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2023 Alzheimer's Association Research Grant to Promote Diversity (AARG-D)

Role of glypican-4 in APOE4-mediated neurodegeneration

How do specific gene variations impact tau levels in Alzheimer’s?

Sivaprakasam Ramamoorthy, Ph.D.
Centre for Brain Research
Bangalore, India


The apolipoprotein E (APOE) gene provides instructions for making ApoE, a protein believed to help carry fats throughout the body. There are several genetic variations of APOE, including APOE-e2, APOE-e3 and APOE-e4. Studies have shown that in some populations,  individuals who possess APOE-e4 have an increased risk for developing Alzheimer’s, compared to individuals with other APOE variants, but the mechanisms linking APOE-e4 and Alzheimer’s risk are not yet understood.
One of the hallmark brain changes in Alzheimer’s is the accumulation of the tau protein to form tangles, and some studies show that APOE-e4 is associated with high levels of abnormal tau protein in the brain. In previous research, Dr. Ramamoorthy and colleagues found a specific protein called Glypican-4 that physically interacts with the ApoE-e4 protein and potentially increases the accumulation of tau tangles.

Research Plan

Building on these findings, Dr. Ramamoorthy and the team will study the links between Glypican-4, APOE4, and abnormal tau in Alzheimer’s. They will do this by reducing the levels of Glypican-4 in genetically engineered Alzheimer’s-like mice that either have or do not have the APOE-e4 variant. The researchers will then compare differences in nerve cell damage and tau levels in brain tissue from these mice to examine the role of the Glypican/ApoE-e4 interaction in tau tangle accumulation and Alzheimer’s development. Lastly, they will perform cognitive and behavioral assessments in these mice to study whether changes in Glypican-4 impacts cognitive function.


The study results could help us better understand the connection between APOE and abnormal tau in Alzheimer’s. If successful, the findings could also lead to novel therapies for slowing or reducing risk of Alzheimer’s in individuals with APOE-e4.

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