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.


ARF: What is the primary hypothesis that drives the research in your lab?

BY: The primary hypothesis as you might imgine is that an increase or alteration of Aβ 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 Aβ and produce little toxic response, perhaps due to genetic or lifestyle factors. So the relationship between Aβ and disease is a dynamic one.

ARF: How important do you think genetic factors are relative to environmental ones in late-onset AD?

BY: 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 α2 macroglobulin may interact with environmental factors.

ARF: Such as?

BY: 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 Aβ 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 and environment.

ARF: What kinds of aging-related changes might be important?

BY: There's evidence from Bayle's group that ApoE is critical for Aβ 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 Aβ 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, Aβ deposits may be there, but they need some trauma or stress to trigger neurodegeneration.

ARF: Could you speculate about the chain of biochemical events?

BY: There's lots of in vitro data which suggests that Aβ potentiates the toxicity of a number of insults, including pro-oxidants, hypoglycemia, glucocorticoids and head trauma. Aβ 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 Aβ 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 Aβ leading to contiguous spread. For example, the outer molecular layer of the dentate gyrus of the hippocampus may produce retrograde damage to entorhinal cortex.

ARF: I was under the impression that the entorhinal cortex is the area damaged earliest in AD ...

BY: It's hard to say in AD whether neuronal loss in the entorhinal cortex occurs prior to Aβ deposition in the dentate gyrus. Another issue is that if a neuron is undergoing degeneration due to Aβ 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 Aβ 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 Aβ 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.

ARF: What about Aβ 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?

BY: There's likely to be great variability in the course of Aβ deposition. Clearly in people who get AD, the process becomes accelerated.

ARF: What could cause such an accleration?

BY: 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-β through induction of extracellular matrix proteins, may induce vascular Aβ deposition. So if you accept this hypothesis, there are going to be a number of genetic factors that affect Aβ 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 Aβ. 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 Aβ 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.

ARF: You mention these small fibrils and oligomers. Are you referring to ADDLs?

BY: 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 Aβ 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 Aβ deposition by itself is sufficient. You also need an age-related susceptibility factor. The evidence for that is you can put the same Aβ 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.

ARF: If there's a species susceptibility factor, how useful can transgenic mouse models be?

BY: The plaque-forming APP transgenics are very useful for screening drugs that inhibit Aβ production or aggregation. Their utility for examining drugs that inhibit the neurodegenerative process at steps following Aβ 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 Aβ show much more neuronal degeneration and tau-related pathology. This is consistent with our observation that Aβ is much more toxic in the primate brain than in the rodent brain.

ARF: What clues could we get from comparing rodents and primates?

BY: 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 factor.

ARF: What accounts for the specificity of neurons affected in AD?

BY: 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 Aβ toxicity. There may also be neuronal specificity for Aβ 42 synthesis. It could be at level of where Aβ deposits occur, whether or not they convert to a toxic form, or whether particular neuronal populations are vulnerable to Aβ 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.

ARF: What's the most nagging crirticism of the Aβ hypothesis?

BY: I think the neuropathological observation of neurodegeneration, particularly in tau, that occur in areas where you can't find Aβ histologically, is something that needs one day to be explained if the Aβ 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.

ARF: What if we don't yet know what targets to look for in postmortem brain?

BY: 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 issues.

ARF: Will AD ever be cured?

BY: 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.

ARF: What about intervening with apoptotic processes?

BY: 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 percent 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.

ARF: With so many interacting possible factors, how can one say that what the primary cause is, or even if there is one?

BY: 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 Aβ in some form. It may turn out in the long run that the association of Aβ 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, Aβ 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: Aβ 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 Aβ issue unless we have an agent that targets Aβ 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 Aβ—γ-secretase, fibril formation, toxicity, etc.—and they all work, then finally, the textbook can be written.

ARF: If you had no financial or technological constraints, what experiment would you do?

BY: 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 Aβ. 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.

ARF: Do you think Alzheimer research is on the right track now, or should researchers be looking outside the field for inspiration?

BY: 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.


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