ARF: What is the hypothesis driving research in your lab?

SG: We are investigating the role of signal transduction in regulating b amyloid generation; both the possibility (1) that changes in signalling contribute to disease-related changes in b amyloid metabolism and (2) that pharmacological modulation of specific signalling pathways can be employed for therapeutic modulation of b amyloid metabolism.

ARF: How do you account for the anatomical pattern and cellular specificity in the progression of AD?

SG: Generally, I wave my hands. I'd predict that those areas have particularly critical levels of local amyloid-enhancing or amyloid-clearing molecules in the extracellular matrix that are yet to be identified, but I can't prove that. The idea of propagation along established projection pathways is intriguing and may be provable in plaque-forming transgenic mice.

ARF: Describe the cascade of events that lead to AD pathogenesis?

SG: Amyloid starts and causes the disease. Tau changes are related but secondary. I recognize that this is difficult to support based on their differential neuroanatomy, but I would suspect that neurons are different in their ability to form tangles or to die in response to amyloid. The current notion of "misfolded, toxic, but not histochemically visible" amyloid could also be playing a role but it is maddeningly difficult to study in vivo.

I am convinced that AD is an organ-specific amyloidosis, like the visceral and peripheral nerve amyloidoses. I see no evidence that neurofibrillary tangles in particular or neurodegeneration in general can cause typical Alzheimer amyloidosis. The recent data linking b amyloid to tau phosphorylation via cdk5 provide a very attractive way to link the two structures.

I don't understand how neurons and synapses die in AD, but, frankly, I don't spend much time thinking about it: I'd rather invest in preventing, halting or reversing the amyloidosis. I'm convinced that the disease must be prevented or halted early, and that the way to do that is to attack the amyloidosis.

ARF: What key bits of evidence are still missing that would convince you of the correctness of your hypothesis?

SG: Human clinical prevention and treatment trials.

ARF: Are there existing data that contradict your hypothesis?

SG: The most troublesome data are from plaque-forming mice with such heavy amyloid burdens and so little neurodegeneration. However, it is most important to prove that amyloid causes behavioral changes, and strong data along those lines were recently reported by David Westaway, Peter Hyslop, Paul Fraser and colleagues (Janus et al., Nature, 2000).

ARF: What evidence would convince you that your hypothesis is incorrect?

SG: If an effective anti-amyloid compound is administered to preclinical individuals with APP or PS mutations, and they go on to develop an amyloid-free dementing illness.

ARF: What therapeutic strategies will be the most promising?

SG: I still prefer prevention, with gonadal hormone replacement still promising, in my opinion. We believe that these compounds protect against AD by lowering brain levels of b amyloid, so this is a form of b/gamma secretase modulation. Ralph Martins and his colleagues in Perth have recently provided in vivo evidence for this in humans.

I like anti-aggregation agents, the betabloc vaccine, and b- and gamma-secretase inhibitors. The anti-aggregant approach is particularly attractive since this is a direct antagonist of the pathogenic step: the conversion of soluble b amyloid into aggregated b amyloid.

Since I prefer prevention, I'll have to wait for safety and efficacy data to choose which would be most reasonable for asymptomatic people, but I'd like to think that some routine pill...or some routine immunization...will be a usable prophylactic.

ARF: Will we be able to cure AD?

SG: In an ideal world, I'd probably focus on prevention. However, it is difficult, expensive and protracted to do primary prevention trials in normal people. I hope that we will be able to succeed with the same range of anti-amyloid approaches if we intervene at the very earliest sign of AD detectable with neuroimaging or psychometrics, but I'm not convinced that the "horse isn't already out of the barn". The best hope has come from mouse models of Huntington Disease where it is clear that preventing the ongoing synthesis of huntingtin protein permits the brain to recover.

ARF: Where are the most exciting research opportunities for young investigators such as myself?

SG: The greatest need is in preclinical/early diagnosis so that these terrific anti-amyloid compounds can get going! A pharmacogenomic approach might be envisioned in which a particular profile of polymorphisms could accurately predict who was at highest risk as well as what the age at onset would be and which drugs would be most effective and which ineffective. This is now possible with genomic profiling of tumors, e.g. it would be terrific to be able to get to a similar point in AD.

As you might expect, though, the greatest need is also an enormous challenge, so if one were to undertake such a program, some safer projects would also need to be in the mix. One of the biggest mistakes for young investigators is to get into highly speculative and/or highly competitive areas early on in their careers without having "safety projects" to keep themselves productive and funded!


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  1. . A beta peptide immunization reduces behavioural impairment and plaques in a model of Alzheimer's disease. Nature. 2000 Dec 21-28;408(6815):979-82. PubMed.