Julia Hall

Ms. Chawkat
Independent Research Period: 3
24 January 2018
Transcribed Interview and Reflection
JH= Julia Hall
DC = Dr. Jeremiah Cohen
26:06 minutes

JH: Hi, is this Jeremiah?

DC: Yes

JH: Hi, Jeremiah. It’s Julia Hall. How are you?

DC: Good, good. How are you?

JH: I’m good. First off, thank you so much for letting me interview you.

DC: Sure, sure.

JH: And do you have any issue with me recording this conversation?

DC: No, that’s fine.

JH: One of my first questions is, I have done a lot of research about a synapse-restricting protein
called Ephexin5 and how that can be correlated to Alzheimer’s disease. My question is do you
believe that reducing the expression of Ephexin5 is an effective treatment for Alzheimer’s?

DC: At this point I would say that any strong statements about a particular protein of a molecular
difference between people with and without Alzheimer’s are going to be mostly speculative.
There are a few exciting paths that I think people are doing based on the work from the last few
decades about the link to really try and understand the ideology that is the basis of Alzheimer’s
Disease, but there is very little consensus on those things. What we have done well in biology in
general is we have been very reductionist. We could look for example at the proteins that you
studied and intercellular signaling pathways for example, and try to make some statements about
where they look different in a diseased state like Alzheimer’s. As far as using that information
for treating this disease I think that we still have a lot of work to do.
JH: What do you think is the next step would be in the treatment based off the most recent
research?

DC: So, one of the paths that I think is more exciting based on recent work that could be
combined with classical work trying to understand for example at a very molecular level what’s
different in Alzheimer’s disease, is that there are large scale systems level differences in people
with Alzheimer’s that may interact with some of these molecular changes. So, for example, you
may know that there is a kind of a barrier between the blood and the nervous system and it’s
what allows our nervous systems to have special immune status, that is, it’s relatively protected
relative to other organs in the body. So, you can very easily get an ear infection or an eye
infection, or an infection in the skin, but it’s very difficult to get one in the nervous system
because there is a barrier between the blood and the nervous system and it enables the nervous
system to extract what it needs from the blood like glucose and other nutrients but at the same
time stay protected. Now, as it turns out, as we get older, the fidelity of that barrier starts to
decay. So, it can become porous, it can open up a little bit, and it does that naturally in our sleep
cycles for reasons we don’t entirely understand yet. But as we get older, some people end up
with very small holes in their blood brain barrier and that doesn’t necessarily automatically lead
to Alzheimer’s Disease but one thing that people are thinking that combined with some of the
molecular changes that it sounds like you’ve been reading about, may combined may be better
predictors of disease than any of the individual risk factors. So, I think, to answer your question,
the most exciting path forward, is starting to combine information that we’ve learned from
different approaches to get at a useful systems level approach.

JH: Wow, that’s really interesting. So, do you, therefore, believe that Alzheimer’s is more of a
genetic based disorder or is it also factors in your environment that affect the neurological
disease?

DC: Yes, I think, like virtually disease or natural state in any human or animal, there are some
combination of natural and genetic factors that contribute to pretty much everything. You know,
the balance, for some diseases or states, and by states I mean, anything from the color of your
hair, to how tall you are, to the rate at which you digest food, or anything that is a property of
your physiology, is determined by some combination of genes and environment so some of those
things are relatively strongly genetic so it takes a lot of environmental force to be able to push
against that genetic factor and others are more or less completely determined by environment.
Everything is going to be some combination of those so Alzheimer’s, as is the case with most
diseases of the nervous system, probably has some flavors that are strongly genetic, and there are
known genetic links across generations in certain forms of Alzheimer’s but it is unlikely that if
one is predisposed that they are guaranteed to develop the disease, rather it’s probably subject to
strong some environmental factors about which we don’t know a lot about other than the slew of
studies that link, for example, exercise to a lower risk of Alzheimer’s.
JH: So, do you think, by keeping your brain stimulated and more engaged in activities, could that
possibly slow the progression?

DC: So, it could but it is not necessarily all activities. So lately it’s become popular recently for
companies to advertise “brain training” for example. Most of those are “snake oil”. It’s a good
sales pitch but not really based in reality. So, it terms of keeping your brain engaged it’s of
course a good idea to do that, in the kinds of ways you might as your normal routine as a
productive member of society, but actually exercise, is one of the factors of late life brain health.

JH: I didn’t know that. That’s pretty cool. With people at risk of Alzheimer’s with parents or
relatives with Alzheimer’s, the best case for them would be to keep exercising?

DC: Yes, as is the case with most diseases, not just the nervous system but the whole body. If
you combine all of the things that we know, that are able to predict some disease, it’s only a
fraction of our full possible ability to predict disease. Most of what accounts for disease, is stuff
that we have not fully understood yet and yes, in general, exercise and reading books, probably
can’t hurt but in the end most of these diseases are relatively unpredictable.

JH: So, you talked about the way we detect Alzheimer’s disease and there are new imaging
scans that seem to be coming out about that so, like new proton magnetic resonance imaging
scans and there are also traditional memory tests that people use for indicating Alzheimer’s. Do
you believe one is more accurate in predicting Alzheimer’s?

DC: That’s a good question. I don’t know the answer to that although certainly pushing for good
behavioral tests would make sense because it would be easy to administer by a primary care
physician regularly and hopefully detect Alzheimer’s early whereas magnetic resonance is
expensive and unlikely to be a regular test that the general population would get. So, in terms of
what is most promising is going for behavioral tests, which seems to make the most sense to me.

JH: Could you describe how they would go about a behavioral test?

DC: So, I’m not a physician or expert but there are several kinds of tests for “working memory”
so for example, if I tell you a phone number and then ask you to remember it for an minute and
then I ask you to recall it a minute later, that’s called “working memory” – keeping something
online for a relatively short amount of time. That kind of memory, in addition to longer term
memory, is particularly disruptive in Alzheimer’s and other forms of dementia. So, I don’t know
what the most sensitive of that kind of memory deficit is but that’s what you should look up if
you are interested in learning more.
JH: There have also been other studies that have linked restricted spine growth, like synapse
development in Alzheimer’s, and how those symptoms can be related. Do you believe there is a
strong correlation there?

DC: So, yes, this is a really interesting topic that cuts across, that really gets at the heart at some
of the questions in neuroscience. Which goes far beyond individual diseases, such as, what is the
function of individual synapses, the connections between neurons that occur at these spines? A
lot of these types of neurons have these so called spines, which are little outgrowths, which are
the sites of a lot of these synapses where neurons that are sending information to a target neuron
make one of these synapses. A lot of these synapses and certain kinds of neurons occur at these
spines. A lot of the early work showed this correlation in the growth of spines on a neuron and
what the area was being used for recently. So, for example, if you ask an animal to learn some
complicated movement, then the area of the brain involved in generating those movements will
show growth of spines. That correlation led a lot of people to think, you practice something and
that means more synapses and more spines in the types of neurons that happen and case closed.
Turns out, that breaks down when you start looking more globally at the nervous system. What
are these really for? For example, female rats in their estrous cycle will have more, in one part
of the brain called their hippocampus, the amount of spines across all of the neurons there
fluxgate by about 30%. That is a huge number. A little bit of an increase in the number of spines
in some region correlates with some complicated behavior like learning something new. It is
really unclear what the function of increasing or decreasing numbers of synapses are more
generally. Any of these types of correlations in, for example, in models for Alzheimer’s disease,
may be useful but may be obscuring what the really important information is. So, one has to be
really careful about interpreting those kinds of correlations.

JH: Is this research relatively new, about the spine growth?

DC: The one about rats in estrous?

JH: Yes.

DC: That’s a line of work over the last 15 years or so. One important piece of advice I can give
you is looking up answers to the questions you have is each study by itself should be taken with
a large grain of salt. Science really progress over the timescale in 5 or 10 year chunks so each
individual study will suggest something. If it is something new and exciting, the field will
converge on that problem and see if it is really true or only true under certain conditions. That
makes it more challenging for you, of course, as you are trying to learn about these things. But
also it means that it is important to understand, you may see, especially in early days of the field,
lots of contradictory things until people arrive at a consensus about things. And that consensus
usually arrives after much scientific experimentation and debate. Science is not always straight
forward and you make an observation and you don’t always immediately know what it means.
You can adjust how much you believe a certain study by how new the field is in some sense.

JH: The newer research needs to be questioned a bit more because it is still being debated?

DC: Everything needs to be questioned, but there are some things we are sure about. There are
other things that require a lot more work to nail down. A lot of what you might read in the media
focuses on newer studies partly because of the excitement surrounding a lot of the new work.
But it is just as important to realize that one has to arrive at consensus over many years. But for
me, this is the fun in doing this. We really get advanced knowledge over long time scales.

JH: There seems to be a lot of treatments which help manage the symptoms of Alzheimer’s
disease. However, there doesn’t seem to be currently a treatment to stop the progression. Why do
you think?
DC: In terms of treating a disease that focuses on different pieces of evidence from different
fields. One, for example, that focuses on different proteins and another that focuses on the
integrity of the blood brain barrier. But I think at a more fundamental level, we don’t have
enough of a basic knowledge of the physiology of the nervous system. If someone has a heart
problem, they go to a cardiologist, and that cardiologist diagnoses the problem based on what
they know about how the heart functions. That’s perfectly sensible but we don’t have that kind
of information for the nervous system. So, the basic nuts and bolts of how the brain works, we
don’t have that information. We as a society are way behind in the brain vs. the heart or liver.
It’s probably going to take a few more decades of work in basic neuroscience of understanding
how the system works normally and then hopefully understand where it fails in the disease state.

JH: The brain is definitely a complicated organ.

DC: Yes, it’s complicated but we don’t know what we don’t know. The stage of the field right
now is one of a lot of excitement but also confusion. For me in the field and hopefully for you,
as an informed citizen or scientist or whatever you are planning to do, this is a great time to
enjoy watching the discoveries arise.

JH: Do you believe we are on the verge of a major new discovery in the field?

DC: I wouldn’t say there is a single major discovery in neuroscience or really in any science.
That view of the sciences is often sensationalized. Science is very much incremental. After
years and decades, we collectively arrive on knowledge of things based upon work from many
different people. I think this time is exciting in neuroscience because we are in the early stages
of the science where we are starting to understand some things that we think are really true. And
it has big implications but I don’t think there will be a single “ah hah” moment for any one
person. Fifty years from now we will look back and realize how much we’ve learned and that
will be what is exciting.

JH: Interesting. Do you believe that the dysfunction of monoaminergic signaling is present in
Alzheimer’s disease?

DC: Here again, there are correlations. Monoamines are these neurotransmitters chemical
signaling pathways in the brain that are special. What’s special about them is the neurons that
release the mono amines are comprised of small numbers of neurons in the brain. One of the
monoamines in our brain is a neurotransmitter called serotonin. There are only a few 100,000
serotonin releasing neurons in our brains. They send their messages to most of the nervous
system. That’s relatively unique in the case of all the monoamines that you have a small number
of neurons that is sending a message that the rest of the brain is listening to. And so, in that
sense, those neurons and the monoamines that they release are involved in everything – sleep,
wake, eating - all the normal functions of the nervous system, also, where it goes wrong in the
case of Alzheimer’s disease. Yes, there is going to be some dysfunction of monoamine signaling.
That’s sort of where it is tricky to ask about the relationship between these kind of correlations
and whether that is useful information in treating the disease. So there I do not have a good
answer for you but certainly there are significant correlations between Alzheimer’s state and the
properties of the monoaminergic systems.

JH: How can monitoring monoaminergic systems lead to discoveries with Alzheimer’s disease
treatment?

DC: That’s a great question. We don’t know yet. We don’t understand yet the basic nuts and
bolts. I hope that by understanding how the nervous system functions at a basic level including
the monoaminergic drones that it will give us insight any diseased state including Alzheimer’s.
Just like we know how the heart works, it’s a pump for blood with four chambers, etc., so once
we have that basic information for the brain, it will naturally lead to better explanations and
treatments for the diseased states.

JH: Thank you so much for your time Dr. Cohen! I hope to talk to you again soon.

DC: You’re welcome.

JH: Goodbye.

DC: Goodbye.
 Reflection
I thought that the interview went very well because Dr. Cohen was able to answer my
questions thoroughly and he gave me advice about conducting research in the field of
neuroscience. In my next interview, I plan to read more academic journals about current
neurological research in treating Alzheimer’s disease, so we can further discuss new treatment
protocols the next time we talk. I would also want to read more about proton magnetic resonance
imaging scans as a new method to predict Alzheimer’s in hope that it could lead to advancement
in the treatment of Alzheimer’s disease. It was easy to find a time to meet with my advisor and I
felt comfortable talking with him about the field. It was difficult to come up with my questions
about current neurological research because it took a long time to understand the findings and
conclusions of the academic journals. However, I do feel that I was able to come up with good
thought-provoking questions that intrigued Dr. Cohen, therefore I believe the interview was a
success.