrane eight times, and you enlarge this part of the molecule, there are two Ds, the single letter code for apartates in the middle of the sixth and seventh transmembrane domain.  What does this mean?  We did a bunch of experiments and so did others to suggest that these two Ds that are circled in red are crucial for presenilin when mutant to cause Alzheimer's Disease.  And the way they do that is shown here.  The 2 Ds or aspartates coordinate with APP.  And they actually represent the cutting machine that cuts APP  to release amyloid beta peptide.  This is the so-called gamma-secretase reaction, the second of the two cuts that I mentioned.

In a nutshell then, presenilin appears to be the long sought gamma-secretase.

Now, there's a very interesting biological problem with addressing gamma-secretase.  And that is that as Gary Sturhl and Iva Greenwald showed, if a presenilin molecule on the fly is knocked out or dysfunctional, the fly gets a very abnormal wing, the so-called notched wing.  And nerve cells and the nervous system of the fly are disordered. 

Now what's going on here is that presenilin is not only a bad guy leading to the most aggressive form of Alzheimer's, but presenilin is necessary for life. It's necessary for the development of the fly to have wild type wing rather than a notched wing.

In summary, presenilin shown in purple here uses its two intramembrane aspartates by the letter D to cleave a protein called notch.  Its name was given to it by a biologist many years ago because absence of notch function leads to a notched wing.  And so presenilin is necessary for notch to be cut in the membrane of the cell.  This part is released and does good things inside the cell, in the nucleus. This is necessary for life in all multicellular animals on the planet. And therefore this mechanism was conserved during evolution.  Unfortunately, an alternate substrate called amyloid precursor protein gets processed essentially identically to notch.  This doesn't seem to make much difference when many individuals or almost everyone died shortly after reproductive life. And only when this cleavage, which does occur throughout life and pops out the blue box here, the amyloid beta, when that accumulates over a lifetime, there is a risk of developing memory failure.

So from my perspective biologically I feel you're looking at why it is that Alzheimer's arose in the human population. Now we'll see if this turns out to be true. Only therapy with anti-amyloid drugs can prove this hypothesis.  But I think that you need this machinery for life, for sulfate determination in metazoans and a byproduct of it is that you also generate amyloid beta peptide throughout life, which didn't make much difference when most of us died in our 40s and 50s.

Now I won't go into further scientific detail.  If you produce A(Beta) at 1.2X compared to 1.0Xp normal and you degraded at 1.0X, you're going to accumulate it over life and it's going to aggregate, which is what it did in that Down's patient already at age 12 years.

We recently figured out what that aggregation does to brain cells, to memory cells.  We studied the aggregation of A(Beta) is a simple culture system. The black lines here represent the actual A(Beta) peptide, A(Beta) 42.  This is the main beta, but if you have a presenilin mutation in the cell, you make doublets and triplets and quadruplets of A(Beta). It starts to gum together.

We've taken advantage of this phenomenon in a simple cell and harvested the medium of these cells and injected them into rats. What happens is that the rats have trouble in a task we taught them.  We've taught the rats to press lever A two times, go to lever B and press it six times, return to lever A and press it ten times, go to lever B and press it 16 times according to the quadratic function X square minus X.  So these rats do algebra.  And if you give them a microinjection of the lateral-ventricle of the brain of this doublet/triplet rich form of A(Beta) from our cultured cells, they do what you see in the dark symbols. They make switching errors.  They switch to lever B too soon or they perseverate. They remain on lever A not too counts, but three counts or they remain there for 16 counts. They go all the way up, by the way, to whatever the number is, 56 I think it is, and then they do down by themselves down to two again.  They learn how to do that. So this is a very sophisticated tests designed by Jim Cleary and Karen Hsiao Ashe, my collaborators at the University of Minnesota.

If you give them the singlet of A(Beta), the monomer, there is no significant effect on switching or perserveration errors. 

Why do I tell you this?  Because I think it's evidence that this little peptide when it mounts up in doublets and triplets is trouble.  And this interferes with the memory of a learned behavior in the hippocampus of a rat.  Whether this does this in a human we simply don't know.

So let me summarize and tell you where we are therapeutically.  This cartoon illustrates one way of thinking about the Alzheimer's riddle.  That cells in the brain make the amyloid-beta peptide, which is simply diagrammed as little sheres here.  Blood cells make it.  Big neurons on the left make it.  And by the time that someone who is destined to get Alzheimer's Disease at 75 is 55, we suspect and there's evidence for this that there are these diffused plaques, cloud like amyloid-beta peptide clusters.  And an axon that happens to be passing in the vicinity here, and there are many axons of course in this vicinity at all times, is okay.  This is not just hallucination, but Brad Hyman at the Mass General Hospital is showing this kind of phenomonology by beautiful microscopic studies.  But if you fast forward 20 years the image looks like this. And again it's supported by electron and microscopic data. The plaque is more robust or larger, the amyloid-beta has aggregated into chain like structures, doublets, quadruplets, etcetera, that are probably trouble.  The microglial cells, which are inflammatory cells, move into the fray and an axon is now inflamed or damaged at this point.  It probably can't conduct information very well.  This is the synapse here that I cartooned in my first slide.

I want you to know that Bill Klunk at the University of Pittsburgh has been, I think, the first to publish the most striking images of actually seeing the amyloid in the brain of a living patient.  So here a control 75 year old woman, and here a woman with AD at the same age or similar age.  The red and yellow signal represents Klunk's ability to use Pittsburgh Compound-B to actually image her amyloid deposits in the brain.  You can't see them plaque by plaque, but you can see this total signal.  And the signal to noise ratio is better with his compound than the current best positron emitting dye that we use, fluorodeoxyglucose, which has been used for more than a decade.

So I'm very excited about his work in this regard. I have nothing to do with this research. And I think ultimately many of us will want to get an amyloid scan once this is fully validated and, of course, approved for general use.

So let me end by telling you where we stand on the treatment modalities, that is treatments beyond those I listed earlier, which were symptomatic.  These we hope will ultimately be disease modifying.

We would like to inhibit the A(Beta) generating enzymes, the beta and gamma-secretase.  And many pharmaceutical companies are working hard on those targets.  A gamma-secretase inhibitor has been tried by Eli Lilly Company in human trials and the results were announced in April. There were no spectacular results.  It was simply a short trial showing that amyloid protein levels fell in the blood, but they happen not to fall in the spinal fluid in that study.  So they need to go back and figure out why that was. My guess is because the drug didn't penetrate the brain sufficiently.  That's the only gamma-secretase trial in humans so far that's been discussed. I think actually both of these are good targets on theoretical grounds, and we'll see whether they can actually reduce amyloid and make a difference in the clinic.

This is the approach that has caught the attention of many people. It is the idea of actually vaccinating against Alzheimer's.  You give the amyloid-beta peptide by a shot a deltoid muscle. The patient makes antibodies and the antibodies circulate throughout the blood stream and some of them get into the brain. And I'll show you an image of that.

You could also inhibit the inflammatory process and interfere with the toxic response of neurons, but that may be too little too late.

So the amyloid vaccine, a work that I had nothing directly to do with, was pioneered by a fellow called Dale Shenk, and saline injection into mice that develop Alzheimer plaques.  Over six months that saline injection did nothing to prevent the amyloid build up. But injecting the amyloid-beta peptide, the molecule that I am today claiming is a principle bad guy in Alzheimer's, led to a dramatic clearing of these deposits in a mouse.  Many further studies were done, including with monkeys, and this entered human clinical trials.

There is good and bad news.  The good news shown here was that a patient who died for another reason, from a pulmonary embolus, had skipped areas in her brain where there the wall of amyloid plaques suddenly was interrupted.  And in another area of the brain, the only thing that was left were little microglial cells engulfing amyloid.  A very similar picture that was seen in the mouse model.

So it looked like amyloid was being cleared.  There are now five patients who have succumbed from natural causes post an amyloid vaccine trial.  And in each case, there have been these areas where there is less amyloid in the brain.

And the last slide is does this matter however clinically? This is a small subset of 30 subjects in particular published by colleagues from Zurich, Switzerland of a larger trial of 375 subjects.  The full data have not yet been released, but they're apparently going to be released on July 22nd in Philadelphia. But the data that's publicly known is that in these 30 subjects in this amyloid vaccine trial, if you develop no antibody, no rise in antibody levels in your blood, your mental status examine fell over the subsequent six months. If you developed an intermediate increase in antibodies, you didn't as much of as a fall.  If you a strong antibody titer there was essential no change in this commonly used test, MNSE where we ask, for example, to tell us your place of birth, your date of birth and to remember items.

And the accrual of cases of moderate to severe Alzheimer's Disease or patients remaining with mild disease didn't fall as much in the dark symbols than the patients who had strong antibody responses.

So, this is a complex riddle. I've given it perhaps more detail than you cared to hear, but an overview of the biology and clinical aspects of the disease.

We don't yet know where the leading hypothesis will turn out to bear fruit, but we do know that it's in clinical trials and patients have been enrolled. So probably this group should know in three years or two years whether this has merit or not.

Let me stop there and just hope that there's time, perhaps after David speaks, if there's any questions.

CHAIRMAN KASS:  Thank you.

Dan Foster?

DR. FOSTER:   Leon, could I just ask one technical question.

You didn't mention the possible target of the alpha-secretase here which will clip through the beta peptide there, did you, or maybe I missed it when it—

DR. SELKOE:  Right, I did not.

DR. FOSTER:  And I think there are sort of two advantages. I mean, I've tried to follow your work.  Not only would you then stop the production of the amyloid-beta peptide there, but that maybe the soluble remainder of the precursor protein supposedly has anti-protective effects that are not released when you use the beta gamma-secretase.  So I just wondered if you'd given up on the idea enhancement of the activity of the alpha-secretase, this—it's another peculiar enzyme.  It's called an atom enzyme. Could you just comment very briefly about that, because I thought that maybe you would focus on that more than you did about the immunization here.

DR. SELKOE:  You're absolutely right.  That is a very valid target and I didn't focus on it primarily in the interest of time because I felt I had said it and said enough. 

The alpha-secretase target has recently been validated in mice by over expressing alpha-secretase, atom 10 in particular, one of the atoms. And showing that you reduce the amount of plaques in the mouse's brain. Just like inhibiting beta-secretase and inhibiting gamma-secretase have also been shown to reduce plaques.  So your point is absolutely correct. 

The reason I haven't focused on that as much is because alpha-secretase activators are not as much in the forefront in the biopharamacutical industry and they're, after all, the ones who are going to do the chemical trials and deliver the therapeutics.

There are ways to do this in the lab, but chronically stimulating alpha-secretase to both cleave A(Beta) in the middle to prevent its production and to provide a protective effect, we wonder whether that will be readily achievable pharmaceutically and whether that will also have side effects to chronically stimulate alpha-secretase.  But I think there're ways of doing that, and I like that way of going about it.  And there's a very nice paper just out, The Journal of Clinical Investigation that suggests it's conceptually possible.

CHAIRMAN KASS:  Thank you very much.

David Shenk, good to have you with us.  We look forward to your presentation.

MR. SHENK:  Thank you.

This is a little awkward for me because Dr. Selkoe has just said what I was pretty much going to say.  A terrible overlap here.  No, I'm going to switch gears quite a bit.

Thank you.  It's such a honor to be here. I particularly want to thank Dr. Kass for his kindness in our conversations leading up to this conference.  And if my book has shed an ounce of light on the issues at hand for the people at this table, it is indeed a high honor and I would say a lifetime of satisfaction for a writer.   And I'll do what I can to contribute to today's conference.

Let me first put my expertise and training in context for you.  I have no expertise; I'm not an expert and I have no training.  I'm not a medical doctor, although I have been accused many times of having the handwriting skills of a doctor.  I am not a molecular biologist or a geneticist.  I can assure you that I did go to college; that's about it as far as training, high education.

It is the conceit of my work as a writer, as a generalist, that perhaps outsiders can also bring something to these highly complex discussions.  And sometimes maybe even add a little something that the insiders are a little too inside to notice.

I was dragged into this subject not by any family experience, but by a conversation I overheard about six years ago now over lunch.  And I don't want to spend too much time on it, but it was concerning a middle-aged couple in their 50s. The man was taking care of his wife who was in the middle stages of Alzheimer's Disease I would now recognize.  But she had gotten to the point where she didn't know who he was anymore.  And that single fact dragged me into the subject and has not let me go.  It just raised so many questions and I found in subsequent weeks and months that as I started to try to answer some of those questions, that many, many new questions popped up as a result.

And, of course, I do not want to take anything away from the insiders, the valuable specialists of this world starting with the amazing army of Alzheimer's researchers and scientists represented here by the extraordinary Dennis Selkoe.

When I first started this research I realized that there might be a book here.  I thought I would probably learn about scores of extraordinary scientists who were going to hopefully come along and rescue us from this disease. And I was so wrong about that.  There are thousands of these people.  It's really an incredible thing to witness the energy that is going into stopping this disease.  And I think Dr. Selkoe has helped to give us a glimpse of how enormous even slowing it down would be.  But if we were to stop it, just to give you a taste of this, in the next 50 years we're talking about tens of millions of lives worldwide who would be spared, and not billions as you've seen—as you've learned today, but trillions of dollars.

Now as important as these scientists are, there is another even larger group of heros to me in this story, and that is the caregivers.  And I'm speaking of the family caregivers and the professional caregivers, and the people who support that community. And they will be best represented in this next session, your next session, by Geri Hall.

I want to deliver what I see as a preamble to Dr. Hall's remarks at a very general level, not getting into too much detail. Geri Hall is one of the most knowledgeable people I know on the details of caregiving and the surrounding legal concerns.  So I'm going to provide an overview, hopefully in preparation for her remarks.  And I'm going to focus on five central challenges. I did not bring any slides.  I apologize.  Five central challenges that I think are highly relevant to your work as an ethics panel.

Number one, the slow fading away of the patient and the threats to dignity and self.

Number two, denial and avoidance by patients, family and friends.

Number three, the shifting nature of the disease.

Number four, how Alzheimer's Disease can mask and therefore complicate other medical problems.

And number five, Alzheimer's Disease is a wedge in already fractured and dysfunctional families driving them further apart and complicating care.

So now let me address each one of those concerns in a little bit of detail. And there's a lot of ground to cover, so I'll move rather quickly.

First to start with, the most well known characteristic of Alzheimer's Disease, the fading away.  The existential nature of this disease terrifies patient and family like no other.  We're talking about a condition that essentially erases the thinking part of the brain very slowly over the course of ten years time, although we've just learned that the biology of it actually starts quite a bit before that, leaving a physical shell of a person.

Let me very briefly give you a firsthand feel for what this is like. Throughout my presentation today I'm going to occasionally read remarks straight from caregivers that capture the spirit of this disease better than I ever could.  This first testimonial is from a caregiver living in Washington state.

"This was the second day of near total confusion for Ed. He was back pretending to drive the locomotives and imagining that I was one of the crew. I was asked to call the dispatcher and find out how to get back to Walla Walla. I drove him around town for two days to help him get his bearings. When he finally realized he was in Walla Walla, he was distressed at being so confused and told me he didn't know what he would do without me.  But then half a minute later he was back in a neighboring town or up in the mountains or who knows where.

Periodically he asked me what Arda was doing and if I heard from her and telling me what a special person she is to him. I am Arda.

This afternoon we went for a ride and then stopped for a bite to eat. Our bill was $13.00, which Ed insisted on paying. He pulled out two 50 dollar bills out of his wallet.  I told him I had the right change, so I took the bill and paid it. 

When we pulled up under the carport at home he said 'I'll wait here.  What are we stopping here for?'  He said he'd forgotten.

He's at least cheerful and relaxed, much like a little child waiting to be told what to do.  It could be worse."

Well, as many of you no doubt already know, it is often much, much worse. This is a very gentle dip into this world.

Caregivers are dealing simultaneously with the emotional pain of watching their spouse or parent fade away, trying to manage the immense confusion and frustration of the patient and the physical burden of having to make up for lost functioning 24 hours a day, 7 days a week.  Extreme stress is a guaranteed part of this job and caregiving itself quite often leads to clinical depression and other stress related health problems.

One desperate and ultimately unanswerable question that seems to constantly gnaw at caregivers is this:  How much is left inside that head?  What does he or she truly understand right now?  What can he still remember?

It's impossible to ever know for sure and even harder to keep up with since the disease is always progressing, always getting worse.

Two more aspects of the caregiver experience with respect to fading away:  A sense of deep humiliation which quite often first bears down on the patient.  The shame of fading away, the shame of not being able to do what they have been able to do for so long. And then that humiliation paradoxically passes to the caregiver.  The shame of having to take care, the shame of having to take care of someone who is losing themselves and, arguably, losing their dignity.

We're talking about a spouse or child who gradually has to take over their loved one's dressing, bathing and toilet functions:  Essentially having to treat this adult figure as a child.  This is obviously excruciating and exhausting.  And coupled with that is the issue of honesty, or more precisely as I learned in observing caregivers, talking to them, learning how important it is to not be honest.  After we've spent the first half or two-thirds of our lives trying to be honest at all moments, now is the time to learn to not be honest.  It's a lesson that every caregiver seems to experience early on.  And to illustrate this, here is a caregiver from New Hampshire speaking directly to that issue.

"I have really struggled with the honesty issue.  One thing that I have learned is that the best decision for me is not always the best decision for my mom. At first I decided that she should know just why we were having her stay with us when she was begging to go home. But she was in a strong denial and could not reason.  She became extremely angry and the entire family suffered from my honesty.  She suffered most of all.

"What do you say to someone who sits on her bed and says that she has never stayed out overnight without letting her parents know where she is?  What do you say to someone who thinks she is a teacher and if she doesn't get home or into her classroom, there will be a whole class of children left unattended? What do you say to someone who thinks she has no money to pay bills and will lose everything she owns if she doesn't get home to a job that you know she has been retired from for years?

"I couldn't find any reason for telling her over and over that she has a horrible, terrible degenerating disease that was making her feel the way she does.  I found as the days went on that she seemed to become less anxious if I tried to just listen and have empathy with what she was saying and feeling.  Sometimes saying nothing was better than anything I could say.  Telling her that I would take care of some of these things put her a bit more at ease.  It may have felt better for me to verbalize the facts, but comfort and security is what she really needed, not the truth about her having this darn disease. The truth won't change things for her in any way."

I'm going to move onto challenge number two now, denial and avoidance.  And as you can tell, these things overlap quite a bit.  This is just a way to organize my thoughts.

Alzheimer's Disease seems almost to beg those who come into contact with it to at first ignore it or deny it, or in some other way sweep it under a rug somewhere. This applies to patients, family members, friends, neighbors, even family doctors believe it or not.  I should say some family doctors, no disrespect to the ones here or to the many that truly do "get" this disease.

No one wants to be near this disease if it comes too close and our first impulse is often to deny.  I believe there are two parts to this phenomenon.  The first part is a rational response to a terrifying truth.  Everyone who has ever heard of Alzheimer's Disease is, rightly, terrified of this. I got into this business because I was terrified of it.  Because for those who are actually facing a diagnosis, it is overwhelming.  Psychologists will tell you that in certain instances denial is actually an extremely healthy psychological response.

Aside from the trauma of diagnosis, though, there is a part of this that goes way beyond the rational fear of Alzheimer's, and that is the stigma that is unfairly associated with this disease.  Friends and neighbors actively shun people after their diagnoses.  Caregivers will tell you over and over again how even close friends just vanished from the scene entirely, immediately and entirely.

Family members are afraid ashamed to use the word Alzheimer's.  To this day, ten years after Ronald Reagan's public announcement that he had been diagnosed, very few obituaries contain the words Alzheimer's  or dementia.  And as a recent illustration of this Estee Lauder, I don't know how many of you know this, died of Alzheimer's Disease.  She had it for quite some time.  She was very well cared for, obviously.  Her family has donated tens of millions of dollars to fighting this disease and are, obviously, to be commended for it.  But I just find it absolutely fascinating that when she died, they did apparently everything they could and successfully so to keep the words Alzheimer's and dementia out of her obituaries. It's virtually unknown that she had this disease.

I believe that this stigma, this taboo comes from a vast ignorance about what the disease actually is. Because it's in the brain and because you can't see it with your own two eyes, people get the impression that it's a mysterious mental failing or old people just going loopy.  People do not get that this is a disease, pure and simple.  Something is going wrong with the chemistry and biology in the brain, as we've just learned so much about.  Just like something goes wrong, although in a different way, just like something goes wrong in skin cancer or in diabetes or in heart disease.  And I would say we communicators have not done a very good job of explaining the basics that malignant protein fragments called plaques and tangles cause the disease by killing neurons and stopping synapses in certain specific regions of the brain.  It always starts in one region of the brain called the hippocampus which is responsible for the formation of new memories, which is what explains the early symptoms of the disease, and the plaques and tangles always very predictably travel to other regions of the brain so we can know what's going to happen.

I believe that if people understood the basic outlines of this disease, we could take back some, not all, of the power that this disease has over us.  And let me just add that this is my personal mission with regard to this disease.  And in my talks around the country this is how I see my small role as trying to help ordinary people understand the basics of this disease so we can get past the stigma.

Challenge number three, the shifting nature of the disease.  From the caregiver's perspective, Alzheimer's Disease is not one disease.  It is an exhausting ever changing storm.  Consider the trajectory of this illness.  You begin with someone who looks, sounds and feels normal except for the occasional strange memory lapse.  At the end of this disease, let's say five or ten or 15 years later—it varies quite a bit, the average is about 10 years—the patient cannot think, cannot move much and finally cannot swallow or breath.  In between there are a thousand subtractions.  Over months and years the ability to form new memories slowly deteriorates, the patient's facility with words shows signs of breaking down, math becomes a problem, tasks and chores become difficult.  So that's the beginning of the disease. So the family adjusts to this. They maybe get some help, perhaps shift work schedules around, make some plans.  But then the disease marches on.

Following instructions becomes impossible.  Conversations become difficult. Frustration and tempers rise.  Really a whole new set of symptoms. Again, the family adjusts to the new conditions and the disease keeps moving.

Older memories start blurring now.  Earlier it was just the ability to form new memories, now it's the connection with older memories.  Serious confusion and paranoia set in. The patient wakes in the middle of the night and wanders off down the street, an entirely new problem. Again, the family adjusts to new challenges which is a paradigm for them.

Some more time passes now.  Now the patient cannot get dressed by  herself and is incontinent.  Again, the family has to adjust.  A whole new set of physical burdens and emotional ones.

So you get my point. I've run out of words for how distressing this disease is, but it's worth noting that while any particular stage of Alzheimer's  is devastating in and of itself, and we would be here having plenty to talk about if it was just any one of these stages, the way it morphs from one condition into another is a challenge for even an energetic and well-trained caregiver.

Challenge number four, how Alzheimer's Disease can mask and therefore complicate other medical problems.  And I think we got a good taste of this this morning with the two presentations.

Let's say some 90 percent or so of Alzheimer's patients are over the age of 70.  And so it is a given that these people are going to have other serious medical issues to contend with. That leads to this question:  How do you detect, explore, diagnose, treat and monitor a medical condition in someone who cannot communicate very well or at all?  How can you treat a patient who can still experience pain and discomfort but can't discuss it and may not even be able to even vaguely understand what it is they're feeling?  Dementia masks and inevitably complicates every other potential, emotional or physical distress associated with old age.

To get a small feel for the complexity of this, consider a relative modest list of medications taken by one Alzheimer's patient which her caregiver allowed me to reprint in my book.  I'm sure I'll mispronounce some of these medications.  Propulsid, 20 milligrams twice a day.  K-Dur, 20 meq tab once a day.  Synthroid, .025 milligrams once a day.  Imdur, 30 milligrams once a day.  Procardia XL, 60 milligrams once a day.  Prilosec, 20 milligrams once a day.  Aspirin, 325 milligrams once a day.  Betagan eyedrops, 2 drops for each twice a day.  Transacon faracon once a day. Paxil, 30 milligrams once a day.  Nerontin, 10 milligrams once a day.  Nizoral cream, once a day.  Ditropan, five milligrams once a day.  Extra strength Tylenol, one a day.

As I said, I suspect this list is rather modest compared to some. Imagine a list twice as long with drugs that might be interfering with one another or causing a combination of unpleasant side effects.  Imagine all the ailments that go undetected in the first place or are misdiagnosed and subsequently mistreated thanks to all the confusion and miscommunication.

We in the Alzheimer's world are very often quick to point out the one saving grace of this disease, which is that it causes no direct pain.  And I'm very guilty of this.  While that is true, it arguably I think misses the point.  And I'm correcting myself here. I'm going to try to do better in my talks.  It's a simple fact that Alzheimer's frequently leads to needless pain and discomfort because of how the disease complicates every other aspect of care.

Finally, challenge number five.  Alzheimer's is a wedge in already fractured and dysfunctional families.  I know no one here has any kind of dysfunction in their family, so of course we're speaking of people outside the room.

Alzheimer's brings out the best in people, I should start by saying that.  In my six years in observing this world I have been continually impressed by the compassion, sacrifice, generosity and eloquence in the caregiver world.  Time and time again people of ordinary means with very limited resources truly rise to the occasion and exhibit a level of humanity that they probably didn't even know they were capable of, and that is no exaggeration.

It also brings out the worst in people.  Thieves, con artists and just slightly less than scrupulous car dealers, and other sales people, can easily, very easily take an Alzheimer's patient for their life savings.  Unscrupulous or vindictive family members can do the same, taking advantage of the confusion to divert funds or take over property.  Here is one brief statement to that effect from a caregiver in Kentucky.

"We've been trying for two weeks to stop my sister and brother-in-law from stealing and from moving into mom's house, which they have. I suppose we'll find out Monday if the legal system moves on her behalf. The bottom line to all this is that I have mom and she is safe, happy and in good physical condition.  To her this is home and she expresses her desire to remain with us all the time.

"This whole situation is so sad.  I loved my aunts and uncles and certainly loved my sisters.  That's loved in the past tense.  Greed on their part has destroyed my mother's family when she needed them the most.  If it weren't for my children and my husband, there would be little daily help with mom.  When the others failed to get control of her assets, suddenly no one sent cards, letters, called or tried to see her."

This sort of violent family implosion is all too frequent.  But that's really not the main point I want to make in this challenge. That's not what most people experience. In between the best and the worst if often, frankly, a fairly ugly middle ground. Extended family members who all mean well but who don't entirely trust one another or who are perhaps a little jealous of one another, or who live a thousand or 2,000 miles away and are finding it very hard to believe that things are really so bad.  One sibling living nearby reports that mom's memory is shot and she needs to be watched over constantly.  Another sibling living four states away says I just talked to her and she seemed fine.

In the early stages of Alzheimer's, patients can look and sound fine and appear in every other way normal.  They can also can leave the stove on and burn the house down.

Different siblings have very different interpretations of the situation. I cannot stress how common this is.  If a family has any underlying issues of resentment or mistrust before facing this disease, and what family doesn't, Alzheimer's is perfectly suited to exploit them.  Fundamental questions of home care, medical care and control over financial decisions can rip even fairly stable families apart.

I'd like to close my remarks today with a portion of an email I received recently from a daughter of an Alzheimer's patient who speaks to this issue and also more broadly, to the enormity of what Alzheimer's does to everyone in its path.  This is from Omaha, Nebraska.

"My grandfather was recently diagnosed with Alzheimer's. He's in the early stages.  Last month he had to close his carpet business, which he had owned for 50 years.  They had an auction, which was very difficult. I tried to convince the whole family that the point of his life's work was not the things that people were walking away with for pennies but to raise a family, to own a home, to see the world; he had all of this and more.  The end was just details.

He raised four daughters, three of which have raised their own families.  We all still live very close to each other. My grandmother is overwhelmed.  She chooses not to speak of this at all. My mother and her sisters are trying to make sense of it. They're helplessly fumbling for answers, for help, for a solution. I think they know there is no real solution.  They have told me privately that they expect a big blowup sometime soon since no one agrees with what the others are doing.

Life is happening, I think.  It has been happening and we've all been growing older but now it is really coming at us full force.  Does that make sense?  Thank you."

That's from, as I said, from a daughter of a patient in Omaha, Nebraska.

Thank you so much for inviting me here today, and I hope to have an interesting discussion from here.

CHAIRMAN KASS:  Thank you both very much.

Let me just open the floor for comments and questions.  Dan Foster, please.

DR. FOSTER:  I want to just make a couple of points.  Leon asked me as a physician to maybe add a point or two about taking care of these—I don't do anything like Dennis does, but I have been involved with academic people who have had early onset.  And I wanted to make just one point about this.

In the course, as we heard earlier, the worst thing is when people, the patients, know that they have it and before it becomes irrelevant to them. 

I recently had a member of our faculty who was involved with all of the early space involvement, all the human experiments in space. And he asked to see me urgently. And when he came in, he sat in the chair. He has these very blue eyes and looked at me, and just looked at me.  I said so-and-so what is it- I don't understand what you wanted to see me about. And he said nothing works anymore.  And I saw a single tear drop down his cheek.  He said I was diagnosed fully last week, as far as one can do clinically, with Alzheimer's Disease, they took away my medical license and said I couldn't drive anymore. And I came to ask you if I might have one favor from you.  And I said anything that I can do I will do. And he said can I keep my office.  He said I want to try to finish some papers that go on.  And I said of course you can keep your office and your wife can drive you in.

We had almost everybody from NASA, astronauts and so forth, came at a symposium for him. And he still comes in every day.

But the point I want to make more specifically in another case is that through this loss that occurs there is often times a strong quest to maintain the essence of what the person was.  And I want to tell a story just to end it very quickly with two ways.

Abraham Lincoln says "They tell me I tell many stories, and I reckon I do, but I've learned that for ordinary people telling stories is the best way to communicate."

And I want to just give you, because I might not remember it well, I want to tell you what I said at this person's funeral, just very briefly.  I said now to the core of his essence, he was a teacher. He thought that the highest calling was not research or clinical care, but teaching. I never asked him this, but if I had asked him to define what he was he would answer in one word:  A teacher.  And so this is what I said. 

There was a prayer about teaching written by Gabrielle Mistral who won the Nobel Prize for Literature in 1945. She said "give me simplicity and give me depth. Free from the temptation of being vain and glorious or commonplace in my teaching.  May the splendor of my enthusiasm be reflected from the bare walls and fill the room."

And I said so-and-so filled the room with that splendor day after day, year after year. 

A final picture of his essence.  He died of an early onset and rapidly progressive Alzheimer's dementia.  It was an awful thing, it is an awful thing when the cognitive function of the brain dies and the biologic function remains.

I was Allen's physician from the time the disease first appeared until Dorothy took him to California for the end months; that was his wife.  And the last year and a half or two years in Dallas he could not write a check or tell time, yet he wanted to come to the school everyday just like the first case. I saw him formally in our ambulatory care center once a month. There was really nothing I could do. But I periodically, once a week or so, would come by to his office.  To be a teacher you have to study continually. You have to be a life student because medicine changes quickly.  Often when I came, this man who could not tell time or write a check had a medical journal open marking sentences with a yellow pen.  He could not remember a fact he had read, but there was a remnant somewhere there amongst the beta amyloid plaques and neurofibrillary tangles for the Alzheimer's lesion that said beneath his consciousness I am a teacher and I have to study.  And that was his essence.  To the end he tried to be what he was.

Both these professors tried to be what they were.

I wasn't going to say this, but—and I don't want to offend anybody by the specifics, but he and his wife were estranged.  And you said that Alzheimer's brings out the best of people sometimes. They had lived separately for quite a long time, never divorced.  It brought out the best in her. She kept him at her home in California and would call me frequently while there.  

His wife had a very strong religious faith.  She was a woman who was able to hold the Christian faith. And she was describing to me how he was defecating and urinating all over the floor and she would have to clean that up. She hadn't put him in an institution.  And I said well, Dorothy, it seems to me you're operating in a very Christ-like way, because I knew the details of the estrangement. And this is what she said to me:  "Did Jesus ever scream?"

So it's a story.

CHAIRMAN KASS:  Thank you, Dan.

DR. FOSTER:  Well, I didn't mean to interrupt the conversation here. He just asked me—I always do what Leon tells me.  And he said he wanted me to tell a story.  So, to get back to this.

CHAIRMAN KASS:  You did splendidly.  Really splendidly. The silence means that it was not going to be easy to follow.

Janet, please.

DR. ROWLEY:  Well, I feel my sort of mundane and pedestrian questions are almost inappropriate at this particular point, but maybe just to carry on.  I do want to thank both of the speakers for their illuminating discussions.  And I have three questions for Dr. Selkoe.

One, you pointed out that there are more women than men who have Alzheimer's.  One can think that maybe it's related to estrogen or some such and recent reports that it may be more common in women who receive supplemental estrogens post-menopausal might support that. But I was curious. The second, is why the hippocampus or are certain regions really preferentially hit or is it universal and memory is just the one that we noticed, but then we think that's not so because motor functions continue; why the hippocampus?

And finally, recent reports that suggest there may also be some relation to lifestyle and the kinds of changes in lifestyle that are being recommended in terms of more exercise and better diets, etcetera, whether you think that has any role possibly in prevention or delay?

DR. SELKOE:  Well, thank you. Those are very important questions.

The gender difference is simply not well understood. It clearly is there even if you take into account the greater longevity of women and all the other factors that we know about.  I think that it may have to do with the more abrupt menopause that women experience than men and the rapid change in the estrogen levels.  I'm not an endocrinologist, so I can't speak more to that. But I do think that estrogen balance may well have a contribution.

I also think that there's genetic evidence of something on the x-chromosome that could play a role, too.  And perhaps having that in two doses has some effect on that. The gene has not been found, but the x-chromosome is one of five chromosomes that look like they contain genetic factors that predispose to this disease.  This would not be recessive now, this would be something that would be dominant that if you had it in two copies it would be worse than having it in one. So we don't know exactly why.

And I have to say that in everyday practice there are an awful lot of men who have this disease, so it's not like—I thought that statistic that I quoted was surprising to me. I think my practice is not skewed that much towards women.

PROF. GEORGE:  Could you just clarify for us, are we talking about the sex differential in all the dementias or strictly Alzheimer's Disease?

DR. SELKOE:  No, Alzheimer's Disease.  Only Alzheimer's.  Yes.

In the case of why selective areas of the brain are vulnerable, we know a little bit about what might be going on.  The amyloid protein and the tau protein are everywhere.  And, indeed, amyloid plaques even occur in parts of the brain important for movement, like the caudate and putamen that are so devastated in Huntington's Disease, they may have a lot of amyloid plaques.  Even more than the hippocampus, per se.

But what's different is that the plaques in the striatum are early immature lesions. We call them diffuse plaques and they don't seem to mature even when we look at the brain at the end of life, the plaques have all stayed immature.  That suggests in the hippocampus there are some maturing factors. And my guess is that in the fullness of time we'll discover some, in my view of things, pro-aggregating factors in the hippocampus.  It's not just in the hippocampus, it's certainly in other areas of association cortex, but it's apparently not as much in the motor cortex where you see the early plaques, but not the more mature ones.  Or the glial cells are different in these two different regions.

I think at the end of the day there has to be a biological difference, and I think a good place to start looking is in terms of pro and anti-aggregating factors for amyloid-beta protein or for the response elements of the neurons.

And the third point about lifestyle, indeed I tell my patients that they should try and, most importantly the children of those patients because they're the ones who most want to know what to do, that they should try to do all the good things that the world is teaching them, the biomedical community is teaching them about exercise, cholesterol, hypertension, etcetera because they can make it less likely they'll develop vascular dementia.  And that means they won't have a double whammy.  They won't have both a tendency to Alzheimer's, potentially genetic or otherwise, and also have vascular dementia.

Whether vascular disease directly causes Alzheimer's Disease or is a direct risk factor, I personally am agnostic about.  There is some evidence that vascular factors in animal models can accelerate the process I spoke about, the Alzheimer's in the brain. But I think most of the impact of exercise, etcetera, is in avoiding other bad things in your brain rather than avoiding Alzheimer's Disease. But we'll see.

CHAIRMAN KASS:  Let's see, I have Gil and then Rebecca.

PROF. MEILAENDER:  This is partly a comment and partly a question for Mr. Shenk.  Trying to think about the relation of a couple of things you mentioned in your five points. You said when you were talking about denial and the stigma that is involved in that, that that is in fact the thing that you have come to emphasize especially as you give talks and so forth, that people need to realize that it's a disease and there's no reason to stigmatize it simply because it's a disease.  And that makes sense to me.  I understand that.

I wonder though if in fact there isn't a deeper issue that relates to your very first category about the fading away and the humiliation you said we feel about it.  I wonder if we should accept that?  Accept the fact, the notion that fading away is, in and of itself, humiliating?  And you know, whether there's a disease base or not if we didn't think of it as humiliation, if we thought that a person at every stage of his or her life was to be equally valued, we might learn to think differently about it.  And it seems to me that in some ways that may actually be more fundamental than even the question of stigma.  And I'd just like to hear what you'd say about it.

MR. SHENK:  I don't know what I can add to that.  I think that's an ideal that we should strive for. I think that's wonderfully said.

I think as a practical matter this is how people react. They do live a lifetime being proud of all things that they can do.  And as we get older, we're taught we acquire  more knowledge and hopefully more wisdom and we know that we have more skills and, yes, we get a little slower and this and that, but as the gentleman talked about this morning—at least to middle age but I guess now we've kind of pushed middle age upward so that we think that we just get better and better. And it is humiliating.  I mean, it is just extremely disturbing to someone that they should start to lose any of those skills.

And I think the other thing I would say, which I write about quite a bit in my book, is that once you start to lose your memories, your ability to remember recent things and then your ability to make connections with past memories, you are very much losing a part of who you are. There's no getting around that.  We are, in many ways, the accumulation of our memories and our reactions to the things that we've experienced.  And I think that we want to strive to not feel shame and humiliation for all the right reasons, but I'm afraid that there is just something that does rob you when this disease comes along.  And at a certain point there's no way to get around that.

I hope I've addressed what you said. I think you said it more eloquently than I did.

CHAIRMAN KASS:  Could I have just the Chairman's privilege a tiny bit? I was struck by that also, David. You seem to think that knowledge that this really is just a bad brain disease would go a long way towards at least moderating some of the humiliation felt if not by the patient, at least by the caregivers.  Gil thinks that there's another theory, namely some theory of the dignity of the human person no matter how reduced that could cure people from humiliation. But it does seem to me, as just a phenomenological and psychological matter, if one can no longer remember the name of one's loved one or if one has lost bowel and bladder control, it's not a question of some kind of modern deformity of thought or failure to understand the brain that would lead a person to some kind of profound shame and humiliation. 

And I don't think that there's any way that either biology or theology is going to get us around this brute fact of that experience.  And the attempt I think to think otherwise is I think wishful thinking. I don't know—

PROF. MEILAENDER:  There's no such thing as a brute experience that's uninterpreted, I think.

CHAIRMAN KASS:  I'll let that sit.  I shouldn't have interrupted. Rebecca, please?

PROF. DRESSER:  I have a question for each speaker. Maybe I'll start with Dr. Selkoe.

To some extent I've heard this disease described as iatrogenic in that it's a byproduct of success in medicine in other areas so that more people are living longer. And I guess as an aside, I wonder how much that has to do with the gender differences.  It's just there are more older women around.

But in any event, this is a question I always have with treatments.  If an effective treatment does come along, I think it's important to think about, you know, that the impact of that could be positive and negative.  So to what extent would it just give more years of life, some less impaired but then some more impaired?  Because as you point out the lifespan with people with—I forget if it was all dementia or just Alzheimer's is shortened.  So would this treatment then remove some of the reasons people die at an earlier age so that you would then have this longer lifespan, but it would also include many years of impairment after the treatment loses effectiveness?

DR. SELKOE:  Well, I think it depends on whether the treatment slows the progression but you eventually develop the full blown disease anyway, so you have lots of bad symptoms. It's later on in life maybe at a time you could cope with them even less well than when you're 75 or 80. If it does that, then it may not be a blessing or not an unmitigated blessing.

My sense is that, and frankly speaking so much depends on whether we are getting the biology right. If we're getting the biology wrong, then we're in trouble and scientists have generally voted with their test tubes, as I like to say, and they're doing a lot of experiments around the topic that I discussed and related topics and many other ones that I haven't talked about. But if we get the biology wrong, well then we obviously have to start over and figure out some other way. But if we're getting the biology right there are other human diseases in which little proteins build up in which the disease can be cured completely and the patient is free of that disease.  Of course, they're now prone to a lot of other diseases.

So I think that much of the field is attempting to find therapies that will stop the disease entirely or really prevent it from happening. And the therapies would be given to people in their 50s and 60s.  So I believe, and I've written this myself and many others in the field have written it, that the brave new world of Alzheimerology is that we will do risk assessment for this disease in detail in the 50s and 60s if our society can afford it as part of health screening as we do for vascular disease.  And we will take a careful family history.  We will measure amyloid data protein in the blood. You can't measure tau in the blood, but you can measure both proteins in the spinal fluid.  You could do an imaging scan such as Dr. Bill Klunk has begun to show us how to do, and others as well. And even you would now do I believe for geno typing because you would have something to offer.  And you would put the patient almost in a numerical category of likelihood once you got enough experience with these numbers and then offer treatment.  Either a very early treatment, prevention I should say, or something that's not as aggressive or robust and therefore has less side effects.

I think that's where we're going.  We're going to attempt to allow people not to have this disease at all.  And then what will the outcome be?  It's quite scary to think about it, and I'm  interested in that question and think about it a lot, and interested in answers from around this table, which would be enormously informative.

I think people will develop other diseases and we'll have other problems of late life.  But they, presumably, won't get the condition that we now call Alzheimer's Disease, and that would be good.

PROF. DRESSER:  I think it's an interesting ethical question if something were just, say, to delay it but then the onset will occur and then there will be these future years, is that a worthwhile benefit?  I think we would probably jump on it and want it and then deal with the consequences later.

DR. SELKOE:  You know, this is an aphorism that's been put forward I think in part by the National Institute of Aging.  And it's not one that I warm to, the idea of delay it by five years and you get five full less, delay it by ten years you get ten full less, or whatever it is.  I don't think that's a compelling model.  I think that we have to think about stopping the disease entirely and not delaying it. I think delaying it, as you point out, could turn out not a good idea.

And I don't think that, frankly, the way that we treat most medical conditions—you know, there's the way that we are attacking this at its genetic roots, that we would think that our interventions would delay it.  We'd think that either they don't work at all or they just don't allow the buildup of this protein at all, or very, very little. 

So I hope that we are mostly aiming at full prevention.

PROF. DRESSER:  Thanks.

CHAIRMAN KASS:  Frank—

PROF. DRESSER:  Could I ask my other question?  Really quickly.

I think that the beautiful thing about your book and the point that Dan makes is that people with Alzheimer's and dementia don't lose their subjectivity until later on.  And so to some extent they still remain individuals and a lot has to do with their earlier history and so forth. And then that material on the man, Morris Ferdell, was really fascinating in that way.

I think when we're thinking about our ethical obligations that's a very important element to factor in; what do we owe to people and in terms of treatment, care, end of life.

And also, and I think you were doing this a little bit, the danger of blurring the burdens on the caregivers with the burdens on the patients.  And it's not to say that burdens on caregivers are not something we should worry about and try to reduce and so forth, but some patients are quite content when their families are going crazy, you know.  And so we just have to be—it's very easy, I think, to say oh well, you know I shouldn't do this because she wouldn't want that when it's really I don't think I would want that in her position or—there's just a loss of boundaries there I think.

MR. SHENK:  Well, I take that point.  Let me rebut that just a little bit, that last point.

The caregiver has to look after the caregiver first.  We're talking about a ten year prison sentence where they are going to be spending most of their energy and time and resources taking care of this person.  Obviously, they have an ethical obligation to do that as best they can. But I would say the real danger, what I've seen more often than the way you phrase it, is that the caregiver doesn't take good enough care of themselves or look after their own interests enough and end up hurting themselves through stress and other ways, and then doesn't do their patient any good.

So just to make that—not really to contest what you said.

CHAIRMAN KASS:  Frank and then Michael Sandel.

PROF. FUKUYAMA:  Well, I'm actually just restating a question that Rebecca asked, but I didn't quite hear the answer for Dr. Selkoe.

If you converted the absolute, the numbers you put up for absolute incidence of the disease and the projections forward into a rate at different ages, is there any evidence that the rate of incidence has increased over time or is the increase in the absolute numbers simply the result of greater longevity.

DR. SELKOE:  Right. I don't think there's any evidence of an increased rate incidence or attack rate.  And I think it's the prevalence that's risen tremendously because of the successful aging population.

An enormous factor in this is definition.  It was called other things before; hardening of the arteries as we heard earlier this morning.  And so the prevalence of Alzheimer's Disease jumped dramatically after 1968 when three scientists in England said look it's not actually hardening arteries, it's this disease that this guy Alzheimer described.

So I would say that I don't know of evidence that the incident factor.  So in that sense what's the causative agent here?  What is the actual cause?  We don't know that it's an infectious agent.  We have no evidence for that.  So if it is a genetic agent, well then it takes times for that gene to express itself. And time is crucial for Alzheimer's Disease.  I think it's prevalence, not incidence.

CHAIRMAN KASS:  Michael Sandel?

PROF. SANDEL:  I have a question really as much for the group as for our presenters, but prompted by this discussion and the one we had earlier.  And it has to do with stigma and the moral import of biological explanation.

In the earlier discussion  Paul McHugh was expressing a certain nostalgia for the old fashioned, nonmedicalized picture of old gramps was just kind of went soft in the head or the hardening of the arteries, kind of went loopy.  And Mr. Shenk actually expressed the opposite.  So there's a certain nostalgia.

It also came up when we were talking about the old fashioned diagnoses of squirminess of boys when we were talking about now ADHD.  So in both of these cases Paul expresses a certain nostalgia for the nonmedicalized description that has been displaced when we have more precise or at least different biological accounts.  And then the mission that David Shenk stated in the preface to his account, his mission was once we understand the physical basis of disease, then we get past the stigma.  So in a way, that's the opposite to the nostalgia.  It's saying we'll get past the stigma if we can find the proper physical and medical and biological description.

And it's really those different pictures, those different accounts about the moral significance, the biological explanation that struck me.

So compare the stigma, David Shenk's worried about the stigma when people just said well so-and-so's going loopy and didn't have this account about the hippocampus.  And so my question is this, and it's not directed to anyone in particular but it's a question that seems to me to be raised by these presentations.  If the condition of loopiness is worthy of stigma, then why should the discovery of its physical basis in the hippocampus dissolve the stigma?  Or, to put the same question from the opposite direction, if loopiness is not worthy of stigma, why should we need to discover a physical basis for it in order to become more tolerant and accepting of it?

CHAIRMAN KASS:  David?

MR. SHENK:  I would like to speak to that just for a moment.

I'm going to try not to use the word "loopy."  But I think generally you've hit on something really, really important, which I also talk about quite a bit which is these two worlds that we are now encountering simultaneously and which we occasionally or quite often need to remind ourselves are often kept distinct.

We have the world of the condition, the human condition which we now call Alzheimer's Disease which is this person who is going through this horrible ordeal which we can't treat very well.  You know, we do the best we can, but basically we are caring for that person, and that is a human condition and it has to stay human and we have to deal with it on that level.  A lot of ethical and moral concerns there.

Then there is this world of science. There is this idea that we are calling it this disease.  We call something a disease when we decide as a society that we have the moral obligation and perhaps the capability to do away with this condition.  We are now in the middle of this extraordinary war to do away with what we now call a disease.

The people who are living with the human condition need to know about the disease increasingly as we have treatments and as we just know more about it that can help them. They also need to be reminded, as I try to do, not to get caught up completely in the medicalization of this disease.  Because I think that that tends to drag away from some of the human questions.

Let me leave it there. But I think that's really important.

DR. McHUGH:  Can I jump in, my name having been used in vain.  Let me say to Michael that it wasn't nostalgia that I really wanted to speak to.  I was speaking about the natural human condition in relationship to our evolving knowledge.  That we begin with thinking these are natural events.  Then somebody comes along and says no this is disease, Alzheimer's Disease, we have no cure for it, it probably runs in your family.  It's going to be awful. And then that's a necessary age in order to differentiate from hardening of the arteries and other things.  And ultimately find the kind of cure that Dr. Selkoe and David are talking about.

So I didn't mean it in the sense of nostalgia. I meant it in the sense of how you deal yourselves with the ultimate dealing with stigma by saying to people we are all in this together as a community.  We know what you're going through now and we, by the way, doctors have brought it to you because this is the way that medicine advances.

During this time, by the way, we want to take care of you just like we did take care of old gramps.

And it's that side of things that I want to make us aware of that as we progress and all of us thinking that we're making progress as we've got disease identified by its characteristics, both pathological and clinical, that we are sending a message out to other people that is really tough. 

And I'd like to, by the way, end up by saying again these presentations are wonderful.  I'd like to get my patients onto to the vaccine, if you know how do it, Dr. Selkoe. I'm in the retail business, and how can I do it?

CHAIRMAN KASS:  Peter, did you want a brief comment on this thing?

DR. LAWLER:  I don't see the stigma issue with loopiness, hardening of the arteries, Alzheimer's Disease.  It's no one's fault.  But meanwhile, you scared us to death in a way that mere loopiness or hardening wouldn't because you've described this disease in a very plain yet poetic way is utterly predictable and utterly devastating.  And so it's no wonder that people—and I'm not blaming you for this or anything—that people really back off because it's so extraordinarily terrible in the way Leon was describing it.  It's not a stigma, but it's just necessity and a really kind of awe inspiring form; that you know exactly this is going to happen in this progressive way to this person once this thing's identified.

MR. SHENK:  If I can just briefly reiterate, thank you very much for that.  Just to speak personally, you know I've been in this world now for only 6 years as opposed to 25 or more. I started out terrified and completely ignorant, and now I know a fair amount and I'm still terrified.  I'm utterly terrified of the disease.  People ask are you able to come to grips with it by knowing more about it.

So I'm not denying that people who know more about the plaques and tangles, I'm not saying that they won't be afraid of it anymore.  I think they'll still be terrified of it. We're rightly terrified of it. But there is something about the mystery which so many people experience.  You can live with this disease as a caregiver and a patient for ten or 15 or 20 years and never really have a clue about what is going on.

And also as something I talk about in talks that I didn't get into today, is that there's a very practical side effect to knowing about plaques and tangles in the hippocampus and knowing that it's then going to move to the front of the brain, and then knowing that it's going to move to these areas, which if you have a sense in your head that there are stages and you know what you can prepare for.  You can predict what future failings and dependencies are going to be in play.

CHAIRMAN KASS:  We have a problem.  It's five of one.  I'm going to let a couple of people that have been waiting, and we've got a guest at 2:00, and because at the end of the day we're going to have to be fairly prompt.

Let me simply ask Ben and Alfonso to make their comments.  We'll make sure that the people who are on the list who haven't gotten a chance to speak will speak first in the subsequent session, if that's okay.

DR. CARSON:  Well, my questions are quick.

I wonder if either one of you are aware of any cases of spontaneous regression of a diagnosed case of Alzheimer's Disease?  And also, is the incidence of AD different in nonsophisticated areas of the world?

DR. SELKOE:  No, I don't.  I see patients who plateau for 3 years, 4 years sometimes, very little change, maybe even longer than that.  But I don't recall a case where I or another clinician felt this is very likely to be typical Alzheimer's Disease and then 10 years later everything is fine or the patient's gotten better.

Obviously we have to worry about the confusion with other behavioral problems like depression.  And if we don't diagnose it right, you know, and it's hard sometimes to diagnose Alzheimer's Disease accurately. But I think no.  I think if it's Alzheimer's Disease and it turned out to actually be Alzheimer's Disease, we don't see regression.

And the other point was about the? —

DR. CARSON:  In nonsophisticated areas of the world—

DR. SELKOE:  Yes, that's a very important issue.  See, I forgot already, so my wife is right.  Forgot the question, there were only two questions.

Bob Katzman and UCSD has done, among others, some studies in China in people who had very limited education and looked at incidents of what he thought was Alzheimer's dementia, he and his colleagues.  And they thought it was higher among people with less education and less wherewithal.  And that's been reflected by other studies.

So there is some evidence that there is a protection from higher levels of education. However, we all know well and this group better than that, that that is a surrogate for many, many other factors. So just educational level—so the health care is better, etcetera.

But the answer is I think that people with less advanced education get, to some extent, more than their fair share of Alzheimer's Disease.

CHAIRMAN KASS:  Alfonso briefly.

DR. GÓMEZ-LOBO:  ­This is an information question for Dr. Selkoe.

Do you foresee or predict any novel therapies for Alzheimer's Disease based on stem cell research?

DR. SELKOE:  It's a wonderful question.  There is a small possibility in my mind from what I know about the biology that a therapy based on stem cell implantation could be helpful here, but it's a rather small possibility and that's why I didn't mention it in my initial remarks.

I certainly would think that other neurogenetive diseases are better candidates for treatment with stem cells than Alzheimer's Disease.

The reason is that it is difficult to say precisely where you would implant the stem cells. Presumably in the hippocampus if they were delivering something beneficial.  While the hippocampus is very important to the disease, there is a lot going on outside the hippocampus and in connections to the hippocampus.  And it all depends on what the therapy turns out to be.

Maybe stem cell implantation into the hippocampus would rescue neurons that project to the hippocampus from elsewhere. Maybe they would diffuse the good factor everywhere in the brain. But the disease is so widespread in the nervous system as compared to Parkinson's or even amyotrophic lateral sclerosis, which is also widespread but affects the motor system more precisely, that I would worry that stem cells would have that uphill battle.

So, you know, editorially I would say that stem cell research is something that's extremely important for understanding brain function and neurodegeneration broadly, but I think the answer to your question from my perspective is that I don't put it high on the list for potential for Alzheimer's. I could be wrong.

CHAIRMAN KASS:  With apologies to the two Bills and Diana, if your comments can hold until this afternoon, we'll find a place to put them in the discussion.

I want to thank Dr. Selkoe, David Shenk for wonderful presentations and for an illuminating discussion.  I hope you'll stay for lunch and people can join you. We'll get you home in time for your anniversary celebration.

Thank you very much.

Please, please let's be back by 2:00.

(Whereupon, the Council adjourned at 12:58 p.m., to reconvene this same day at 2:00 p.m.)