Biomarkers Setting the Pace of Alzheimer's Research

What were the biggest stories in Alzheimer’s care this year? Regarding research? Regarding therapeutic development?

Russell H. Swerdlow, MD: I think it was clinicians trying to figure out how to utilize biomarker tests, such as amyloid scans, within the clinical diagnostic setting.

It will be a process, as there are still a number of issues to be worked out. One issue is third party reimbursement for amyloid scanning. If there is no third party pick-up, the test will continue to be strategically ordered (in cases where there truly is diagnostic equipoise). If third parties start to pay for it, we docs will need to decide whether to routinely order them on all cases, or whether to continue to use them mostly for difficult cases. If we start to commonly use it, we will need to decide whether to abandon the low-yield tests we now routinely pursue (MRI, B12, TSH, blood counts, liver function, blood electrolytes). If we start using it routinely, we will also need to resolve what to do when objectively cognitively intact individuals have positive findings, and what to do when we start finding sometimes the test itself is not clear-cut or equivocal.

In the treatment-testing field, there’s a growing emphasis on the treatment of individuals with brain amyloid plaques but without cognitive decline.

John Trojanowski, MD, PhD: The big news this year is the launch of at least three different clinical trials on Alzheimer’s disease (AD) that are prevention trials.

Bapineuzumab and solanezumab failed in 2012 and this led to intense discussions about why antibodies that seem to work so well in animals—and even appeared to clear plaques from some of the patients who were treated—did not show clinical improvement in the bapineuzumab and solanezumab clinical trials. Long story short, the post-hoc analysis of the solanezumab clinical trial data showed that the milder AD patients may have had a benefit that was washed out or not detected when the mild and the moderate AD patients were analyzed together; the endpoint of that trial was to analyze both together, so in the post-hoc analysis, despite the fact that solanezumab showed a benefit in mild patients, it doesn’t count for the FDA’s approval process.

The solanezumab trial will be re-done in mild patients, and there are three clinical trials that are prevention focused, meaning these are people who have been shown by amyloid imaging to have amyloid deposits in their brain but don’t have dementia, or are at high risk to develop AD for genetic reasons. Thus, some of the clinical trials involve people who have AD gene mutations that mean they will get AD in a short period of time, as exemplified by the Columbian Medellín trial run by Eric Reiman.

These preventative clinical trials certainly are big, big news. And I think what this reflects is the continuing impact of Alzheimer’s Disease Neuroimaging Initiative (ADNI) on clinical trial design because many of the biomarkers that are now being used in these clinical trials have been studied and validated in ADNI. We’ve learned, for example, that in past clinical trials, 25 percent of the people who were thought to have Alzheimer’s, when they were subsequently studied by Alzheimer’s biomarkers through cerebral spinal fluid or amyloid imaging were found not have that pathology. Just imagine clinical trials that are being done on people with dementia with a drug targeting Amyloid-beta who don’t have Abeta. So you’re treating people who are clearly demented but the cause of the dementia is something other than Alzheimer’s disease. ADNI continues to have a profound impact on our understanding of the progression of Alzheimer’s disease.

In the experimental area, I think some of the biggest discoveries this year have been those related to growing body of evidence that Alzheimer’s pathology and plaque and tangle pathology can be seeded and propagated by Abeta, alpha-synuclein or tau fibrils in cell culture and following injections into the brains of transgenic mice and in the case of alpha-synuclein, even wild type mice. It shows there is templated seeding of these pathologies in cultured cells and in animal models and that this is likely to account for the stage-wise progressions of AD. This was first demonstrated in 2009 using pathological tau containing brain lysates and in 2013 for synthetic tau fibrils, and early 1990s for Abeta using brain extracts from human AD patients; but this year there were data showing synthetic Abeta fibrils and synthetic tau fibrils could do this.

The Alzheimer’s disease genetics consortium led by Gerard Schellenberg reported new GWAS data with numerous 50 new Alzheimer’s linked genes, all of which may contribute to some extent to Alzheimer’s risk albeit less than the strong effects of ApoE4, but it’s important to identify as many risk genes as possible.

I think the topline statement is studies continue to expand on and deepen our knowledge of the cell-to-cell spread of tau pathology, Abeta pathology, and also alphasynuclein pathology.

What do you think 2015 has in store for Alzheimer’s care? Are there any studies you’re looking forward to, or think there are any new trends in patient management that might emerge?

Dr. Trojanowski: I think the concept of prodromal Alzheimer’s disease and how to identify people at risk for Alzheimer’s disease will continue in the next year and I think we’ll hopefully learn more about tau imaging. Tau imaging studies were initially published in 2013 on very few human subjects; we’re now waiting on larger studies to complete and they’ll probably be out in 2015 to show how useful tau-amyloid imaging might be in Alzheimer’s diagnosis and also the diagnosis of frontotemporal degeneration, too. Finally, I expect a tsunami of new papers on the transmission of tau, Abeta and alpha-synuclein pathology.

John Trojanowski, MD, PhD is Director of National Institutes of Health/National Institute on Aging Funded Alzheimer’s Disease Core Center at the University of Pennsylvania.

Russell H. Swerdlow, MD, Director of the Alzheimer’s Disease Center at the University of Kansas School of Medicine.