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2019 Alzheimer's Association Research Fellowship (AARF)

Systematic Cataloging APOE e4-Stratified Biology of Alzheimer’s Disease

How may certain genetic variations promote Alzheimer’s risk?

Yiyi Ma, Ph.D., M.D.
Columbia University Medical Center
New York, NY - United States


The apolipoprotein E (APOE) gene provides instructions for making the ApoE protein that is thought to help carry fats throughout the body. Each person has two copies of APOE in their DNA. There are several variations of the APOE gene including APOE-e2, APOE-e3 and APOE-e4. Possessing APOE-e4 compared to the other variations seems to increase a person’s risk of developing Alzheimer’s. However not all individuals with APOE-e4 develop Alzheimer’s. Dr. Yiyi Ma will evaluate other genetic variations that may modify this risk.

Research Plan

Dr. Ma and her team will perform genetic analyses on more than 64,000 people from multi-ethnic backgrounds. These participants are part of several ongoing Alzheimer’s and other genetic studies across the US and Europe including the Alzheimer’s Disease Sequencing Project, Alzheimer’s Disease Exome Sequencing-France, Cohorts for Heart and Aging Research in Genomic Epidemiology (CHARGE) and others.
Given the availability of vast amounts of genetic data, a previous study by Dr. Ma and colleagues has yielded at least 22 genetic variations that may influence Alzheimer’s risk in non-Hispanic/non-Latino white individuals with APOE-e4. Four of these genetic variations have also been found in studies by other scientists that encompass multiple ethnicities. Dr. Ma and colleagues will determine what impact these 22 genetic variations have on dementia risk in non-white individuals who carry APOE-e4 compared to individuals without APOE-e4.Dr. Ma will also identify which cell type in the human brain (such as nerve cell, immune cells etc.) is most susceptible to these genetic variations.


Dr. Ma’s project may provide a clearer understanding of why APOE-e4 may have different risk for every individual. Ultimately, such work could lead to novel, more closely-targeted genetic therapies for Alzheimer’s and other dementias.

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