The lede on Joel Shurkin’s three-part post on Alzheimer’s disease and other dementias at Inside Science is stark and discouraging: “The great plague is coming. After 100 years of research and billions of dollars spent around the world, we still have no protection and there is none on the horizon.”
Full disclosure, Joel and I are old friends and colleagues. But I am being completely objective when I tell you that he is an exceptional science writer with a venerable record, and that this series is an enormously useful explainer about what’s going on (and not going on) with research on this most horrifying of the diseases of aging.
One reason for the laggard pace is that there is still no consensus about how Alzheimer’s develops. Researchers have long been at war over which process is more important for destroying the brain in Alzheimer’s, the tau protein tangles or beta amyloid plaque accumulation in the brain.
My nonquantitative impression is that beta amyloid has captured majority opinion. But the partisans of tau are neither cowed nor silent, and what seems like a significant new Mayo Clinic paper comes down on that side too.
It reports that studies of 3600 postmortem brains show that dysfunctional tau protein drives cognitive decline and memory loss. And it argues that beta amyloid, the other toxic protein that characterizes Alzheimer’s and builds up as dementia progresses, is not the primary culprit. Tau tangles first appear in the brain stem sometimes as early as childhood, whereas beta amyloid is found later in the cortex, a decade or more before cognition declines are obvious. Accumulations of both, the researchers say, probably occur in parallel, “eventually resulting in incompletely understood crosstalk between the pathologies.”
Writing at In The Pipeline about the new paper arguing that pathology from tau is more important than beta amyloid, Derek Lowe points out that, even if the finding holds up, it’s always possible “that amyloid-centric approaches could still be of benefit (just as it’s possible that amyloid still is the real driver of the disease state). But neither of these are sure things. Alzheimer’s has no sure things.”
As Joel Shurkin explains, drug therapies currently used for Alzheimer’s are pretty close to useless. A certain excitement has attended a new experimental drug from Biogen, an excitement especially among investors, who have driven Biogen’s stock price up significantly.
At the HuffPost Science Blog, Howard Fillit, of the Alzheimer’s Drug Discovery Foundation, calls Biogen’s baby a (sigh) breakthrough. It reportedly reduces amyloid plaques in the brain and improves cognitive function. Note that so far there is only is a very early study involving just 166 patients. The drug, called aducanumab, is not a pill. It’s a monoclonal antibody vaccine that must be administered intravenously, probably once a month.
In another In the Pipeline post, Lowe tries to be hopeful about the drug, but honesty forces him to pick some nits. He notes that every other antibody trial has failed, and it will be years before Stage III clinical trials can tell us whether aducanumab can really make a difference in Alzheimer’s.
At HealthNewsReview, Alan Cassels picks more than a few nits, not impressed with media coverage of the Biogen breakthrough and deeply skeptical of any therapy focusing on getting rid of amyloid plaques. “Alzheimer’s drug discovery has sadly experienced an almost universal failure rate of preclinical and Phase I, II, and III testing,” he says, reproducing a startling infographic from a 2010 Nature journal to demonstrate the point.
The graphic is so startling that I’m reproducing it here (and providing a link to a more legible version) to demonstrate how much more effort has gone into Alzheimer’s drugs than into drug therapies for other diseases–with essentially nothing to show for it. Given the billions in public money expended, Cassels says, you’d think there would be a taxpayer revolt.
And can we please PLEASE stop with the silver bullets? Guys, the correct cliché is magic bullets. M-A-G-I-C. The association to silver bullets is the Lone Ranger, not disease therapies.
This disorder takes a very long time to work its evils. Even if good treatments are developed, they are likely to be useless unless they can be applied early enough to halt brain disintegration. Even slowing Alzheimer’s down could contribute significantly to making life less miserable for patients and their families–not to mention saving billions of health care bucks.
Joel concludes his series with a focus on prospects for good ways of diagnosing Alzheimer’s (and other dementias) before–ideally long before–the brain becomes a wreck. There are two main approaches, he says: imaging and biomarkers.
Functional magnetic resonance imaging can apparently see bad proteins like amyloid and tau in living brains. Testing spinal fluid–not fun at all for the patient–can detect the proteins too. Brit scientists have developed a blood test they claim can predict, with 87% accuracy, development of Alzheimer’s disease within in a year among people with mild cognitive impairment. A reliable blood test would be an extraordinary advance.
The test with the most potential, Joel says, is known as A4, and studies on it are just beginning. The researchers will recruit 1100 high-risk but presymptomatic subjects, using PET imaging to try to find evidence of amyloid in their brains. The drug they’re testing, solanezumab, is said to reduce amyloid.
But wait, there’s more. At the NIH Director’s Blog, Francis Collins has just enthused over saracatinib, a not-very-effective cancer drug that AstraZeneca had shelved. Yale researchers have resurrected saracatinib and are studying it for potential utility in Alzheimer’s disease.
And then there are the researchers who say ultrasound treatments fully restored the memories of 75% of its study subjects.
At Neurologica, though, the normally skeptical Steven Novella sounds borderline excited about the ultrasound work, which he hails as a novel and noninvasive treatment. He leavens this unusual stance, though, with his native caution. He warns journalists that mice are not people, and mouse models of Alzheimer’s are not perfect duplicates of human disease because they are definitely associated with amyloid accumulation. Which is, as we have seen, still in dispute for humans.
Needless to say, the evidence that these nostrums can prevent or treat Alzheimer’s disease ranges from rickety to near-invisible. OTOH, they probably won’t hurt. And of course we should all be eating right and exercising and drinking coffee anyway.