Inkwell: Authors and Artists

    
Yes, and I was happy to have that. But when a magazine seriously
considers an excerpt from your book, then assigns a lengthy book review
instead, and this is how it turns out, you can imagine the level of
ambivalence. I can't tell you the number of people I talked to who read
the first two pages of that piece, never got to any acknowledgement of
my book, and then said to me, "Hey -- did you see that Franzen has an
essay on Alzheimer's in the New Yorker?"
  

    

I hear ya.  But you have to figure most people read it all the way through.
Or hope so, anyway :^)
  

    
David, sorry I'm late arriving here, but I just wanted to make the point
that "The Forgetting" is not only a stunning book because of its subject,
but because of its craft.  It's beautifully written -- there were many
times when the hair on the back of my neck stood on end while reading it,
as it did just now when I read the passage about Ralph Waldo Emerson
signing his autograph twice, in the final part of the book.  I think it's
a masterpiece.  Granted, I'm not an entirely objective critic, because you
and I wrote a book together in the early '90s, as some people here know.
But as a writer myself who tackles complex neurological subjects for my
work in Wired, I know just how hard it is to make these scientific matters
comprehensible to a smart, non-professional reader, while retaining the
human force of the story.  A superb book, my friend.
  

    

David, the two types of drugs you mention don't do anything to attack the
root of the problem, they simply address the symptoms for a short while.
In your book you talk about another whole area of research, where 
scientists have been looking for something along the lines of a vaccine
that could stop the disease before it begins. You also touch on an
experiment where scientists were able to actually reverse the build-up
of plaques and tangles. 

Those areas of research seem like they'd be so much more fruitful. What's
on the horizon as far as this kind of work?
  

    
Thank you for your staggering words, Steve. You already know how much
that means to me. To any others out there who've read the book, whether
you liked it or didn't, I'd love to take some time at some point in
this discussion to toss around some of its ideas. This will probably
sound pretentious, but I really aim to produce work that is as much
literature as, say, any well-written novel out there. My heroes are
John McPhee, Joan Didion, E.B. White, Truman Capote and others who have
raised non-fiction to an art form.

I told you it would sound pretentious. 

Meanwhile, I'm of course very happy to answer science questions as
best I can. 

Cynthia: Yes, indeed, the true excitement behind Alz research lies in
the avenues that could potentially slow or stop or prevent the disease.
To do this, they think they'll have to stop the formation of the
plaques and/or tangles. Actually most researchers strongly suspect that
the plaques are the main ones to focus on, that if the plaque material
(known as beta amyloid or "a-beta") could be prevented from forming,
or dissolved as it forms, the disease could be stopped. (Please don't
ask me why plaques are the favorite target right now -- that's a longer
story than you want to get into in this forum). 

Elan Pharmaceuticals' vaccine was the first drug that potentially
could eliminate plaques from human brains. The idea of the vaccine was
so simple and powerful, it took other researchers' breaths away. They
would inject beta-amyloid into human body, stimulating the body to
itself form antibodies to that substance, which would then creep into
the brain and sweep the plaques away. 

No one thought it would work -- it was just too simple of an idea, and
many thought the blood-brain barrier would not admit such antibodies.
But it tested extremely well in mice and a few years ago went into drug
trials in humans. Sadly, it stimulated a dangerous immune response in
some of the human trial subjects, and a few of them died. So they had
to suspend the study. But the data they were able to gather in the
early going was extremely promising, and so researchers are racing to
come up with a new, safer vaccine so they can try it again.

There are other approaches, too, that are just as exciting, and almost
as close to fruition. They are also aimed at preventing/removing
plaques. 
  

    
Fingers crossed....
  

    
> it stimulated a dangerous immune response in
>  some of the human trial subjects, and a few of them died. So they had
>  to suspend the study

I don't understand that part, actually. The study subjects were suffering
from a terminal disease. If I recall the numbers correctly from your book,
it was about 2 percent of those in the study who had the bad reaction to
the drug and died.

Everybody else in the study is going to die of the disease. Why stop it
if 98 percent of the people in the study are showing marked improvement? 
  

    
David, I've heard a LOT of rumors about Alz, about causes and
prevention. Some of the most popular: (1) Alz is caused by aluminum
deposits in the brain, largely from using aluminum cookware with acidic
foods; and (2) Alz is caused by not using the brain, not learning new
things, not having stimulating experiences, etc. Are these myths?
  

    
Cynthia: Whoah. I certainly didn't mean to suggest that 98% were
showing marked improvement. They probably weren't showing much of
anything in the early going. I'm not completely on top of what
happened, but the improvement probably showed up (ironically) in
autopsies of those who had been killed. Remember, they can't see what's
happening to plaques in living brains yet (at least until this
Pittsburgh compound was invented). So they have to watch behavior --
very tough thing to measure except over the long term.

In any case, I believe it's a cardinal rule that you don't continue
with studies of drugs that may kill that many people, even if the
disease is terminal. It does open up some interesting ethical
questions, but I think that thinking is widely accepted. 

By the same token, you could ask why they don't take brain biopsies of
Alz patients who are taking experimental drugs. They could learn a
hell of a lot -- and after all, these people are terminal. But they
just don't do it.

Cindy: Thanks for raising this issue. It's an important one. I write a
lot about rumors and about shysters in my book. Alz is the *perfect*
disease if you're a con artist "healer" or a  pseudo scientist, because
it is so complex and because millions of people are desperate to
believe anything that sounds simple and hopeful. So if you look around
you see lots of b-s artists telling you what causes Alz, how to cure it
with this or that elixir, etc. Some say outright that Alz doesn't
exist.

Aluminum does not cause Alzheimer's, as far as anyone can tell. It has
been found in Alz brains, but that's because the disease has
compromised the blood-brain barrier early on and allowed all sorts of
crap into the brain that doesn't normally get in. 

Your #2 is a lot trickier. As stated, it is false. Alz is certainly
not caused by lack of use.  And there are plenty of brilliant people
who get Alz. But what may be true -- they're still not sure -- is that
you might be able to push off the onset of the disease, or perhaps slow
down the progression of the disease, by living a vigorous and
intellectually challenging life. You won't innoculate yourself, or stop
the disease in its tracks. But maybe you'll get it a few years later
than you would have -- which is a huge deal. Researchers estimate if
they can find a way to delay onset by 5 years, they'll cut the number
of cases in half -- meaning that half of the people who would have
gotten Alz will die of something more merciful in the meantime.
  

    
david, dont know if you are familiar with the slim elegant
novel 'moral hazards', in part about watching a loved
one go thru alz...anyway, there is a  great bit where
the caretaker/partner of the alz sufferer is hearing
all these news stories about use yr brain/it's aluminum/
take vitamin e/ whatever --- while meanwhile, the
homehealthcare workers in the nyc alz community,'
by and large a smart but not terribly formallu
educated immigrant pop --- think alz comes from
too much education. for -they- are taking
care of all these former professors/lawyers/docs
who have it...i see that in my own life,
where one of my mother's best friends, a remarkably
active smart fit woman (went back and got her
collefe degree at at 65; always had a mad
social life going into her 80s; read wiselu
and well and are her oat brain and did her yoga)
--- got alz. whereas my evil mother, whose idea
of exercise consisted of ordering the cleaning
lady around and who would have been happy
living on a diet of ham sandwiches and chocolate
malts, even -after- she was diagnosed with diabetes...
in some sense has had a much slower mental decline
than her wonderful athletic conscious intellectually
engage friend. sigh.
istr your book was written -before- all
the nNo Longer Take HRT study came out, and
one of the side effects of hrt was -now-
considered to be alz. i have wondered if the
pop now in their 60s -80s, the 1st gen
of woman to have been so hormonized, are having
some of the uptick in alz because of this. i also
seem to recall that women are twice as likely
to get alz/dementia?
  

    
and oh, i didnt mean to sound persnickety about
pureform alz vs more mixed dementias. simply
that i thot they were different diseases, with
somewhat different courses (my mother's fits
with the rest of her general vascular collapse,
small strokes, etc etc). the progression of
her illness is not like what i know of
pureform alz i.e. she has known for yrs
her memory is not what it was, she has
physical frailty somewhat matching the
mental ga-ga ness, etc etc...
  

    
Paulina,

You're right that a study last year of hormone replacement therapy --
estrogen plus progestin -- showed an increased chance of getting
Alzheimer's, and demonstrated plenty of other reasons not to pursue
hrt. But regarding Alz, the hormonal picture is still very imcomplete.
Previous studies have shown that increased estrogen may significantly
decrease the chance of getting the disease. So the hrt study shocked
researchers and they're still trying to figure out what it means. There
was also a recent study that showed increased testosterone reduces Alz
risks somewhat. What I take away from all this is: non-scientists
should ignore all this stuff. There is no particular road map on how to
prevent Alz, other than eating right, exercising the body and the
mind, and keeping stress to a minimum -- and even all of that may not
make much of a difference. Women do have a *slightly* higher incidence
than men -- not anything like double. (I think you may have confused a
stat from the hrt study). But in truth, no man can look at a woman and
say, "you'll probably get Alz and I probably won't." Each one of them
runs a risk that will closely correspond to how long they live. 

I haven't read Moral Hazards, but I like the point very much. There
are so many examples of the supposedly smarter half of a couple getting
Alz -- and so many of the converse. You just can't tell. Ed Markey,
the Congressman from MA who leads the fight for Alz funding on Capitol
Hill, likes to convey to people his dismay that his hyper-intellectual
math whiz mom got Alz while his working class, mildly-educated Dad did
not. Ronald Reagan got Alz, but so did Ronald Reagan.
  

    
> There is no particular road map on how to
>  prevent Alz, other than eating right, exercising the body and the
>  mind, and keeping stress to a minimum -- and even all of that may not
>  make much of a difference.

My mom took care of herself all her life. Good diet, minimal alcohol
consumption, regular exercise for her body, worked as a primary grade
teacher in an experiemental public school open ed program and did
crossword and acrostic puzzles for amusement (IOW: she gave her brain
a workout regularly, too). Oh, and didn't take HRT. But there she is,
goofy as all get-out now. So I tend to go with the "may not make much of
a difference" idea, myself. 

>  Cynthia: Whoah. I certainly didn't mean to suggest that 98% were
>  showing marked improvement. They probably weren't showing much of
>  anything in the early going. 

Ah. Yes, sorry. I think I blurred two different stages of that research 
together. The experiments were initally performed on mice, with astonishing
results.

Can you talk a bit about transgenics and Dale Schenk's work with knockout
mice? Is he still exploring that avenue? Are there any new developments
on that front?
  

    
Mice have been critical in Alz research, because there are so many
obvious ethical restrictions on what you can do with live human brains.
(Animal activists will, of course, argue that it's unethical to
exploit mice bodies and brains, but so far that argument has not
carried the day). Scientists need animals to study how plaques and
tangles form, and what substances might inhibit their formation. 

The problem is that no animal besides humans get Alzheimer's. (A few
get plaques or tangles, but none get both). So geneticists figured out
a way to play with the genes and create "transgenic" mice who have
plaques in their brain. Those mice have been critical in the
development of the vaccine and other strategies to eliminate plaques.

You asked about Dale Schenk (different name spelling from mine, no
relation), who works for Elan Pharmaceuticals. That's the outfit that
invented the vaccine. They're of course still pursuing that vaccine,
and I'm sure other avenues as well. I haven't checked in with them in a
while. But you can be sure of two things: 1. A lot of people are
racing -- RACING -- to come up with the right treatment, for
humanitarian reasons and because there are billions of dollars to be
made. 2. When they break through, you'l hear about it.
  

    
ah, the 'women twice as likely to get dementia' factoid was
a fact i gleaned from reading a current issue of
psychology today, while in my physical therapist's waiting
room. it was one of those roundup diffs on the real/observed
diffs between men + women --- include everything from
how much more likelt women were to get arthritic
knees to how much more likely men were to get
autism + schizophrenia, etc etc. i think it
was an issue from this summer...anyway, the
dementia stat really leaped out at me because
it wasnt somethingt i'd kjown. but then, this
could be a function of the fact that women
tend to outlive men, so have, say, 7 more yrs
in which to develop alz/dementia...
  

    
I'll have to hunt that down and see where they're getting that. It's
true that a woman is slightly more likely to get Alz than a man her
same age AND that women tend to live longer. So if you put those two
together, that is pretty significant. But when one boils it down to a
simple phrase like "twice as likely," the danger is that people think
that women are much more at risk for the disease for any given age, and
that men are basically off the hook. 
  

    
totally admit i may have garbled/exagerated the stat. but it
was significant enuf that it leapt out at me. if i were
to guess, it was the aug 2003 iss of psych today.
also, to continue to treat you as the snopes.com
of alz --- had you heard that bypass surgery in folks
over 80s in 40 percent of cases leads to irreversible
mental decline into dementia? this wasone of many
reasons i quietly raise some ah question to my
evil mother when she was a candidate for such
a few yrs back --- even then, she was considered
too frail, for example, to have her carotids reamed
out -- and lo and behold, that's exactly
what happened. her dementia got precipitously
worse afterwards --- whiuch makes an intuitive
kind of sense, giving what an invasive shock
to the system such surgery is. prob is, i dont
remember where i read that stat when i was
doing the research back 5 yrs ago --- and havent
been able to come across it since..
  

    
I haven't heard that one, either. That also sounds very high to me.
I'm pretty confident  that there is no known association between
surgery and Alz -- people ask me about that all the time. It does sound
conceivable that there could be a connection to vascular dementia, but
I haven't heard that -- and I think I would have if it really existed.
But I can't be snopes on this one. 

I'm getting that you're not crazy about your mother.
  

    
nope, not crazy about my evil mother. but i still make sure
she has the best and most considerate of care...
yeah, i do feel sorta nuts about the surgery/vascular
dementia thing, because it is NOT the sort of thing
i would be inclined to make up...but it could have
been in a study not well known; obviuously not the
sort of thing vascular surgeons would like to focus
on, etc etc
also, there was an age issue here. it was only
in folks in their -80s- where this effect
was noted. not an issue, afaik for folks
in their 50s + 60s, who constitute perhaps
a larger pop of folks getting such interventions...
  

    
I just did a little digging and will email you two articles -- too
long to post here I think. Both speak to the very real problems of
post-bypass cognitive deficits, distinguishing between short and
long-term deficits. Neither one seem to point to any definitive info on
actual dementia setting in, which leads me to believe that there's
very little data available on that. 
  

    
well, it's a very small pop --- folks in their 80snhaving
bypasses, and then being studied for cognitive malfunction....
issue with my mother is that it -exarcerbated- a
relatively slow decline into dementia. again, that's
a hard pop to find/study i.e. folks who have perhaps
mci, have bypasses, are much worse 6-12- months
later...the surgery sure  didnt seem to help
blood flow to the brain...anyway, this is probably
wayn too off topic for folks who are more concerned
with the tradtional and mysterious pathways to dementia...
  

    
Hi David, I am a live-in caregiver for an 87 year old couple. The
husband has Parkinson's and they are both showing signs of early stages
of Alzheimer's. I can't tell you how much I appreciate all your
efforts. I found your book very helpful and PBS rebroadcast The
Forgetting last night - what a powerful presentation.

The links from both PBS and your site are excellent. We should
probably keep posting those as we go along.
http:www.pbs.org/theforgetting and http://www.theforgetting.com Hope I
got those right.

I sense that your book has drawn you full-time into the Alzheimer's
front. I can't think of anyone better and am glad we have you. Did you
see any of this coming? And are you feeling a bit like the train is now
pulling you along? 

Also, I can't help wondering about the greater ethical issue of
outliving ourselves in terms of quality of life. Seems like we are
caught in the middle of what science can give us as we live longer and
the consequences of that as our bodies are unable, as yet, to handle
it. Would you speak to that a bit?
  

    
Hi Ted. Thanks for the very kind and welcoming words. See this coming
-- absolutely not. If someone had told me years ago that I would one
day be jetting around the country giving lectures about Alzheimer's
disease, showing excerpts of a film named after a book of mine, I'd
have recommended a neuropsychologist for that person.

Alz is not my full-time life. Part of my brain has moved on to my next
book on something completely different (a cultural history of chess
and chess's surprising influence on culture and ideas). But, yes
indeed, it is a huge and important part of my life, and has made me a
much better person I think. 

You touch on a central issue of our time, one which fascinated me as I
was writing the book. Living longer is a natural human craving which
has no chance of abating, but it is packed with unexpected
consequences, paradoxes, and some just plain ugliness. 

Jonathan Swift wrote about this in Gulliver's Travels. He created an
immortal race called the Struldbruggs in order to satirize the quest
for immortality. His character Lemuel Gulliver is at first thrilled to
find out about the Struldbruggs' immortality. He anticipates what they
will be like: 

"Happy People who enjoy so many living Examples of antient Virtue, and
have Masters ready to instruct them in the Wisdom of all former Ages!"
The immortal elites, he reasons, will provide the best possible
insurance against the repeating of past mistakes. With a living history
as its guide, civilization will inevitably become smarter and
stronger."

But Gulliver has gotten it all wrong. After much laughter at his
expense, he is told that  immortality, far from being a blessing, is in
fact the worse imaginable curse. The actual lives of the Struldbruggs
fell into this pattern:

"They commonly acted like Mortals till about Thirty Years old, after
which by Degrees they grew melancholy and dejected....When they came to
Fourscore Years, which is reckoned the Extremity of living in this
Country, they had not only all the Follies and Infirmities of other old
Men, but many more which rose from the dreadful Prospect of never
dying. They were not only opinionative, peevish, covetous, moreose,
vain, talkative; but uncapable of Friendship, and dead to all natural
Affection, which never descended below their Grand-children....They
have no Remembrance of any thing but what they leartned and observed in
their Youth and middle Age, and even that is very imperfect....In
talking they forget the common Appellation of Things, and the Names of
Persons, even of those who are their nearest Friends and Relations. For
the same Reason they never can amuse themselves with reading, because
their Memory will not serve to carry them from the Beginning of a
Sentence to the End."

Swift himself was obsessed with senile dementia, and foretold his own
case of it. It's an incredible story that I get to tell in some detail
in my book. 

Today, we have a burgeoning immortality industry, gearing up to tweak
our genes so that we may live an extra hundred or two hundred years or
more. It would be laughable if it wasn't serious and even plausible.
They'll be doing all this and more as the genetic revolution unfolds. 

But do we want it? My gut tells me that there's a wisdom built-into a
billion years of evolution that we won't ever fully comprehend, and
that tinkering with it is akin to tinkering with the atom. Let's ask
the people of Hiroshima or Chernobyl if they think that is such a good
idea. 

I may have jumped ahead of your question a bit. I think you were
really aiming at more conventional means of helping us live longer, and
of course there it gets even more difficult to parse the ethics. If I
told you at age 75 that you had 2 years left, but I could extend that
by 15 years with a bypass -- BUT that the final 10 of those years would
be marked by Alz and would decimate you and your family's emotional
and financial lives -- what would do you? Something close to that
scenario is playing out thousands of times every year now, except we
can't tell for sure which ones of us will get Alz and which won't.
It'll really get interesting when we have better tests and can predict
our final years better. 
  

    
You were right on target. Thanks. Ray Kurtzweil speaks about this
quite eloquently in The Age of Spiritual Machines. I think our
generation is in for a not-so-pleasant future while we make these
transitions.
  

    
The question you ask in your last paragraph is a fascinating one--
fascinating for us as a species I guess I mean, since as individuals we
don't get to make that choice (and it would probably not be a hard one for
most of us).