that the oligomeric forms, small assemblies of three to 10, are more toxic than
the long fibrils,” Finch says.
In fact, mice with a form of A-beta
that can’t accumulate into large fibrils
still show memory troubles, Takami
Tomiyama of Osaka City University
Graduate School of Medicine in Japan
and colleagues reported last year in the
Journal of Neuroscience.
This result “adds powerfully to our
theory,” Finch says.
Right now, there’s no way to visual-
ize these A-beta oligomers in a living
human brain. Autopsies and recent
developments in brain imaging allow
researchers to see larger A-beta plaques,
but working backward from the plaque
to estimate amounts of the smaller oligo-
mers is tricky. This elusive relationship,
says Sam Gandy of Mount Sinai Medi-
cal Center in New York City, throws a
wrench in studying oligomers in the
brain. “It’s really hard to get a good
accounting of how much is there.”
Lots of simulations and test-tube exper-
iments have attempted to demystify the
oligomer-plaque relationship — for exam-
ple, by considering whether there’s a criti-
cal mass of oligomers required for plaque
formation. But the “exploded drugstore”
in the brain confounds the math, Finch
says. Chemicals and salts floating around
in the brain may influence the conver-
sion rate of A-beta oligomers into plaques.
“You can do beautiful model assemblies
in a test tube … but how relevant that is to
the mess of small molecules in the brain
is imponderable,” he says.
A-beta logistics
Even though it’s not yet clear how to
measure oligomer levels from plaque,
or vice versa, new brain imaging
techniques may help clear up another
problem: identifying who’s at risk.
In 2002, University of Pittsburgh
researchers William Klunk and Chester
Mathis tested a compound, Pittsburgh
Compound B or PiB, that sticks to
plaques of A-beta in the brain and may
serve as an Alzheimer’s beacon in an
imaging scan. Though relatively new, PiB
is gaining more and more credence as a
reliable measure of A-beta plaques. An
autopsy on the first Alzheimer’s patient
to ever undergo a PiB scan confirmed
that the tracker was indeed detecting
A-beta plaques, Swedish researchers
reported January 1 in Brain.
A major question researchers expect
PiB to help answer is when A-beta buildup
starts. Though PiB hasn’t been around
long enough for long-term studies, preliminary results suggest that A-beta
plaques appear years before brainpower
declines. Healthy people with a strong
PiB signal in their brains are more likely
to exhibit mild dementia within the next
few years, a small study published in 2009
in the Archives of Neurology found.
This potentially long lag time bet ween
the start of the disease and debilitating
symptoms fits with clinical observations,
says neurologist Randall Bateman of
Washington University School of Medi-
cine in St. Louis. “Clinical symptoms are
only seen when the neurons are dead,” he
says. “We know that people aren’t symp-
tomatic until they lose 60 to 70 percent
of the neurons in key brain regions.”
Waiting until a person exhibits severe
cognitive problems and then trying to
reverse them is like “throwing a rope to
a guy that’s already jumped off the build-
ing,” says neuroscientist Charles Glabe
of the University of California, Irvine,
who is working on a vaccine-based strat-
egy to decrease A-beta in the brain. “He’s
going to hit.”
Modern medicine’s approach to
treating heart disease isn’t to withhold
therapies until after the heart fails, Aisen
and colleagues pointed out January 18 in
Neurology. Once treatments are found,
figuring out exactly when Alzheimer’s
sets in will probably help to make them
much more effective.
Yet caution is needed when interpreting a PiB-positive or PiB-negative
brain scan, especially when considering estimates that 20 to 50 percent of
healthy people go about their business
with brains chock-full of A-beta plaques.
Many of those fully functional brains
would easily earn an Alzheimer’s diagnosis with PiB scanning. It’s not clear
whether, if people were to live long
Healthy
Alzheimer’s (with plaques)
Healthy (with plaques)
Plaque marker In a PET scan, labeled
PiB protein lights up when bound to amyloid
plaques in the brain. A healthy person (top)
has little binding compared with the high levels
seen in an Alzheimer’s patient (middle). But
high levels are also found in some healthy
people with no cognitive problems (bottom).
enough, anyone walking around with
A-beta plaques in the brain would eventually succumb to Alzheimer’s.
“If I’m cognitively normal, do I care if I
have amyloid in my brain?” Klunk said at
the 2010 Society for Neuroscience meet-
ing in San Diego. “Is it irrelevant, or is
it like blood pressure, where you’re not
sick but you’re walking around with 200
over 120? That’s not a good thing.”
A-beta buildup may be the most obvi-
ous, common and even leading cause of
Alzheimer’s. But for some people, A-beta
may indeed be irrelevant.
A new battle plan
Neurobiologist Karl Herrup of Rutgers
University says that the idea of Alzheimer’s without A-beta must be considered.
Herrup points to patients who exhibit
all of the cognitive impairments that follow Alzheimer’s disease, yet for whom
subsequent imaging experiments or
postmortem tests find no plaques in the
brain. “When I talk to clinicians about it,
they all agree that this is a real category,
that it’s not just the occasional person.”
Other pieces of evidence don’t add
up either, Herrup says. The presence of
