Alzheimer's Research at a Crossroads: a new conference report

Summary: A new conference report from the U.S. National Institute on Aging summarizes the presentations, discussions and recommendations of top Alzheimer’s researchers. From my layperson’s point of view, the report shows three reasons why Alzheimer’s research is at a crossroads:

1. We don’t really understand what causes memory loss and dementia.
2. Every brain is different, and multiple factors and diseases may underlie any one person’s memory problems.
3. Overall, research to date has not yielded the hoped-for answers.

Of the many recommendations made to the NIA, the ones involving broadening the concept of Alzheimer’s and collaborating with scientists in other fields make the most sense to me. The NIA meeting and report seem like good first steps towards consensus on which road to take.

Over the weekend, I’ve been reading through an excellent report on a conference on Alzheimer’s convened by the U.S. National Institute on Aging (NIA). The conference took place in October 2006, on the 100th anniversary of Dr. Alzheimer’s discovery of plaques and tangles in the brain of his patient Auguste D.

The report summarizes presentations, discussions and recommendations from top researchers attending the meeting. Advances since the death of Auguste D. are clear – better understanding of the biology and chemistry involved in plaques and tangles, the ability to “see” into the brain using neuroimaging techniques, the development of drugs to treat symptoms, and identification of genes for rare familial Alzheimer’s.

Despite the wealth of scientific advances, this report shows Alzheimer’s research at a crossroads. Interspersed with the details of biochemistry, genetics and neuroimaging are the reasons why we’re at this crossroads - I’ve added some relevant text from the report for each reason below.

1. We don’t really understand what causes memory loss or dementia. The roles of beta amyloid [the protein that makes up Alzheimer’s plaques] and tau [the protein that makes up tangles] are unclear. The significance of plaques and tangles in Alzheimer’s brains is unknown. We still don’t know much about the protein misfolding underlying Alzheimer’s and other diseases.

It, therefore, may be time to rethink the way we approach AD [Alzheimer’s disease]. Given the range of AD phenotypes [observable characteristics of the disease], we may actually be underestimating the magnitude of the problem posed by the disease. Many risk factors for the AD phenotype appear to cause the disease, but are not related to plaques or tangles or A-beta [beta amyloid] or tau. …Some emerging data from humans are indicating that other risk factors are associated with cognitive decline and risk of a clinical syndrome called AD, but really have no direct relation to the accumulation of A-beta or tangle formation, at least from a clinical-pathological point of view. [from the report’s summary of a presentation on Clinical-Pathological Relationships in AD]

AD is a disorder of protein folding and the major risk factor is aging. Studies are needed to examine what aging does to the metabolism of the proteins that are misfolding, and focus particularly on the early stages of the folding process. [from the report’s summary of general group discussion]

2. Every brain is different, and multiple factors and diseases may underlie any one person’s memory problems.

Many diseases of aging have multifactorial etiologies. For example, the average person with AD has five or six comorbidities [co-existing diseases]….we must broaden the framework in which we conceptualize the development of AD pathology. [from the report’s summary of general group discussion]

Data from 150 participants in The Rush Memory and Aging Project who came to autopsy show that in those with dementia and those without dementia, the people with only AD in the brain are roughly equivalent in the two groups. The major characteristic that discriminates between the two groups is having multiple pathologies (i.e. AD with cerebrovascular disease and/or Parkinson’s disease). …All of these pathologies are accumulating in brains that are different. Our brains differ right now. Our brains differ before we accumulate pathology. …As we accumulate pathology, we have different amounts of efficiency and ability to compensate for the accumulation of pathology. Right now, quantifying these differences in brain tissue from large numbers of persons has proven very, very difficult, but that’s something that we’re going to need to learn to do in human tissue. [from the report’s summary of the presentation on Clinical-Pathological Relationships in AD]

Five distinct pathological processes must be considered: plaques, small-vessel disease, Lewy bodies, hippocampal sclerosis [loss of cells] and atrophy. [Researchers constructed a model to see how much of the difference in cognitive functioning could be predicted by five pathologies and by age and education level]. Education was associated with 1.3 percent of the variance, plaques could be attributed with 12.2 percent, followed by [small-vessel disease] at 6.7 percent. Neocortical Lewy bodies added almost as much, and hippocampal sclerosis, even though it wasn’t particularly common, added a very significant amount. The index of brain atrophy added another 7.4 percent. Overall, however, 63.4 percent of the variance was unexplained. …Age explained nothing significant beyond what the lesions themselves had explained. [from the report’s summary of a presentation on Clinical-Pathological Relationships in AD, the vascular contribution to Alzheimer’s and the Honolulu-Asia Aging Study]

3. Overall, research to date has not yielded the hoped-for answers. Research using animals, studies of populations and risk factors, and even clinical trials all have significant shortcomings.

We must be careful when interpreting data from current animal models because the pathology is modeled through massive overexperession of selected proteins. This does not truly recapitulate the human disease because overexpression does not generally occur naturally. [from the report’s summary of general group discussion]

In summary, all AD trials designed to slow disease and delay endpoints have been negative, and there are a couple of notable treatment failures…. Despite numerous epidemiological studies demonstrating associations between risk factors and AD, no useful therapeutic has been developed from this approach. In many of these primary prevention trials, we clearly are either choosing the wrong subjects, the wrong drugs, or we’re not carrying out the trials properly. [from the report’s summary of a presentation on clinical trials]

The problem is we don’t know enough about what is happening inside the individual brain so it’s difficult to know who to include and who to exclude from trials. [from the report’s summary of a discussion about recommendations for new initiatives for NIA]

With Alzheimer’s research at a crossroads, ideas from meeting participants on how to move forward range from basic science recommendations to suggestions for improving clinical trials and starting new initiatives at NIA. With limited funding, I think it’s unlikely all the recommendations can be implemented. The NIA meeting and report seem like good first steps towards consensus on which road to take.

I don’t pretend to understand all the scientific recommendations in the report. But some of the recommendations seem interesting and feasible from my layperson’s point of view:

1. ”Consider a conceptually broader outlook: AD and its relationship to aging may be more heterogeneous than we have defined it to date.”

2. “Foster collaborations among NIA, the National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK), and the National Heart, Lung, and Blood Institute (NHLBI) to take advantage of growing evidence of involvement of cerebrovascular disease and renal disease in AD.”

3. “Bring together investigators in aging research with people working with AD models to foster progress in these issues.”

Any decisions on changing the direction of Alzheimer’s research will likely be painful for hard-working researchers and for those waiting for a cure. In mythology and in music, crossroads are mystical places associated with strange happenings and deals with the devil. With difficult decisions to be made, this scientific crossroads is not likely to be any different.

Comments

[Gail Rae Hudson]

Whoa! Thanks! Excellent summary!
Funding, of course, is a problem, but as I read this a parallel track in my brain was thinking, "Look how far we've come in cyber research in such a short time, primarily due to two factors: the glamor of the industry and its suitability to our current capitalistic economic system. Although I'd like to see capitalism overthrown, immediately and globally, this isn't practical (yet). However, it is practical and possible that medical research and, as well, the practice of medicine can be glamorized, and, by the way, universalized so that the ordinary smart person can imagine herself becoming a medical researcher without too much trouble (economic and partisan trouble) and discovering 'the next big avenue' in medicine."
The problem of money and medicine, right now, is, I think, a problem of thinking that medicine is somehow rarefied and only certain types of people stand the O2 level, thus, have any kind of a contribution to make; usually people whose families have money. Once this assumption was abandoned by the cyber industry, well, look what we're walking around with now. I wonder if the same assumption is what is holding up medical progress.
Just a thought...

[Richard Taylor]

I just came across this. You are a living treasure for folks wrestling with the diagnosis of Dementia,and the associated symptoms of probably of this or that type, and their loved ones.\

Thank you, again, and again, and again.

Richard