Alzheimer’s: Syndrome or Pathology, Revisited
In yesterday’s presentations and discussions, some researchers noted that they use the term Alzheimer’s to refer to Alzheimer’s pathologies (plaques and tangles) but also to a set of symptoms which, at least in old age, is commonly caused by a number of pathologies. This can be confusing, at least to laypeople.
This came up again today, with Ron Petersen of the Mayo Clinic noting that not separating the syndrome from the underlying pathology caused trouble yesterday. In response to a question from a panel member about diagnosing people with biomarkers when there’s no good treatment and when there would be psychological and financial implications, Dr. Petersen said he endorsed this concern, especially with respect to the role of amyloid biomarkers. “All they tell us is about the presence or absence of cerebral amyloidosis, which may not equal Alzheimer’s disease,” he said. These tests are valuable to have as indices in the clinical picture, but it’s very different to say they mean someone has Alzheimer’s, he added.
David Bennett from Rush University said that even in clinical trials, it will be a challenge to document that biomarkers (such as amyloid imaging) are valid indicators of the disease process.When it comes to using biomarkers for people with mild memory loss, or even no symptoms, panel members had even more concerns. One issue was that using data on progression from mild cognitive impairment to Alzheimer’s from memory disorder clinics doesn’t reflect what’s going on in the overall population – rates of progression, or “conversion” might be much higher in memory clinic patients. Again, Dr. Petersen urged “real caution” in identifying people with no symptoms with biomarkers – “we just don’t know yet,” he said.
“A whole lot of things happens to brains that can lead to dementia,” Hugh Hendrie from Indiana University School of Medicine said. Chances are we’re looking at different mechanisms. The problem is, sometimes these mechanisms are difficult to detect. We’re good at detecting Alzheimer’s disease, getting better at detecting cerebrovascular disease. But we’re not good at detecting others – separating the mechanisms from the outcomes is not an easy thing to do.” [I loved Dr. Hendrie’s presentation – he is the Gore Vidal of the Alzheimer’s research world. I’ll try to write more about it later.]
Finally, one panel member asked presenters to predict how long it will take for the science around identifying “this disorder” [Alzheimer’s?] to become so certain that to not provide prevention or treatment would be unethical. Although he didn’t address the question directly, Dr. Hendrie said the problem is we don’t know how to prevent Alzheimer’s, and he’s not sure we really know how to treat it. No one else (at least not the other two presenters on the platform) was brave enough to attempt an answer.
Possible Interventions, Revisited
These presentations could be summed up with a quote from Dr. Bennett. “What factors have been conclusively shown to protect against either Alzheimer’s disease or cognitive decline? None.” Duke University’s systematic review of all quality data also showed that there is not yet enough high quality evidence to support any of the interventions that have been proposed.
But the following were discussed:
- Mediterranean diet, physical activity and cognitive engagement may decrease the risk of Alzheimer’s and cognitive decline
- Diabetes and smoking may increase the risk of Alzheimer’s and cognitive decline
- Brain training may improve mental function in the areas trained, and the results of one trial (the ACTIVE trial) hinted that there could be improvements in other areas.
- Trials of estrogen, blood pressure medicines and nonsteroidal anti-inflammatories have not shown they prevent dementia, but there were metholodogy problems with these trials. Estrogen and anti-inflammatories may actually increase the risk of dementia.
- Trials of Vitamin E and ginkgo were negative
- Trials of cholinesterase inhibitors (Aricept, Exelon and Razadyne) for Mild Cognitive Impairment were negative.
Much of today’s discussion was devoted to wrestling with issues with trial design – too many issues to cover in one post! But there were two interesting themes discussed:
- The idea of lifecourse studies following people from before birth to death, presented by Dr. Bennett. These studies would presumably take into account negative and positive factors that accumulate throughout a lifetime, and could not be captured by clinical trials.
- The idea of using cognitive change over time as the end point or outcome measured in studies (also presented by Dr. Bennett), rather than whether or not a person developed Alzheimer’s disease. “We’re really interested in people losing cognition, and that is the most powerful approach to looking at risk factors,” he said. “You’re losing the specificity you get with a clinical diagnosis, but I think that specificity is a mirage.”
Ready to Make Recommendations?
Several presenters and panelists expressed doubts that the state of the science can support recommendations. Others discussed the issue that people don’t follow recommendations anyway.
Making a Real Difference
Two presenters and some panel members expressed doubts about making a real difference with any recommendations. Dr. Hendrie pointed out that most people don’t stick with exercise programs. Frederick Unverzagt, also of Indiana University, pointed out the need for more study of how brain training might (or might not) improve real life function. Finally, one of the panelists asked if study outcomes really reflect quality of life.We’ll find out tomorrow what recommendations the panel will make from all this data.