ARF: Dr. Mayeux, your research has revealed several risk factors that are associated with AD. What do you think are the most important risk factors for the development of AD?
RM: I think the most significant risk factors are genetic. The evidence accumulated over the last decade is pretty clearly pointing to a genetic etiology for the disease. For example, there is no question that in early onset familial AD, mutations in 3 key genes (APP, PS1, PS2) almost invariably result in disease. What remains to be established is whether there are other mutations, as yet unidentified, in other genes that explain the remaining cases of early onset, familial AD (EOAD). In addition, there are sporadic cases of EOAD that are unexplained and that don't appear to have a strong family history. Because we have learned that presenilin1 may have new mutations, it is possible that something like this causes EOAD in the remaining cases.
ARF: Are these presenilin mutations somatic or germ-line mutations?
RM: Germ line.
ARF: What about late onset AD?
RM: With late onset AD, the APOE story has been truly remarkable. There is no debate that APOE-e4 is a strong risk factor for late onset AD (familial and sporadic), but what we don't know is exactly how APOE-e4 increases the risk. We also don't know whether the polymorphism is modified by other factors—either genes or environmental—that also contribute to the risk of AD. There is weak evidence that head trauma or smoking may interact with APOE in some curious way. There is currently no other known polymorphism in any other gene that is associated with late onset AD to the degree that APOE-e4 is associated.
The alpha-2-macroglobulin polymorphism remains controversial. There are hints from other large studies suggesting that there are other loci in late onset AD. However, no specific mutation or polymorphisms in genes have been identified. It may just be a matter of time and luck before that happens.
Now, having said that, a number of case control studies have looked at genes that might be biologically related to AD. The IL-1 polymorphism on chromosome 2 has been the subject of three reports that now suggest an association with AD. The same group of investigators has been involved with each study, but they are in different populations. This is pretty interesting and it may hold up. If it is true, it will be first polymorphism associated with AD that was found using this non-traditional study design. That in and of itself would be pretty remarkable. Again this points to a disease in which genetic influences are perhaps the strongest risk factors and may account for the highest contribution to disease risk.
What is intriguing about all the genes that have been implicated in AD is that they all point toward a disturbance in amyloid metabolism from amyloid precursor protein (APP) down to the deposition of A-beta. So that I think is very simple and biologically sensible.
ARF: What about environmental factors such as head trauma?
RM: The head trauma story is controversial and inconsistent. About half the studies show that there is a strong association between AD and head trauma, while half the studies do not. If true, the association is probably weak and the association of head injury to AD risk must be very small. Head trauma may interact with genes such as APOE. In one study we found an interaction between head trauma and APOE-e4 . However, others could not confirm this study. So it is not yet clear whether environmental factors, like head trauma, trigger AD among people who are genetically susceptible or whether the genetic susceptibility is the driving the relationship.
ARF: Will treatments be aimed at these aberrant genes?
RM: It look like scientifically based treatments are starting to emerge. Obviously, if the primary cause of AD is the overproduction of A-beta 42, as in EOAD, and if late onset AD is a result of faulty clearance of A-beta 42, then targeting A-beta 42 would be the first logical step. The amyloid vaccine being developed by certainly looks promising and could directly attack A-beta 42. The animal studies looked very encouraging. Vaccine use in people that are genetically susceptible will be an important preventive step.
However, there is also encouraging data concerning PS1 as either "the" gamma secretase or the active site for this enzyme. If gamma secretase inhibitors currently in development prove to be safe and effective in diminishing the amount of A-beta 42 generated, such a drug in people at high risk would also seem logical. I imagine that we will eventually use genetic factors to identify people who are at extremely high risk and then we will target prevention therapies, either vaccines or drugs, which reduce the risk of AD to a minimum. The first prototype will probably be drugs that target the amyloid pathway. At least that is my guess.
ARF: What about current treatments? Will they be obsolete? For example will cholinesterase inhibitors not be used in the future?
RM: I don't know. It may be that once you get rid of the amyloid or halt the amyloid deposition process, you still may have memory impairment and we may need cholinesterase inhibitors as well. If I had to make a guess, I would say that you see the use of cholinesterase inhibitors decrease once preventive strategies are developed.
ARF: Is there still a need to map out more susceptibility genes?
RM: Absolutely! The problem is that those contributing most to AD have probably already been found. Probably the remaining genes that the AD gene hunters are looking for are genes in which mutations or polymorphisms are rare. These mutations and polymorphisms may account for only a small proportion of disease. It is also possible that new allelic polymorphisms modify existing AD genes by some, as yet unknown, gene-gene interaction. In other words, I think it is going to be difficult.
On the other hand, seeking them out is very important since there still are a very large number of people whom we cannot explain why they have AD. The gene hunters and the epidemiologists interested in AD are beginning a dialog. We should help in this effort. It is going to be important to keep this line of research open.
As the biology of this disease continues to be worked out, more targets along the amyloid cascade may become available. Perhaps tau or alpha synuclein will be important targets too. It is conceivable that we will create genetic profiles to assess risk in people. It won't be a single gene, but a cluster of genes that we will have to understand. And then probably some of these inconsistencies in environmental factors, such as smoking and head injury will start to become clearer. If I had to make a prediction, I would say that genes will tell the story and environmental factors will be modifiers of genetic risk but only subtle modifiers and not major modifiers.
ARF: Could you please describe the goals and aims of your own research?
RM: I'm trained both in neurology and epidemiology, so most of my research is centered on the epidemiology of AD. We were the first to show in a prospective study that estrogen in post-menopausal women might be useful in disease protection . We have also looked at education and head injury all in prospective studies . These are at an advantage to cross-sectional or case control studies.
Our strategy is to identify healthy populations and test hypotheses such as, what is the effect of estrogen use among post-menopausal women on AD risk? What is the effect of having an APOE-e4 allele in a healthy person over a 5-7 year period? Primarily large scale prospective longitudinal epidemiological studies examining both genetic and environmental risk factors for AD. Paying attention to risk factors, either genetic or environmental, that increase risk. Also examining behaviors, drugs or dietary supplements that lower risk. We have also worked in various ethnic groups to determine how APOE-e4 and other genes segregate in those groups and how they affect disease risk.
ARF: Has the data regarding estrogen use been demonstrated in other studies?
RM: There are about 5 observation studies now showing basically the same results that post-menopausal women who use estrogen have lower risk of AD. Currently, one of my colleagues, Mary Sano, is leading a study in which women who have a family history of AD are randomized to estrogen or placebo to see whether or not we can actually reduce the risk of the disease.
ARF: Is the diagnosis of AD currently accurate enough that those studies can be performed or do we need to wait for post-mortem analysis.
RM: There is myth that the only way you can diagnose AD is through post-mortem histopathology. This may, in part, be correct but neuropathologists do not always agree on the criteria to make this diagnosis at death. This make the concordance between the clinical diagnosis and the pathological diagnosis difficult. Nonetheless, a clinico-pathologic study from the 27 AD centers yielded an overall accuracy of ~90% at least at AD research centers . The clinical diagnosis has high sensitivity, but lacks specificity. Physicians seldom confuse dementia with normal cognitive function, but they can incorrectly attribute dementia to AD when another diagnosis is present. So I would say the accuracy of clinical diagnosis is pretty good. It has gotten better with MRI, neuropsychological testing and supporting laboratory studies. Someday soon we may also include genetic information.
ARF: What is most confounding diagnosis?
RM: I think cerebrovascular disease. The dilemma is because cerebrovascular disease and AD often coexist. Some investigators have postulated that cerebrovascular risk factor increase the risk of AD, while others do not support that view. There are data that suggest that if you have AD and then have a stroke the disease onset may occur earlier. Does long standing HTN predispose one to AD? These are questions that people have that are currently unresolved. Obviously having multiple strokes and AD is not good and is certainly worse than having one disease. So whether cerebrovascular disease has a causal relationship to AD or whether cerebrovascular disease and AD simply share risk factors is unclear right now.
About 25% of healthy elderly have a stroke on MRI or CAT scan for which they have never had symptoms. Silent strokes occur in a good portion of the population. We don't know whether that triggers something or is even important. Currently vascular biology of the brain is extremely important and not fully worked out in terms of the relationship to degenerative disease.'
ARF: What advice can you offer to young investigators in the AD field?
RM: This is the renaissance of AD research. We know a lot more, the methods are better, the imaging is helping us sort out who is going to get AD and who is not. The genetics are very exciting, and AD is a major public health problem that will only increase in the immediate future. Unraveling the biology of A-beta, tau and alpha-synuclein will making it a tremendous time for those involved in applied research. There will be more tools to ask more and more specific questions. The jump form bench to the bedside will become easier. So I think that it is quite an exciting time to work in clinically oriented research especially from the avenue of biological markers or epidemiology.
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