22 Scientific American, December 2019THE SCIENCE
OF HEALTHClaudia Wallis is an award-winning science journalist whose
work has appeared in the New York Times, Time, Fortune and the
New Republic. She was science editor at Time and managing editor
of Scientific American Mind.Illustration by Celia KrampienShifting Tactics
on Alzheimer’s
After a string of drug failures, it’s time
to look beyond targeting amyloidBy Claudia WallisFor more than 25 years one idea has dominated scientific think-
ing about Alzheimer’s disease: the amyloid cascade hypothesis. It
holds that the disorder, which afflicts about one in 10 Americans
age 65 or older, is caused by a buildup in the brain of abnormal
amyloid-beta protein, which eventually destroys neurons and
synapses, producing the tragic symptoms of dementia. There’s
plenty of evidence for this. First, the presence of sticky clumps or
“plaques” containing amyloid is a classic hallmark of the disease
(along with tangles of a protein called tau). It was what Alois Alz-
heimer saw in the autopsied brain of patient zero in 1906. Second,
families with inherited defects in amyloid precursor protein
(APP) or in genes encoding proteins that process APP are plagued
by early-onset Alzheimer’s. Third, mice genetically engineered to
churn out excess amyloid tend to develop memory problems and
do better when the amyloid pileup is stopped.
This evidence and more has led grant makers and drug com-
panies to pour billions of dollars into amyloid-targeting therapies.
More than a dozen have been tested, and one by one they have
flopped. One of the biggest heartbreaks came last March, when a
promising antibody to amyloid, called aducanumab, performed
no better than placebo in patients with very early Alz heimer’s.
Meanwhile researchers pursuing nonamyloid approaches were of-
ten left out in the cold, struggling to get grants and to have their
work published. Science journalist Sharon Begley spent more than
a year reporting on the lost opportunities in an article for the Web
site Stat entitled “The Maddening Saga of How an Alzheimer’s ‘Ca-
bal’ Thwarted Progress toward a Cure for Decades.” Begley notes
that the amyloid crowd was “neither organized nor nefarious,” but
its outsized influence stifled other avenues of investigation.
And there are so many avenues! Genetic and other evidence
points to inflammation and immune dysregulation as big contrib-
utors to the disease—and likely targets for therapy. The same goes
for vascular issues. Other suspected pathways include changes in
how the brain handles lipids, glucose, protein folding, communi-
cation with gut microbes and a possible role for viruses. How and
if this dizzying array of pathways might intersect is unknown. “I
don’t think there’s an obvious linear way to put these pathogene-
sis stories together where A causes B and B causes C,” says Sam
Gandy, director of the Center for Cognitive Health at the Icahn
School of Medicine at Mount Sinai.
In choosing targets for intervention, “we can’t pick one system,”
says Mary Sano, director of Alzheimer’s disease research at Mount
Sinai. “We have to try as many shots on goal as possible.”
Gandy and his colleagues are pursuing several. In an intrigu-
ing 2018 paper, they showed that certain types of herpes simplex
virus are overrepresented in Alzheimer’s-affected brains and
might influence dementia-related human genes. “We are still
grappling with how to understand it,” Gandy says. He is also test-
ing a molecule called BCI-838 that promotes the growth of syn-
apses in the hippocampus and improves brain function in rodent
models of Alzheimer’s. Synapse preservation is probably the key
end point in beating back dementia.
Currently 96 different agents are in clinical trials aimed at al-
tering the course of Alzheimer’s, according to a 2019 analysis. Six-
ty percent target pathways other than amyloid. “Right now this di-
versity is the most important imperative,” says Richard Hodes, di-
rector of the National Institute on Aging (nia)—the top public
funder of Alzheimer’s research. In October the nia announced a
new $73-million effort to speed and diversify drug discovery.
Still, the nia is not giving up on antiamyloid drugs. Hodes be-
lieves they may prove useful in staving off dementia in people at
high risk for early-onset Alzheimer’s, such as those with inherited
mutations or Down syndrome. Blocking amyloid may be less cru-
cial or insufficient for those with the more common version of the
disease. Such people typically have vascular lesions in the brain in
addition to plaques and tangles, and they may have other age-re-
lated changes that have little to do with amyloid. Some may have
look-alike forms of dementia, including two newly proposed types
known as LATE and SNAP. Ultimately, thwarting what we broad-
ly call Alzheimer’s is likely to require more careful diagnosis and,
Sano says, “a more personalized approach.”
In the meantime, there are a few things we all can do that
might help preserve our brains: Manage blood pressure. Try cog-
nitive training. Get serious about regular exercise. And, Hodes
would add, please volunteer for clinical trials.© 2019 Scientific American