Study gives clues as to why Alzheimer’s disease damages parts of the brain – Washington University School of Medicine in St. Louis

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Findings could help explain rare symptoms such as language, vision problems

Diana Hobbs

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 clumps of protein first concentrate in the brain’s temporal lobes – 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 damage from Alzheimer’s disease. It depends on the gene APOE, the greatest genetic risk factor for Alzheimer’s disease. The parts of the brain where APOE The most active areas are those that take 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 rare and atypical forms of Alzheimer’s in which people first develop language or vision problems rather than memory problems,” said lead author Brian A. Gordon, PhD, assistant professor of radiology at the Mallinckrodt Institute of Radiology in the School of Medicine. “When you scan their brains, you see damage to language or visual areas, and not so much to memory areas. People with atypical Alzheimer’s disease are often excluded from research studies because it’s 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 disease develops the way it does. There is a reason why certain areas of the brain are damaged and not others, and we don’t yet know that reason. Each mystery we uncover with this disease brings us closer to what we need to deal with it.

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

To understand why Alzheimer’s brain damage occurs where it occurs, Gordon and his colleagues – including first author Aylin Dincer, a technician in Gordon’s lab – studied 350 people who volunteered for memory studies. and aging through Charles F. and Joanne Knight of the School of Medicine’s Alzheimer’s 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 various brain areas.

The researchers compared the patterns of protein aggregates and tissue damage in the volunteers to the gene expression patterns of APOE and other genes associated with Alzheimer’s disease as described in the Allen Human Brain Atlas, a detailed map of gene expression in the human brain compiled 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 psychological and brain sciences. ” And not only APOE. If you look at, say, the top 20 genes associated with Alzheimer’s disease, they’re all expressed in the temporal lobes in similar patterns. There’s something fundamentally different about these regions that makes them vulnerable to Alzheimer’s brain damage, and that difference is likely built in from birth and influenced by a person’s genetics.

Everyone wears 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 disease researchers have long known that APOE4 increases the buildup of beta-amyloid in people’s brains. By studying mice that develop tau tangles but no amyloid plaques, David Holtzman, MD, Professor Emeritus of Neurology Barbara Burton and Reuben M. Morriss III, and colleagues have shown 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, the researchers categorized each participant as whether or not they carried the high-risk variant, and analyzed their brains for protein clumps and atrophy.

APOE4 carriers are more likely to start accumulating amyloid, which puts them on the road to Alzheimer’s disease,” Gordon said. “Then for the same amount of amyloid, they get more tau tangles, which leads to more atrophy. That’s a double whammy on the brain.

In future work, Gordon and his colleagues plan to explore how gene expression patterns relate to patterns of tau damage in people with atypical Alzheimer’s disease.

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

Dincer A, Chen CD, McKay NS, Koenig LN, McCullough A, Flores S, Keefe SJ, Schultz SA, Feldman RL, Joseph-Mathurin N, Hornbeck RC, Cruchaga C, Schindler SE, Holtzman DM, Morris JC, Fagan AM, Benzinger TLS, Gordon BA. APOE ε4 genotype, amyloid-β, and sex interact to predict tau in regions of high APOE mRNA expression. Science translational medicine. November 16, 2022. DOI: 10.1126/scitranslmed.abl7646

Support for these analyzes was provided by the National Institutes of Health (NIH), grant numbers P30AG066444, P01AG003991, P01AG026276, K01AG053474, RF1AG053303, and RF1AG044546; the Alzheimer’s Association, grant number AARG-17-532945; the Alzheimer Association International Research Program, grant number AARFD-20-681815; and the National Science Foundation, grant number DGE-1745038. Calculations were performed using facilities at the Washington University Center for High Performance Computing, which were partially funded by NIH grants 1S10RR022984-01A1 and 1S10OD018091-01 to the University of Washington. Computing and research infrastructure was supported by the NIH, grant numbers UL1TR000448, P30NS09857, and R01EB009352. Support also provided by the Hope Center for Neurological Disorders; The Foundation for Barnes-Jewish Hospital Willman Scholar Award; and Avid Radiopharmaceuticals (a wholly owned subsidiary of Eli Lilly), which provided the technology transfer and precursor to AV-1451.

About Washington University School of Medicine

WashU Medicine is a world leader in academic medicine, including biomedical research, patient care, and educational programs with 2,700 faculty. Its National Institutes of Health (NIH) research funding portfolio is the fourth largest among U.S. medical schools, has grown 54% over the past five years, and with institutional investment, WashU Medicine dedicates more a billion dollars a year for basic and clinical research. innovation and training. Its faculty practice is consistently ranked among the top five in the nation, with more than 1,790 faculty physicians practicing at more than 60 sites who also serve on the medical staff of BJC HealthCare’s Barnes-Jewish and St. Louis Children’s Hospitals. WashU Medicine has a rich history of MD/PhD training, recently dedicated $100 million in scholarships and curriculum renewal for its medical students, and is home to top-notch training programs in every medical subspecialty as well as physiotherapy, occupational therapy, and audiology and communication sciences.


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