Time until dementia symptoms appear can be estimated via brain scan
Alzheimer's dementia predicted by brain amyloid levels, age

Date:
September 17, 2021
Source:
Washington University School of Medicine
Summary:
Researchers have developed an approach to estimating when a person
who is at high risk of Alzheimer's dementia but has no cognitive
symptoms will start showing signs of cognitive decline. The
approach is based on data from a single brain scan, combined with
the person's age.



FULL STORY ========================================================================== Researchers at Washington University School of Medicine in St. Louis
have developed an approach to estimating when a person who is likely to
develop Alzheimer's disease, but has no cognitive symptoms, will start
showing signs of Alzheimer's dementia.


==========================================================================
The algorithm, available online in the journal Neurology, uses data from
a kind of brain scan known as amyloid positron emission tomography (PET)
to gauge brain levels of the key Alzheimer's protein amyloid beta.

In those who eventually develop Alzheimer's dementia, amyloid silently
builds up in the brain for up to two decades before the first signs of confusion and forgetfulness appear. Amyloid PET scans already are used
widely in Alzheimer's research, and this algorithm represents a new way
of analyzing such scans to approximate when symptoms will arise. Using
a person's age and data from a single amyloid PET scan, the algorithm
yields an estimate of how far a person has progressed toward dementia --
and how much time is left before cognitive impairment sets in.

"I perform amyloid PET scans for research studies, and when I tell
cognitively normal individuals about positive results, the first
question is always, 'How long do I have until I get dementia?'," said
senior author Suzanne Schindler, MD, PhD, an assistant professor of
neurology. "Until now, the answer I'd have to give was something like,
'You have an increased risk of developing dementia in the next five
years.' But what does that mean? Individuals want to know when they are
likely to develop symptoms, not just whether they are at higher risk." Schindler and colleagues analyzed amyloid PET scans from 236 people participating in Alzheimer's research studies through Washington
University's Charles F. and Joanne Knight Alzheimer Disease Research
Center. The participants were an average of 67 years old at the beginning
of the study. All participants underwent at least two brain scans an
average of 4 1/2 years apart. The researchers applied a widely used metric known as the standard uptake value ratio (SUVR) to the scans to estimate
the amount of amyloid in each participant's brain at each time point.

The researchers also accessed over 1,300 clinical assessments on 180 of
the participants. The assessments typically were performed every one to
three years. Most participants were cognitively normal at the start of
data collection, so the repeated assessments allowed the researchers to pinpoint when each participant's cognitive skills began to slip.



========================================================================== Schindler spent years trying to figure out how to use the data in amyloid
PET scans to estimate the age at which symptoms would appear. The
breakthrough came when she realized that amyloid accumulation has a
tipping point and that each individual hits that tipping point at a
different age. After this tipping point, amyloid accumulation follows
a reliable trajectory.

"You may hit the tipping point when you're 50; it may happen when you're
80; it may never happen," Schindler said. "But once you pass the tipping
point, you're going to accumulate high levels of amyloid that are likely
to cause dementia.

If we know how much amyloid someone has right now, we can calculate how
long ago they hit the tipping point and estimate how much longer it will
be until they are likely to develop symptoms." People in the study
who reached the tipping point at younger ages took longer to develop
cognitive symptoms than those who reached it later in life.

Participants who hit the tipping point at age 50 typically took nearly
20 years to develop symptoms; those who hit it at age 80 took less than
10 years.

"When we look at the brains of relatively young people who have died with Alzheimer's, they typically look pretty healthy, other than Alzheimer's," Schindler said. "But older people more frequently have damage to the
brain from other causes, so their cognitive reserves are lower, and
it takes less amyloid to cause impairment." The power of this new
technique is that it requires just one brain scan, plus the person's
age. With that data, the model can estimate the time to symptom onset,
plus or minus several years. In this study, the correlation between the expected age of symptom onset and the true age at diagnosis was better
than 0.9 on a scale of 0 (no correlation) to 1 (perfect correlation).

After age, the genetic variant APOE4is the strongest risk factor for Alzheimer's dementia. People who carry one copy of the variant are two
to three times more likely to develop Alzheimer's dementia than the
general population, and people who carry two copies are 10 times more
likely. In this study, people with the high-risk variant hit the tipping
point younger, but once that point was passed, they followed the same trajectory as everyone else.

"APOE4 seems to have a seeding effect," Schindler said. "At very low
levels, below the tipping point, you see amyloid rising in people
with APOE4 while it's not changing in people without APOE4. That means APOE4carriers are going to hit the tipping point sooner. People with
two copies of APOE4 hit the tipping point about 10 years earlier than
people with no copies. But after that point, we see no difference between
the APOE4carriers and noncarriers." At an out-of-pocket cost of about
$6,000, amyloid PET brain scans are too expensive for routine clinical
use. However, this algorithm could help accelerate the pace of drug
development by streamlining clinical trials.

"Most participants in clinical trials designed to prevent or slow
Alzheimer's symptoms do not develop symptoms during the trials," Schindler said. "That's a lot of time and effort -- for the participants as well as
the researchers - - that doesn't yield useful data. If we could do trials
only on people who are likely to develop symptoms in the next few years,
that would make the process of finding therapies much more efficient." ========================================================================== Story Source: Materials provided by
Washington_University_School_of_Medicine. Original written by Tamara
Bhandari. Note: Content may be edited for style and length.


========================================================================== Journal Reference:
1. Suzanne Schindler, Yan Li, Virginia D. Buckles, Brian Andrew Gordon,
Tammie L.S. Benzinger, Guoqiao Wang, Dean Coble, William
E. Klunk, Anne M. Fagan, David Holtzman, Randall J. Bateman,
John C Morris, Chengjie Xiong. Predicting Symptom Onset in
Sporadic Alzheimer Disease With Amyloid PET. Neurology, 2021;
10.1212/WNL.0000000000012775 DOI: 10.1212/ WNL.0000000000012775 ==========================================================================

Link to news story: https://www.sciencedaily.com/releases/2021/09/210917122052.htm

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