Why Alzheimer's disease damages certain parts of the brain

Memory loss is usually the first symptom of Alzheimer's disease, followed by confusion and difficulty
thinking.
These symptoms reflect a typical pattern
of worsening brain tissue damage.
Toxic protein clusters first concentrate in the temporal lobe (memory area) of the brain and then spread to parts
of the brain that are important for thinking and planning.

A study conducted by researchers at Washington University School of Medicine in St.
Louis reveals why certain parts of the brain are particularly vulnerable to Alzheimer's disease
.
This depends on the gene APOE, which is the biggest genetic risk factor
for Alzheimer's disease.
The part of the brain that APOE they found was the most active in the most damaged areas
.

The findings, published Nov.
16 in Science Translational Medicine, help explain why Alzheimer's symptoms are sometimes different and highlight an unstudied aspect of Alzheimer's, suggesting that undiscovered biological mechanisms may play an important role
in the disease.

Senior author Dr.
Brian A.
Gordon said, "There are some rare atypical Alzheimer's diseases where patients first develop language or vision problems, not memory problems
.
" Dr.
Brian A.
Gordon is an assistant professor of radiology at the Mallinckrodt Institute of Radiology in the College of
Medicine.
"When you scan their brains, you see that the language or visual areas are impaired, and the memory areas are less
impaired.
People with atypical Alzheimer's disease are often excluded from research studies because it's easier
to study a group where all people have the same symptoms.
But what this heterogeneity tells us about how and why Alzheimer's develops the way it does, there's something we still don't know
.
There is a reason why some areas of the brain are damaged and others are not, and we don't yet know why
.
Every mystery we find about this disease brings us closer to what
we need to solve.
”

Alzheimer's disease begins with a brain protein
called β amyloid.
This protein begins to form plaques
20 years or more before people experience the first symptoms of neurological problems.
After years of amyloid accumulation, tau protein, another brain protein, begins to form tangles
.
Soon after, the tissues of the affected area begin to wither and die, and cognitive abilities begin to decline
.

To understand why brain damage from Alzheimer's disease occurs where it occurs, Gordon and his colleagues — including first author Aylin Dincer, a technician in Gordon's lab — studied 350 people
who volunteered to study memory and aging at the Charles F.
and Joanne Knight Alzheimer's Research Center in medical school.
Participants underwent brain scans, so the researchers could measure the number and location of amyloid plaques and tau tangle tangles, as well as the volume of
different brain regions.

The researchers compared the pattern of protein clumps and tissue damage in the volunteers to gene expression patterns in cancer APOE and other genes associated with Alzheimer's disease, which is described in the Allen Human Brain Atlas, a detailed gene expression map of the human brain compiled by the Allen Institute for Brain Science
.

"There's a close race in the high places you see," said Gordon, who is also an assistant professor of psychology and brain sciences at APOE
.
It's not just APOE.
For example, if you look at the first 20 genes associated with Alzheimer's disease, they are all expressed
in a similar pattern in the temporal lobe.
These regions have some essential differences that make them susceptible to Alzheimer's brain damage, differences that may be innate and influenced by a person's genes
.
”

Everyone has a different version of APOE Jean, but people with the APOE4 variant are 12 times more likely to develop Alzheimer's and suffer from it at a younger
age.
Alzheimer's researchers have long known that APOE4 increases the accumulation
of amyloid β in people's brains.
By studying mice that produced tau tangle but no amyloid plaques, the researchers demonstrated this: APOE4 also increased damage due to tau, even in the absence
of amyloid.

To assess the effects of high-risk variants of APOE in Dow-related brain damage, the researchers classified each participant as carrying or not carrying high-risk variants and analyzed protein clusters and atrophy
in their brains.

"APOE4 carriers are more likely to start accumulating amyloid, which will put them on the path to Alzheimer's," Gordon said
.
"Then, the same amount of amyloid produces more tau tangles, which leads to more shrinkage
.
" This is a double whammy
for the brain.
”

In future work, Gordon and his colleagues plan to explore the relationship
between gene expression patterns and patterns of tau damage in atypical Alzheimer's patients.

"When we see someone having vision problems, is there a specific genetic signature that corresponds to a damaged area of the brain?" Gordon asked
.
"We wanted to know why some people's patterns have changed, what this means for the development of Alzheimer's disease, and how to treat
it.
"