Selective Vulnerability in Posterior Cortical Atrophy

Alzheimer’s disease typically causes patients to have significant problems with short-term memory. However, there are some atypical variants of Alzheimer’s disease that cause cognitive symptoms besides short-term memory loss. One of these atypical variants is called posterior cortical atrophy (PCA), which causes significant problems with vision processing (such as distortions in the field of vision and difficulty judging distances). Although the symptoms may differ, the same proteins accumulate in the brain in Alzheimer’s disease and PCA. The two proteins that accumulate are amyloid beta, which accumulates outside cells, and tau, which accumulates inside cells. The presence of tau accumulation in cells is more closely associated with loss of nerve cells and cognitive difficulty than the presence of amyloid beta. In typical Alzheimer’s disease, tau aggregates first develop in a part of the brain that helps with short-term memory formation. As the disease progresses, the tau aggregates spread to other brain regions in a predictable pattern, likely due to how the nerve cells in different brain regions are connected. Because the pattern of spreading is predictable, the extent of spreading can be used to grade the severity of the disease. In PCA, the tau accumulations happen in the back part of the brain, which is involved in visual processing. Thus, the same disease process happens in different parts of the brain in Alzheimer’s disease and PCA. However, we do not know what causes these changes in the different regions in the first place. From previous studies, we know the distribution of tau aggregates is different in Alzheimer’s disease compared to PCA, but we do not know if there is a predictable pattern of spreading. We hypothesize that there will be a predictable pattern of spreading of tau aggregates in PCA but in a different pattern from Alzheimer’s disease. This study will examine why the back part of the brain is vulnerable to developing tau aggregates early in PCA and the pattern of spreading of tau aggregates after the process starts. To understand how tau spreads as PCA progresses, we will stain donated brain tissue from PCA cases for tau to visualize the tau aggregates under a microscope. We can then see how much tau accumulates in different brain regions at different disease severities. To study the vulnerability of the back part of the brain to develop tau aggregates, we will use donated brain tissue from mild or severe PCA, as well as cases without neurologic disease as a control, to isolate individual cells and then perform advanced sequencing of the RNA in each individual cell in the tissue. Different cell types have signatures of RNA, so we can use the sequencing information to identify the different types of cells that are present. From this, we can tell which types of cells are particularly missing from the PCA cases. We can also look at the RNA levels to see how cells respond to changes in the internal and external environment to understand what types of change may be happening early in the disease process. Ultimately, these studies will help us learn about which cells are most affected by disease-related changes in PCA, identify the types of disease-related changes that are likely to occur early in the disease process and develop a disease severity staging system for PCA based on which regions have tau accumulating in them.