A key change within the criteria is the assurance issue, according to Dr. Mayeux, a member of the Alzheimer’s disease dementia workgroup. “While we still don’t know which, if any, biomarkers will turn out to be the best, we felt that there was some ability to use biomarkers in reviewing what is or is not going to stick and what is going to help with diagnosis down the road,” he said.
“For example, if you had somebody who met all the criteria clinically for Alzheimer’s disease but was biomarker negative, that would push that person more into the ‘possible’ range,” Dr. Mayeux continued. “Whereas if you had somebody who met all the clinical criteria and had biomarkers pointing in that direction that were supportive of that diagnosis, then it would increase the likelihood that this is indeed Alzheimer’s disease. The other thing is that, for example, people who carry early-onset mutations, those things weren’t even known when the original criteria were developed, so now we can incorporate that into the diagnostic paradigm.”
Will the New Criteria Be a Boon for Drug Development?
Despite a track record of failure for drugs in clinical trials, Dr. Fagan believes that effective treatments for Alzheimer’s disease are on the horizon. “For years, we have hypothesized that it’s because the clinical trials have been designed poorly,” she said. “They’re choosing to enroll people who already have dementia, and by the time dementia is apparent, you’ve already lost tremendous numbers of neurons in the brain. You’re not going to get those back no matter how much you remove the pathology. The best thing to do is to actually intervene earlier in the disease process before symptoms. There are all kinds of ethical and medical issues that come along with that, but I think that’s where the field is going.”
Dr. Fagan also recommended retesting some drugs that have not panned out in prior clinical trials. “This new categorization and new appreciation of this preclinical phase may make companies be willing to test those therapies again, but in populations before the onset of symptoms,” she said.
Most drug studies have also specified that participants had to have memory loss, Dr. Weintraub added, pointing out that some patients with Alzheimer’s disease initially have other kinds of cognitive deficits and may respond differently to medications. “We don’t take that into account when we’re lumping everybody together in Alzheimer’s disease or when we exclude those people because they don’t have memory loss, so I think that it’s going to increase the purity of the sample,” she said.
“The biomarkers are getting closer to the biology, and so another way the treatments could be evaluated is by their effect on the biomarkers,” commented Dr. Weintraub. “For example, maybe for five years your brain has been shrinking at a rate of 1% a year, and then you take a medication and it’s not shrinking anymore … or your CSF fluid looks different because we’ve given you a medication that causes you not to release amyloid into your CSF. I think the biomarkers are going to be really important in terms of medication impact on the disease course.”
New Guidelines in Perspective
“The intent is to be more accurate and to get people the help that they need, and the best way to help people is to cure the disease or stop its progression before clinical symptoms appear,” said Dr. Fagan. “It was well acknowledged at the meeting that the working group of the preclinical criteria had the hardest job, because not only is there less known about that, but the implications of it are still unclear. So that’s another reason why it’s still definitely in just the research setting…. It’s really important not to overstate things or to understate things. And these criteria are based on what we know in the literature to date, and that’s going to change.”
Dr. Weintraub emphasized that there are different levels of certainty regarding a diagnosis of Alzheimer’s disease. “We do not have a single pathogen with Alzheimer’s disease,” she said. “We are really not at that point yet. So what we do is gather all the available bits of evidence to increase the level of suspicion. Do we have a blood test for Alzheimer’s disease? No, but that’s what we’re aiming for…. There’s not a single cause. It’s many things that combine to increase the risk that one person is going to produce more of these pathologic features in his or her brain than another. And it may be a combination of what’s going on in your brain and then what you’re doing in the rest of your body to reduce your risk, like controlling blood pressure and cholesterol, exercising, and eating properly.”