Why does Alzheimer's disease damage 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 is due to the APOE gene, which is the biggest genetic risk factor
for Alzheimer's disease.
They found that the most active part of the brain with apolipoprotein E was the most damaged region
.

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
.
When you scan their brains, you'll 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 patterns of protein clumps and tissue damage in the volunteers with gene expression patterns in apolipoprotein E and other Alzheimer's disease-related genes, which were described
in the Allen Human Brain Atlas.
The Allen Human Brain Atlas is a detailed map
of gene expression in the human brain compiled by the Allen Institute for Brain Sciences.

Gordon, who is also an assistant professor of psychology and brain science, said: "Where you see high APOE expression, where you see tau protein tangles and tissue damage, there's a close match
between the two.
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 carries some kind of APOE gene, but people who carry the APOE4 variant are 12 times more likely to develop Alzheimer's and have the disease at a younger
age.
Alzheimer's researchers have long known that APOE4 increases the accumulation
of β amyloid in people's brains.
Professor David Holtzman | and his colleagues studied mice that developed tau tangles but no amyloid plaques, and they found that APOE4 also increased the damage caused by tau protein, even in the absence of amyloid
.

To assess the effect of high-risk variants of APOE on tau-related brain damage in people, 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 puts 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 protein 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.
"

Aylin Dincer, Charles D.
Chen, Nicole S.
McKay, Lauren N.
Koenig, Austin McCullough, Shaney Flores, Sarah J.
Keefe, Stephanie A.
Schultz, Rebecca L.
Feldman, Nelly Joseph-Mathurin, Russ C.
Hornbeck, Carlos Cruchaga, Suzanne E.
Schindler, David M.
Holtzman, John C.
Morris, Anne M.
Fagan, Tammie L.
S.
Benzinger, Brian A.
Gordon.
APOE ε 4 genotype, amyloid-β , and sex interact to predict tau in regions of high APOE mRNA expression.
Science Translational Medicine, 2022; 14 (671)