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Findings may help explain rare symptoms such as language and vision problems – ScienceDaily

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Memory loss is often the first sign of Alzheimer’s disease, followed by confusion and difficulty thinking. These symptoms reflect a typical pattern of worsening brain tissue damage. The toxic protein clusters first concentrate in the brain’s temporal lobes — the memory region — 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 damage from Alzheimer’s disease. The matter comes down to Gen APOE, the largest genetic risk factor for Alzheimer’s disease. Parts of the brain where APOE They found that the most active are the areas that cause the most damage.

Findings published on November 16 in Scientific translational medicine, helps explain why Alzheimer’s symptoms sometimes vary, and highlights a poorly understood aspect of Alzheimer’s disease that suggests that as-yet-undiscovered biological mechanisms may play an important role in the disease.

“There are some rare, atypical forms of Alzheimer’s disease in which people first develop problems with language or vision rather than memory,” said senior author Brian A. Gordon, Ph.D., assistant professor of radiology at the Mallinckrodt Institute of Radiology at the School of Medicine. . “When you scan their brains, you see damage to the language or visual area, not so much the memory area. People with atypical Alzheimer’s disease are often not included in research because it is easier to study a group where everyone has the same set of 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 some areas of the brain are damaged and others are not, and we don’t know the reason yet. Every mystery we uncover with this disease pushes us closer to what we need to solve it.”

Alzheimer’s disease starts with a brain protein known as amyloid beta. The protein begins to form plaques two decades or more before a person shows the first signs of neurological problems. After many years of amyloid accumulation, tangles of tau, another brain protein, begin to form. Shortly thereafter, the tissues in the affected areas begin to wither and die, and cognitive function declines.

To understand why brain damage from Alzheimer’s occurs where it does, Gordon and his colleagues — including first author Eileen Dinser, a technician in Gordon’s lab — studied 350 people who volunteered to participate in memory and aging research through the Charles F. and Joanne Knight of the School of Medicine’s Alzheimer’s Research Center. Participants underwent brain scans so researchers could measure the number and location of amyloid plaques and tau tangles, as well as the volumes of different brain regions.

Researchers compared patterns of protein clots and tissue damage in volunteers with patterns of gene expression APOE and other genes associated with Alzheimer’s disease, as shown in the Allen Human Brain Atlas, a detailed map of gene expression in the human brain compiled by the Allen Brain Sciences Institute.

“There was a close match between where you see high APOE facial expression, and where you see tangles of tau and tissue damage,” said Gordon, also an assistant professor of psychology and brain sciences. “And not only APOE. If you look at, say, the top 20 genes associated with Alzheimer’s disease, they all appear in the temporal lobes in a similar pattern. There is something fundamentally different about these regions that makes them vulnerable to brain damage from Alzheimer’s disease, and this difference is probably ingrained at birth and depends on the individual’s genetics.”

Everyone carries some version APOE gene, but the people who carry st APOE4 the variant is up to 12 times more likely to develop Alzheimer’s disease than the general population, and at a younger age. Alzheimer’s researchers have known this for a long time APOE4 increases the accumulation of beta-amyloid in the brain of humans. By studying mice that develop tau tangles but not amyloid plaques, David Holtzman, MD, the Barbara Burton and Reuben M. Morris III Professor of Neurology Emeritus, and colleagues showed that APOE4 also increases damage due to tau, even without the presence of amyloid.

A high-risk option is used to evaluate the effect APOE of tau-related brain damage in humans, the researchers classified each participant as a high-risk variant carrier 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 for the brains.”

In future work, Gordon and his colleagues plan to investigate how patterns of gene expression correlate with 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 areas of the brain that are damaged?” Gordon asked. “We want to know why some people have such altered patterns and what that means about how Alzheimer’s develops and how it can be treated.”

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