The research highlights an understudied aspect of Alzheimer's disease

The research highlights an understudied aspect of Alzheimer's disease

Memory loss is often the first sign of Alzheimer's disease, followed by confusion and difficulty thinking. These symptoms reflect the typical pattern of worsening brain tissue damage. Toxic protein clusters initially concentrate in the temporal lobes of the brain -; the memory area -; before spreading to parts of the brain important for thinking and planning.

A study by researchers at Washington University School of Medicine in St. Louis provides clues as to why certain parts of the brain are particularly vulnerable to Alzheimer's damage. It comes down to the APOE gene, the biggest genetic risk factor for Alzheimer's disease. The parts of the brain where APOE is most active are the areas that suffer the most damage, they found.

The findings, published Nov. 16 in Science Translational Medicine, help explain why Alzheimer's disease symptoms sometimes vary and highlight an understudied aspect of Alzheimer's disease that suggests yet-to-be-discovered biological mechanisms may play an important role in the disease.

There are some rare, atypical forms of Alzheimer's in which people initially develop speech or vision problems rather than memory problems. When you scan their brains, you see damage to the language or visual areas and not so much to the memory areas. People with atypical Alzheimer's disease are often excluded from research studies because it is easier to study a group in which everyone has the same symptoms. But this heterogeneity tells us that there are things we still don't understand about how and why Alzheimer's develops the way it does. There is a reason why certain areas of the brain are damaged and others are not, and we don't yet know that reason. Every secret we uncover with this disease brings us closer to what we need to tackle it.”

Brian A. Gordon PhD, senior study author and assistant professor, radiology, Mallinckrodt Institute of Radiology, Washington University School of Medicine in St. Louis

Alzheimer's disease begins with a brain protein known as beta-amyloid. The protein begins to build up into plaques two decades or more before people show the first signs of neurological problems. After years of accumulation of amyloid, tangles of tau; another brain protein -; begin to form. Soon after, the tissue in the affected areas begins to wither and die, and cognitive decline begins.

To understand why Alzheimer's brain damage occurs where it does, Gordon and colleagues -; including first author Aylin Dincer, a technician in Gordon's laboratory -; examined 350 people who volunteered for memory and aging studies through the School of Medicine's Charles F. and Joanne Knight Alzheimer Disease Research Center. Participants underwent brain scans so researchers could measure the amount and location of amyloid plaques and tau tangles, as well as the volumes of different brain areas.

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The researchers compared the patterns of protein clumps and tissue damage in the volunteers with the gene expression patterns of APOE and other genes associated with Alzheimer's disease as depicted in the Allen Human Brain Atlas, a detailed map of gene expression in the human brain created by the Allen Institute for Brain Sciences.

“There was a close correspondence between where you see high APOE expression and where you see tau tangles and tissue damage,” said Gordon, also an assistant professor of psychology and brain sciences. "And not just APOE. For example, if you look at the top 20 genes associated with Alzheimer's disease, they are all expressed in similar patterns in the temporal lobes. There is something fundamentally different about these regions that makes them vulnerable to Alzheimer's brain damage, and that difference is likely baked in from birth and influenced by a person's genetics."

Everyone carries some version of the APOE gene, but people who carry the APOE4 variant are up to 12 times more likely to develop Alzheimer's disease than the general population, and at a younger age. Alzheimer's researchers have long known that APOE4 increases the accumulation of beta-amyloid in people's brains. David Holtzman, MD, Barbara Burton and Reuben M. Morriss III Distinguished Professor of Neurology, and colleagues studied mice that develop tau tangles but not amyloid plaques and showed that APOE4 also increases tau damage even in the absence of amyloid.

To assess the effect of the high-risk variant of APOE on tau-related brain damage in people, researchers classified each participant as carrying the high-risk variant or not and analyzed the 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 for the same amount of amyloid, they get more tau tangles, which leads to more atrophy. It's a double whammy to the brain."

In future work, Gordon and colleagues want to examine how patterns of gene expression are related to patterns of tau damage in people with atypical Alzheimer's disease.

“When we see someone with vision problems, is there a specific genetic signature that corresponds to the damaged areas in the brain?” Gordon asked. "We want to know why some people have these altered patterns and what this means about how Alzheimer's disease develops and how it can be treated."

Source:

Washington University School of Medicine in St. Louis

Reference:

Dincer, A., et al. (2022) APOE ε4 genotype, amyloid-β and sex interact to predict tau in regions of high APOE mRNA expression. Science Translational Medicine. doi.org/10.1126/scitranslmed.abl7646.

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