Posted 10 December 1998
Interviewed by June Kinoshita
We invite you to submit comments and questions
on Bruce Yankner's remarks.
Q. What is the primary hypothesis that drives the research in your
A. The primary hypothesis as you might imgine is that an increase or
alteration of A-beta is a primary cause of neurodegeneration in AD, and
the effect can be modulated by genetic or environmental factors that increase
or decrease the barometer for a degenerative response. For example, some
people might overproduce A-beta and produce little toxic response, perhaps
due to genetic or lifestyle factors. So the relationship between A-beta
and disease is a dynamic one.
Q. How important do you think genetic factors are relative to environmental
ones in late-onset AD?
A. I think genetics plays a very important role. In the majority of LOAD
cases, I think it's a combination of genetic and lifestyle factors. As you
know, the APP and PS1 mutations account for a relatively small number of
cases. Predisposing genetic factors like Apo E4 and possibly alpha-2 macroglobulin
may interact with environmental factors.
Q. Such as?
A. We know head trauma is a predisposing factor in combination with the
E4 allele. Another factor may be exposure to heavy metals. The aluminum
issue has never been resolved, although it is highly controversial. One
aspect of the aging process is that the brain becomes more vulnerable to
A-beta toxicity, for example as we have shown in our work with primates.
We haven't identified what those factors are, but clearly there are predisposing
factors in the aging brain, and my guess is those are modified by both genetics
Q What kinds of aging-related changes might be important?
A. There's evidence from Bayle's group that ApoE is critical for A-beta
deposition. Regulation of ApoE with age and as a function of environment,
life style, and possibly dietary factors, may make a great difference in
vulnerability to A-beta deposition. Another factor might be environmental
toxins. Many clinicians have observed that when families bring in Alzheimer's
patients at an early stage, they report they were OK until a certain event,
such as a fall or a loss of a loved one -- some emotional or physical trauma.
It may be a coincidence, but it is a repetitive theme. It could be an issue
of vulnerability. For example, A-beta deposits may be there, but they need
some trauma or stress to trigger neurodegeneration.
Q. Could you speculate about the chain of biochemical events?
A. There's lots of in vitro data which suggests that A-beta potentiates
the toxicity of a number of insults, including pro-oxidants, hypoglycemia,
glucocorticoids and head trauma. A-beta seems to lower the threshold for
neuronal toxicity. If I had to provide you with a scenario -- a roadmap
-- the one that's most consistent with the science is that there's an alteration
of A-beta production, which occurs initially in small fibrilar, oligomeric
aggregates that put local populations of neurons at risk. These neurons
begin to degenerate. Then there may be a catalytic process that leads to
additional production of A-beta leading to contiguous spread. For example,
the outer molecular layer of the dentate gyrus of the hippocampus may produce
retrograde damage to entorhinal cortex.
Q. I was under the impression that the entorhinal cortex is the area
damaged earliest in AD...
A. It's hard to say in AD whether neuronal loss in the entorhinal cortex
occurs prior to A-beta deposition in the dentate gyrus. Another issue is
that if a neuron is undergoing degeneration due to A-beta toxicity, there
may be inhibition of anterograde transport by microtubulues. These affected
neurons will then be unable to provide neurotrophic factors to afferrent
neurons, e.g. basal forebrain cholinergic neurons, so this may be a secondary
neurodegenerative mechanism. Another event that's very important is the
microglial response, which may greatly accelerate neuronal damage. This
may also be modulated by genetics and environment. If you have A-beta deposits
in a quiescent state, and then you expose a stressor, you may get a response
that can be self-perpetuating. I must say many of these responses, such
as microglial activation and tau phosphorylation, appear to be age-dependent
in the primate cortex. In our study, the primary insult was the A-beta injection,
but we saw marked age-dependent responses in tau phosphorylation and the
microglial response. Even in AD cases where there's a well-defined mutation
in presenilin or APP, you still have an age-dependent process.
Q. What about A-beta deposition itself as an age-dependent process?
Is it just absolute time needed to accumulate it, or does the deposition
accelerate with age, and why?
A. There's likely to be great variability in the course of A-beta deposition.
Clearly in people who get AD, the process becomes accelerated.
Q. What could cause such an accleration?
A. I think changes in ApoE metabolism may be an important factor. Apo
E4 may be just one aspect of that. I think age-related changes in extracellular
matrix proteins may be another factor. For example, Lennart Mucke and Tony
Wyss-Coray have shown that TGF-beta through induction of extracellular matrix
proteins, may induce vascular A-beta deposition. So if you accept this hypothesis,
there are going to be a number of genetic factors that affect A-beta production,
clearance, and possibly fibril formation.
There's one other factor that should be mentioned -- the state of energy
metabolism. It's known from PET studies that in the early stages of AD,
there is a marked decrease in energy metabolism. This may render neurons
more vulnerable to toxic insults like A-beta. A PET study of ApoE4-positive
people in their 50s showed decreased deoxyglucose uptake in areas of the
brain that correspond to areas affected in AD., such as the temporal and
parietal cortex, well before there's any clinical disease or cognitive impairment.
This observation suggests that there's a long preclinical prodrome. It's
an encouraging result in a sense, because it may mean that there's a long
period in which we can intervene. The real question is what's going on at
that time. For example, we don't know if these individuals already have
A-beta deposits at this early stage.
Another question is, what's happening early in the disease to impair neurons?
I don't think it's the plaques. I think it's smaller fibrillar deposits
which are produced either intracellularly or extracellulary -- probably
both -- which are likely to have effects well before plaques are formed.
The plaques are a remnant. I think the early deposits probably impair neuronal
fucntion. For example, they may result in synapse loss, impaired signal
transduction, perhaps even affect LTP mechanisms. The order in which things
happen may be different in different areas of the brain. The early effects
I think are probably functional -- impaired signal transduction, etc. The
later effects may be structural -- frank loss of neurons, loss of dendrites.
Alterations in tau may contribute to both of these by impairing anterograde
transport. The problem with looking at a postmortem brain is there's almost
too much information. It's like looking at a battlefield after a war and
trying to figure out who fired the first shot.
Q.You mention these small fibrils and oligomers. Are you referring
A. That's one thing I'm referring to. But we still don't know whether
ADDLs exist in vivo. Early work in Carl Cotman's lab and mine showed that
in culture that you can get toxicity from A-beta aggregates, but they're
not well-formed into plaques. So you don't need plaques to get toxicity.
If the aggregates get too large, their toxic potency actually falls. It
may be that they don't associate with cell membranes as effectively. It's
a point I've been trying to make for a long time. One important criticism
of the amyloid hypothesis is that plaque number doesn't always correlate
well with dementia -- that's true, and raises the issue of whether the plaques
are the pathological correlate of dementia. I think not. Also, I don't think
A-beta deposition by itself is sufficient. You also need an age-related
susceptibility factor. The evidence for that is you can put the same A-beta
into young and old rhesus brains, and the young brain will not show significant
toxicity, whereas in the old one there's a great deal.
Q. If there's a species susceptibility factor, how useful can transgenic
mouse models be?
A. The plaque-forming APP transgenics are very useful for
screening drugs that inhibit A-beta production or aggregation. Their
utility for examining drugs that inhibit the neurodegenerative process
at steps following A-beta deposition may be limited. Neuronal loss and
impaired synaptic transmission have been demonstrated in APP transgenics
with a high amyloid burden by the Novartis group and by Lennart Mucke's
group. The quantifiable neuronal loss in these animals appears to be
restricted to the hippocampus. In contrast, Alzheimer's disease
patients and aged monkeys injected with A-beta show much more neuronal
degeneration and tau-related pathology. This is consistent with our
observation that A-beta is much more toxic in the primate brain than in
the rodent brain.
Q. What clues could we get from comparing rodents and primates?
A. That's a very interesting point. One thing we're looking at is differences
in rodent vs. primate apoE. Another interesting difference might be the
extracellular matrix. Also, the aged rodent brain is only two years old.
There might be a process that needs an absolute time scale in which to occur.
Another issue is oxidative stress. There may be a greater fall-off in antioxidant
enzymes in aged primates than in aged rodents. Another imporant possibility
is that the primate brain may be more pro-inflammatory than a rodent brain.
We cannot exclude the possiblity that inflammation is a major contributing
Q. What accounts for the specificity of neurons affected in AD?
A. The issue of neurospecificity -- you see it throughout neurodegenerative
disease -- and you can make up a bunch of ad hoc hypotheses. It has been
shown certain neuronal populations are vulnerable to A-beta toxicity. There
may also be neuronal specificity for A-beta 42 synthesis. It could be at
level of where A-beta deposits occur, whether or not they convert to a toxic
form, or whether particular neuronal populations are vulnerable to A-beta
toxicity. One interesting observation is that large projection neurons tend
to be affected in AD. It could be argued they have the largest energy burden
because of the metabolic cost of maintaining a very large arborization of
neurites. They also have the largest microtubular architecture. But you
could argue that both ways -- that it could makes them more resistant.
Q. What's the most nagging crirticism of the A-beta hypothesis?
A. I think the neuropathological observation of neurodegeneration, particularly
in tau, that occur in areas where you can't find A-beta histologically,
is something that needs one day to be explained if the A-beta hypothesis
is to be validated. Right now you can wave your wand and say the deposits
are too small. Absence of evidence is not the same as evidence of absence.
I think that will be a key aspect of the hypothesis, to determine if those
degenerative changes are happening because of microscopic deposits. If they
are not, that would be a major fly in the ointment. I don't think this issue
is going to be resolved by examination of postmortem brain. It's impossible
to go farther with that than we have already gone. This will require a reconstruction
in the laboratory of the sequence of events that occur in AD in animal models,
or in cell culture.
Q. What if we don't yet know what targets to look for in postmortem
A. Even if there were microscopic deposits, it's very difficult to see
in postmortem brain. I think animal models will be the way to resolve these
Q. Will AD ever be cured?
A. Ever is a long time. One day, I'll say we'll be able to effect a cure.
However, I'd say you have to intervene at an early stage.
Q. What about intervening with apoptotic processes?
A. You know the old dispute. I don't think the argument that the disease
process is too slow to be explained by apoptosis holds water. If you're
losing 10,000 neurons per hour by apoptosis, you would still have more than
90% of your neurons left by the time you died 10-15 years later. This doesn't
mean apoptosis is a major cause of neurodegeneration, just that that particular
argument against it isn't valid. It's too soon to say whether or not it's
an effective therapeutic strategy. It has been shown if you inhibit apoptosis,
neurons just sit there, they don't extend processes. However, anti-apoptotics
plus neurotrophic factors migth be an effective combination. Good animal
models are needed to address this issue. But ideally, you'd like to treat
the degenerative process at the top of the pyramid. It's just that that
might be very hard to do.
Q. With so many interacting possible factors, how can one say that
what the primary cause is, or even if there is one?
A. My own view is it's too soon to say what the primary cause is. You
have to weigh the data. I think the strongest hypothesis is it's A-beta
in some form. It may turn out in the long run that the association of A-beta
with all the genetic causes of AD may be downstream of an event that's more
fundamental and more important. I would be the last person to dispute that
possiblity. Until that thing is elucidated and supported, however, A-beta
is the most strongly supported culprit. But we should not ignore other possibilities.
On the other hand, the drug companies need a target. They can't sit around
for 20 years waiting for us to figure it out. I think there are some promising
approaches: A-beta inhibitors, such as gamma secretase inhibitors; potent
anti-inflammatory agents; inhibitors of tau phosphorylation. It remains
to be determined whether inhibitors of excitatory amino acids have a role.
If I had to guess, I'd say there'll be multiple agents against different
targets. The thing is, we may never have a clear resolution of the A-beta
issue unless we have an agent that targets A-beta and we give it to patients
and see a therapeutic effect. Even if it worked gloriously, there will be
people who will wonder if it's doing something else. If you have agents
that target different aspects of A-beta -- gamma secretase, fibril formation,
toxicity, etc. -- and they all work, then finally, the textbook can be written.
Q. If you had no financial or technological constraints, what experiment
would you do?
A. I don't think there's any one experiment. I think the way a field
like this evolves is that there's a mass of evidence that becomes so compelling
that it leads to a consensus. Right now, there's a mass of evidence for
A-beta. I don't think finances are the barrier. I think creativity is the
barrier. In fact, I think money and creativity are often inversely proportional!
I think in next five years, we'll make significant progress.
Q. Do you think Alzheimer research is on the right track now, or should
researchers be looking outside the field for inspiration?
A. I think we're well on the way. I think the approaches to looking at
presenilin mutations are very basic -- between all the labs, we're covering
most of the bases. I think it's very important to encourage people with
new points of view to come into the field. For people not to become too
smug. That's the worst thing that can happen. If I had to emphasize one
thing, it's the importance of being open to all ideas, in a field that traditionally
has been ruled by strong personalities.
During his medical school training in neurology at Harvard, Bruce Yankner
was drawn into the Alzheimer field when he found that an APP gene construct
(C100) was toxic to neurons. "Alzheimer's disease was one of few neurodegenerative
diseases at the time that was tractable to genetic and molecular tools,"
he explains. Yankner also has been intrigued by AD's link to the aging process
and whether it might be possible to gain insights through AD research into
fundamental mechanisms of aging. He is also involved in work on Down syndrome.
Yankner currently works at Boston Children's Hospital and is Associate Professor
of Neurology and Neuroscience at Harvard Medical School.
Questions from our readers for Dr. Yankner
Q. Could you elaborate on the role you think microglia play in
Alzheimer's disease pathogensis?
A. Activated microglial are closely associated with neuritic plaques in
the AD brain and several groups have shown that microglia secrete
neurotoxic factors in vitro when incubated with aggregated forms of
Abeta. Thus, it is likely that the microglial inflammatory response
contributes to neurodegeneration in response to Abeta deposition in the
AD brain. Furthermore, there is evidence that anti-inflammatory agents
may decrease the incidence of AD, raising the possibility that drugs
which target the microglial inflammatory response may have therapeutic