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 … Next Page »

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.