To Solve Alzheimer’s Mystery, Better Biological Clues Sorely Needed

7/29/14Follow @alexlash

The other day, I found a video on the website of the Alzheimer’s Association, a nonprofit foundation. It was part of an HBO documentary series produced a few years ago by Maria Shriver to educate the public about Alzheimer’s disease.

The first couple minutes showed people going into scanners, doctors gently examining patients, color-contrasted brain scans, that sort of thing: images to let the viewer know that thoughtful science is taking place. Then one of the voices in the voice-over track said, “We are at the brink of controlling one of the major diseases affecting world health.”

I had to rewind to make sure I heard correctly. Like everyone else, I want that statement to be true, in particular for a recently diagnosed family friend who, as a lover of both science and writing, has been a mentor to me; and in general for us all. According to the Alzheimer’s Association, the disease is the sixth leading cause of death in the U.S., up 68 percent in the previous decade. The societal and financial burden on caregivers and taxpayers alike is already huge and expected to grow from $214 billion this year to $1.2 trillion in today’s dollars in 2050.

But I’m not sure what “brink” that disembodied voice was talking about. Yet another high-profile potential treatment, crenezumab, just delivered disappointing clinical results in people with mild-to-moderate progression of the disease.

A decade of expensive failures litter the clinical landscape. Only two drugs are approved for treating Alzheimer’s, memantine (Namenda) and donepezil (Aricept), both cognitive boosters that at best help people stay sharper for a little while. There is nothing to treat the underlying mechanisms of the disease, which remain elusive, although everyone knows aberrant forms of two proteins, beta-amyloid and tau, are involved. Most recent big failures aimed to use antibody-based drugs to clear masses of misfolded beta-amyloid, called plaques, from the brains of people with obvious disease.

Now the scientific and clinical momentum has shifted to treating Alzheimer’s early in its trajectory, perhaps even before patients start showing symptoms. (Indeed, the recent crenezumab data showed some hope in the subset of people with the mildest Alzheimer’s symptoms, and there were similar findings for Eli Lilly’s solanezumab, even as it failed a high-profile Phase 3 trial in 2012. Lilly has continued testing solanezumab in early-stage patients.)

Problem is, the medical field has no surefire way to tell from someone’s behavior or biology if he or she will eventually descend into Alzheimer’s dementia. That’s why some of the biggest stories to emerge from a major conference two weeks ago in Copenhagen were not just about drugs, they were about biomarkers. Biomarkers are indicators that give clues about the progression of disease, or risk of disease. They could be in our genes, in our proteins, in our behavior, and in images of our organs.

We desperately need good biomarkers to point the way for researchers to develop Alzheimer’s interventions. We’ve known this for some time. One major biomarker project called the Alzheimer’s Disease Neuroimaging Initiative, or ADNI, dedicated to collecting and analyzing cognition tests, brain images, blood, and cerebrospinal fluid from more than 1,000 people, has been underway since 2004.

And if indeed the time to halt the disease with therapeutic interventions is ten, fifteen, twenty years or more before symptoms show up, we’ll need nearly ironclad indicators about who’s going to get the disease for two reasons: First, so drug developers can test their experimental drugs on the right people. Second, so when drugs are eventually approved, doctors can feel secure giving powerful treatments to someone who seems normal (or is showing signs of what could be other kinds of cognitive impairment).

For some major diseases we’ve reached that point with preventive medicine. If someone has elevated levels of the bad kind of cholesterol, his or her doctor is likely to prescribe statins to reduce the risk of heart disease.

But there’s no easy through-line in Alzheimer’s; indeed, the one sure-fire predictor is particularly cruel. People with a rare form of the disease inherit a genetic mutation and fall ill, usually in their 40s or 50s, much earlier than in the far more common non-inherited (or “sporadic”) form of Alzheimer’s. Even if a drug allows people with that rare, desperate genetic profile to avoid illness—as an ongoing prevention trial using the amyloid-clearing crenezumab aims to demonstrate—there’s no guarantee the sporadic Alzheimer’s population would benefit from that treatment. The $100 million trial, currently scheduled to wrap up in 2020, is being funded by Roche’s Genentech unit, which is developing crenezumab; the National Institutes of Health; and the Banner Alzheimer’s Institute in Phoenix, AZ, which is leading the study.

Another genetic biomarker (having two copies of a genetic variant called ApoE4) puts a person at much higher risk of the sporadic course of the disease. But that marker, discovered two decades ago at Duke University, has also proved frustrating. The ApoE4 protein hasn’t been “druggable,” as they say in the business, because it has a role in too many processes in our bodies.

In fact, researchers could identify all kinds of genetic factors and still might not be able to identify with confidence, let alone treat, the people destined to succumb to the common form of Alzheimer’s. John “Keoni” Kauwe, a Brigham Young University geneticist (and the scientific lead of a novel research approach that I’ll discuss in a moment) told me something eye-opening last week. When researchers score their ability to predict whether or not a person will get Alzheimer’s on a scale of 0 to 1—where 1 is a perfect prediction and anything over .95 is clinically useful—just knowing someone’s age and gender gets the confidence level to .73. That’s “better than random but not clinically relevant,” Kauwe said. Add a person’s ApoE status, and the scale inches up to .78.

Add all the other Alzheimer’s-related genes discovered up to 2012, and the score goes to a mere .82. “So the story is, genetics is only going to add a moderate amount to the ability to have prognostic prediction of the disease,” Kauwe said.

That’s why he and many others say it’ll take more than one type of marker to not just identify with confidence people with high risk of disease, but also treat them. In addition to genetics, the data will come from brain images, measurements of proteins in our blood and cerebrospinal fluid, behavior and memory tests, and perhaps other noninvasive but high-tech scans of our eye movements and retinal deposits. I’ll run through some of the latest news in each area at the end of this column, but it’s important to point out how many hurdles there will be, not just in pinpointing the right biomarkers but also turning them into practical solutions.

The Alzheimer’s patient advocate group USAgainstAlzheimer’s has a rallying cry of stopping Alzheimer’s by 2020. But here’s the founder George Vradenburg, a former top media executive, on the complexity of discovering, then validating biomarkers for early detection and intervention: “I think the [technical] sophistication will be there in the next few years, but I don’t know if it will be practicable at a clinical level.”

He thinks a spate of trials in people at risk but asymptomatic, including one called A4 and another called DIAN, that are using “virtually every known technique” to record biomarkers, will point to ones to rely on within a few years. But it could remain complicated. Each stage of the disease could have its own set of markers, and measuring them could be intrusive or costly (or both) for patients. For example, Vradenburg says, imagine a person saying to his or her doctor, “I’m worried my memory is slipping,” but the normal cognitive assessments (which have their own flaws) show nothing. Is the doctor going to prescribe a couple different brain scans and a spinal tap? At that point, says Vradenburg, “you won’t give a test for it unless it’s relatively inexpensive and painless,” which, respectively would rule out the brain scans and the spinal tap, as currently offered.

The novel research model I mentioned earlier—BYU’s Kauwe is scientific lead—is called the Alzheimer’s Disease Big Data DREAM Challenge #1, or AD#1. It’s an open-source competition, of sorts, in which teams of bioinformatics experts are allowed access to three stores of Alzheimer’s biomarker data—from ADNI, Rush University Medical Center in Chicago, and the public-private European AddNeuroMed study—and asked to use their Big Data expertise to make predictions about patient populations. For example, one of the three challenges in the competition asks participants to predict which cognitively normal individuals from the data set might have underlying amyloid plaque buildup. (The idea is to shine more light on why approximately 30 percent of people with plaques never suffer Alzheimer’s-like declines.)

The AD#1 competition is worth watching for a couple reasons. First, it might advance the field toward more accurate biomarkers. But it also might answer a broader question: Given that Alzheimer’s is so complicated, with so many kinds of biological information to analyze, do we need a different structure to tackle it?

Those running the project made the three data sets commonly readable, no easy feat in the world of Big Data, and they’re still a fraction of what’s out there. “The ability to detect pre-symptomatic disease would be very beneficial and it could not be tackled well” with AD#1′s data limitations, wrote Stephen Friend, president of Sage Bionetworks, in an e-mail to Xconomy. Sage is a Seattle nonprofit that builds collaboration platforms for health research, including the DREAM challenges.

If indeed bigger, interwoven data sets are the way forward, the AD#1 challenge should be an interesting test case.

Four decades after the U.S. declared a “war” on cancer, there have been battles won and plenty of advances, but no victory. The medical field has spent far fewer years with a similar focus on Alzheimer’s; it was only two years ago the Obama administration unveiled a national plan to find a cure by 2025.

I don’t think we’re on the brink of “controlling” Alzheimer’s. I think the best we can hope for is for researchers to make advances toward an eventual preventative—in particular by sharpening our understanding of the biomarkers of the disease in its earliest stages. (Earlier I discussed genetic clues. Below, I’ve highlighted recent developments in other main areas of biomarker research.) Before there’s a cure, society needs smaller but helpful ways to lessen the disease’s impact upon those already showing symptoms. If those things don’t happen, we’ll find ourselves instead on the brink of an abyss, into which many of our loved ones, friends, and colleagues are bound to fall.

Imaging

Researchers no longer need to wait for an autopsy to see the ravages of Alzheimer’s disease on a patient’s brain. Positron emission tomography (PET) scans combined with radioactive tracers now show the buildup of beta-amyloid plaques in living patients’ brains. The problem, however, is that the presence of plaques in the brain doesn’t always indicate Alzheimer’s disease. Approximately 30 percent of people with plaques never show symptoms. A second major protein implicated in Alzheimer’s, tau, forms abnormal tangles in diseased brains that are detectable on PET scans, and tau might be more closely associated with cognitive decline. A study discussed at the recent Copenhagen conference pointed toward that association. “Preliminary data suggest that tau in these brain areas is related to memory decline in normal older individuals,” Keith Johnson of Massachusetts General Hospital, the lead investigator, said at the conference. “This study demonstrates the potential for PET technology to be used for early detection, and to help pick participants for prevention trials and treatment trials that target tau.”

Tau imaging is also a big part of a new initiative built as a companion study to the A4 trial. Called LEARN, the study is funded by the Alzheimer’s Association’s largest grant ever. A4 is testing an anti-amyloid treatment in people with amyloid buildup but no Alzheimer’s symptoms. LEARN will enroll some of those who test negative for amyloid buildup, track their cognitive states, and test them for tau abnormalities, among other things.

Cerebrospinal Fluid

Researchers are also tapping into patients’ cerebrospinal fluid to measure the proteins floating around. Variations of beta-amyloid and tau are of keen interest, in part fueled by the realization that beta-amyloid plaques aren’t always correlated with dementia. Could the beta-amyloid still washing about in the spinal fluid be the problem? Some recent research implicates so-called “soluble oligomers”—or certain kinds of free-floating fragments—of beta-amyloid as the trigger that makes tau misfold, clump into tangles, and kill neurons. Acumen Pharmaceuticals of Livermore, CA, one of the few startups braving Alzheimer’s research, is creating a diagnostic to measure the beta-amyloid fragments in spinal fluid, and developing an antibody therapy to clear them. Its lead program was in Merck’s hands for several years but returned to Acumen in 2011. Acumen wants to put it into clinical trials by the end of 2016, said chief operating officer Bill Goure.

Blood

Some people can’t take any kind of needle, but for patients, drawing blood is a lot better than tapping spinal fluid. It would be cheaper, too. A blood test for Alzheimer’s biomarkers would be a big step forward. Researchers from a U.K. biotech, Proteome Sciences, and from King’s College London said in July they had isolated 10 proteins in the blood that seem to predict who with mild cognitive impairment would develop Alzheimer’s within a year. They gave it an accuracy of 87 percent and were careful to frame it as a “significant step” toward a test. But observers remain wary. Bristol-Myers Squibb biomarker specialist Holly Soares, who led a public-private project last decade to analyze the blood proteomics of people with Alzheimer’s, says work in the field in general has been promising and the field will “likely” develop many valid markers. About the Proteome/King’s College work, she only said via e-mail that it was “an independent work stream” from her group’s project. But in general, she said, “the difficulty lies in replicating the work in a prospective study”—that is, following up with a new batch of patients—”and in clarifying….how specific is the test to Alzheimer’s and not to other look-alike dementias.” Drug companies have not yet used blood tests for patient enrollment, “but pharma is definitely collecting samples in the event any of the tests can be validated,” she said.

The Eye

Imagine scanning someone’s eyes to predict Alzheimer’s. This is the most fertile ground for startups, and several are racing to build systems and prove their predictive power. Neurotrack Technologies, of Palo Alto, CA, uses a standard tablet or laptop camera to record the eye movements of a person watching images flash upon a screen. Some images are familiar, some are not. Neurotrack’s software analyzes how long the eyes linger on each image, a function of recognition memory, which is based in the brain’s hippocampus. Alzheimer’s damage starts there, likely years before the patient shows symptoms, and Neurotrack says its software can tease out subtle changes. (A healthy person spends most of the time looking at the novel images.) The test has one full data set so far: a 92-person, five-year study. A second five-year study at Emory University in Atlanta, where the test has its roots, is underway. And it has been incorporated into several studies, including the A4 presymptomatic study. “Hippocampal impairment is as early [a biomarker] as you’re going to get,” CEO Elli Kaplan told Xconomy. “We think our technology will help reduce some of the noise in the biomarker area.”

A second ophthalmological approach is a scan that measures amyloid deposits in the retina, where it turns out there are clues to many diseases, not just Alzheimer’s. But retinal amyloid seems to correlate to brain amyloid, and NeuroVision Imaging of Sacramento, CA, has a scan that can detect new plaques forming in tests three months apart, CEO Steven Verdooner told Xconomy. Those claims are based on NeuroVision’s inclusion in an Alzheimer’s trial run in part by Australia’s national science research organization. The company released interim data two weeks ago from the first 40 patients out of a planned 200 total. The number of patients tested in rigorous trials for both Neurotrack and NeuroVision are very small, to be sure. It’s early days. Both companies hope drug companies look past the small sample sizes and use the tests to help recruit patients for clinical trials. “Different companies have different criteria,” says Kaplan. Using bier tests before they’re fully validated isn’t something conservative pharma companies would typically do, but as Kaplan notes, time is passing. Vradenburg of USAgainstAlzheimer’s expresses that sense of urgency in broader fashion. If a drug has proved safe, which is critical when giving it to presymptomatic populations, the biomarker correlation shouldn’t have to be ironclad. “If you have at least some biomarkers, or strong hypotheses, regulators should lean forward” and let those at greatest risk take the drug, then follow them to understand whether the drugs are truly working. “The standard shouldn’t be that we are 100 percent certain.”

Alex Lash is Xconomy's National Biotech Editor. He is based in San Francisco. Follow @alexlash

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  • Mike Mongan

    If the incidence of Alzheimer’s has been on the rise, it may be beneficial to look at what chemicals have risen in our environment, especially in our food supply. This assumes there is a cause to the disease. People have been “getting senile” for many decades, so there may be a genetic predisposition. But there may be chemical antagonists in our food and environment.

    I remember hearing that back in the 1940′s when I was a child, there were some 40,000 common chemicals in the American environment. That number has increased dramatically. The body and brain can only process and eliminate so many. It may be impossible to go back to a simpler time. That would not eliminate the problem. It may however be productive to begin to search for non traditional antagonists.

    There has been senility in my family. So far my brother and I , both in our 70′s, are fine thus far. I am a vegetarian and prefer organic foods and lots of vitamins. He has a more traditional but conscious diet. That may not be the clue. We grew up in a polluted city back then. But those were not today’s pollutants. My career was in manufacturing, his in banking.

    If the answer lies outside of the body, it can hopefully be identified. That would at least present some avoidance strategies for individuals to adopt.