70 DISCOVERMAGAZINE.COM
A Roller Coaster Year for Alzheimer’s Treatment
Roughly 5.7 million Americans live with Alzheimer’s,
the neurodegenerative disease that slowly deteriorates
memory and other cognitive abilities. For more than
25 years, many experts have pushed beta-amyloid,
a protein fragment that builds up in the brain in
plaques, as one of the main suspects behind the
disease. Pharmaceutical companies are chasing beta-
amyloid hard, racing to develop drugs to ight plaque
buildup and hopefully, in turn, improve patients’
brain function. But 2018 was a mixed bag for those
potential treatments.
Several companies have been developing
products to inhibit BACE1, an enzyme critical
to the production of beta-amyloid. But clinical
trials for three of these BACE1 inhibitors ended
with not-so-promising results. One was yanked
for safety concerns after patients developed liver
problems. Another ended early after participants
had adverse effects such as trouble sleeping and
suicidal thoughts, as well as no improvement in
symptoms, despite lower beta-amyloid levels. The
third trial inished and will move on to its next
phase — even though it also showed a drop in beta-
amyloid levels without signiicant improvement in
participants’ symptoms.
Companies testing another type of pharmaceutical
— antibodies that break down amyloid rather than
prevent its production — checked in with more mixed
results. One company reported that its antibody
reduced plaque buildup at all dosage levels; at the
highest levels, it also alleviated cognitive symptoms.
Another group, though, decided to expand their trial
before its scheduled end date to involve more people
when the antibody wasn’t testing as well as hoped.Nearly all of these results underscore a crucial
question: Is beta-amyloid the real boogeyman
behind Alzheimer’s? Big Pharma seems to have put
all of its eggs in this basket with hardly any payoff.
Most of the drugs are failing, and the one that
did report positive results only overcame the real
hurdle — an improvement in cognitive function —
in people who got the highest dose, despite amyloid
levels dropping for all participants. The confusing
outcome has many experts concerned about what
this means for amyloid’s role in Alzheimer’s. If drug
companies continue hitting dead ends, soon they’ll
have to more seriously consider other culprits,
such as tau, another protein that builds up in
Alzheimer’s-riddled brains.NEUROSCIENCE
2018: Trials and Tribulations
May
Janssen shuts
down its trial of
BACE1 inhibitor
atabecestat
because of
safety concerns.February
Biogen
tweaks
design of its
trial for the
antibody drug
aducanumab.February
Merck stops Phase 3 trial on BACE1
inhibitor verubecestat. The move
comes a year after an earlier trial in
which patients showed lowered beta-
amyloid levels, but with adverse effects
and no improvement in brain function.Healthy brain Alzheimer’s brainTOP: A. PAKIEKA/SCIENCE SOURCE. BOTTOM: NATIONAL INSTITUTE ON AGING/NATIONAL INSTITUTES OF HEALTHBrain slices from two individuals, one healthy (left) and the other
with Alzheimer’s (right), reveal the devastating changes wrought
by the disease, including nerve cell death and decreased volume.Beta-amyloid plaque