Diseased brain tissue from an Alzheimer's patient
showing amyloid plaques (in blue) located in the gray matter of the brain. Dr Cecil H
Fox/Science Source/Getty Images
In a disappointment to
Alzheimer's patients and researchers, drugmaker Eli Lilly said in late November
that a clinical trial of solanezumab, an experimental medication to treat the
degenerative neurological condition, had failed.
The company has pressed
on with tests of solanezumab, despite mixed results in
earlier studies. The latest test, involving more than 2,000 patients, found the
drug didn't significantly slow cognitive decline in patients with mild dementia
from Alzheimer's.
The sad refrain is a
familiar one, unfortunately.
Solanezumab is just the
latest casualty in a decades-long parade of
disappointing dementia drug trials. But the frustration brought by this
particular failure could signal a shift in Alzheimer's research — a shift away
from targeting accumulations of so-called amyloid protein in the brain, long
considered by many in the field to be the crux of Alzheimer's pathology.
Ever since Dr. George G.
Glenner's 1984 discovery that
amyloid is the main component of the plaques that riddle the
Alzheimer's-afflicted brain, it has been assumed that the protein somehow
contributes to the disorder — that it jams up cellular machinery, rendering
neurons unable to effectively communicate, to form new memories, to remember
where the keys are.
Like many other failed
medications for symptomatic Alzheimer's, solanezumab works by attacking amyloid
in the brain.
So in light of the new
findings, is it finally time to let the amyloid theory go? The answer isn't
clear.
"The low magnitude
of effects would lend support to the idea that it might be time to move on from
amyloid," says Weill Cornell Medical College neurologist Dr. Richard
Isaacson, who wasn't involved in the solanezumab study. "Yet though the
study failed overall, there were improvements in cognition and function in
treated patients."
He points out that
perhaps the tested dose wasn't high enough or that the patients' disease was
too advanced to respond. By the time symptoms of Alzheimer's arise, the brain
is already speckled with amyloid. Two other ongoing trials should confirm
whether solanezumab is more effective in patients at risk for Alzheimer's, but
who have not yet developed symptoms, he says.
Solanezumab, an antibody,
works by attacking amyloid floating in cerebrospinal fluid. A different type of
investigational medication, so-called BACE inhibitors, prevent amyloid
formation in the first place, by neutralizing an enzyme that cuts away amyloid
from a larger protein. Biogen's aducanumab, another experimental drug
that's far along in clinical testing,
binds to and clears amyloid that is already ensnared in plaques.
Earlier this year the FDA
granted aducanumab fast-track status after
results from a small, early-stage study suggested that it reduces amyloid
plaques and slows cognitive decline in people with very early stage disease.
Those people did have amyloid deposits visible with positron emission
tomography imaging. At the Clinical Trials on Alzheimer's Disease and Dementia
meeting in San Diego in early December, follow-up data were presented that
confirmed cognitive improvement out to two years of treatment.
"The good news is
that there are a number of trials in progress with different anti-amyloid drugs
in asymptomatic subjects; and that one failed drug doesn't mean that another
won't have an effect," says Dr. James Burke, professor of medicine and
psychiatry at Duke University's Alzheimer's Disease Research Center.
"These trials also suggest that the best chance for a significant effect
on cognition is likely to be treating asymptomatic people with amyloid deposits
on imaging."
Yet, Burke adds, if these
trials don't show a significant clinical benefit, the focus on amyloid will
likely end.
In any event, Weill's
Isaacson feels that researchers should be looking to other options. "I've
never been a firm believer in the amyloid hypothesis being the be-all and
end-all as to the cause of Alzheimer's," says Isaacson. "I think it's
much more complicated and there are probably many roads leading to the
disease."
Fluorescent
deconvolution micrograph of cultured glial cells expressing tau protein (in
red). Glial cells are nervous system cells that provide structural support
and protection for neurons(nerve cells). Accumulation of tau in brain tissue is
linked with a number of neurodegenerative diseases, including Parkinson's
disease and Alzheimer's disease Roger J. Bick, Kha Dinh/Mya
C. Schiess / UT-Houston Medical/Science Source
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