A recent study, published Nov. 16 in Science Translational Medicine, yields clues to why certain parts of the brain are particularly vulnerable to Alzheimer’s damage. It comes down to the gene APOE, the greatest genetic risk factor for Alzheimer’s disease. The parts of the brain where APOE is most active are the areas that sustain the most damage, the study found. The findings help explain why symptoms of Alzheimer’s disease 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 first develop language or vision problems rather than memory problems,” says senior author Brian A. Gordon, PhD, an assistant professor of radiology. “When you scan their brains, you see damage to the language or the visual areas, and not so much to the memory areas. People with atypical Alzheimer’s are often screened out of 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 develops the way it does. There’s a reason why certain brain areas become damaged and not others, and we don’t know that reason yet. Every mystery we uncover with this disease pushes us closer to what we need to address it.”
To understand why Alzheimer’s brain damage occurs where it does, Gordon and colleagues studied 350 people who volunteer for memory and aging studies through the Washington University School of Medicine’s Charles F. and Joanne Knight Alzheimer Disease Research Center. The participants underwent brain scans so the researchers could measure the amount and location of amyloid plaques and tau tangles, and the volumes of various brain areas.
The researchers compared the patterns of protein clumps and tissue damage in the volunteers to 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 compiled by the Allen Institute for Brain Sciences.
“There was a close match between where you see high APOE expression, and where you see tau tangles and tissue damage,” says Gordon. “And not just APOE. If you look at, say, the top 20 genes associated with Alzheimer’s disease, they are all expressed in the temporal lobes in similar patterns. There’s something fundamentally different about these regions that make them vulnerable to Alzheimer’s brain damage, and that difference is probably 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. “APOE4 carriers are more likely to start accumulating amyloid, which puts them on the path to Alzheimer’s,” Gordon says. “Then, for the same amount of amyloid they get more tau tangles, which leads to more atrophy. It’s a double hit on the brain.”
In future work, Gordon and colleagues plan to explore how patterns of gene expression relate to patterns of tau damage in people with atypical Alzheimer’s.
“When we see someone who presents 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 it means about how Alzheimer’s disease develops and how it can be treated.”
Published in Focal Spot Fall/Winter 2022 Issue