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2024 Alzheimer's Association Research Fellowship to Promote Diversity (AARF-D)

Impaired Neuronal Cytoarchitecture in AD/ADRD

How do genetic variations impact the accumulation of abnormal tau in the brain? 

Merci Best, Ph.D.
University of Michigan
Ann Arbor, MI - United States


Tau protein functions to help support nerve cell structure and transport nutrients within the cell. In Alzheimer’s and over twenty other brain diseases (known as tauopathies), such as frontotemporal dementia (FTD), tau protein becomes abnormally folded and clumps into “tangles” in the brain, one of the characteristic features of these diseases. In nerve cells, tau is usually located in the axons, the long, thread-like extensions that nerve cells use to communicate with each other. Early in the course of Alzheimer’s, FTD, and other tauopathies, tau moves to and accumulates in nerve cell bodies and dendrites (the “branches” of a nerve cell).
The gene that provides instructions for making tau is called microtubule-associated protein tau (MAPT). Studies show that a certain variation of MAPT is associated with abnormal tau accumulation in FTD. Other recent studies have identified variations in the gene anchoring kinase protein 9 (AKAP9) that are associated with Alzheimer’s risk in Black and Hispanic individuals. However, the links between these genetic changes and the underlying mechanisms of tau-mediated neurodegeneration are unclear.

Research Plan

Dr. Merci Ngozi Best and colleagues will study how genetic changes associated with FTD and Alzheimer’s impact the structural arrangement and organization of nerve cells, and how this may promote tau-mediated neurodegeneration. The researchers will study a specialized type of stem cell collected from adult human tissue called induced pluripotent stem cells (iPSCs). These are adult human skin cells that can be “reprogrammed” into any type of cell in the human body, including nerve cells. Dr. Best and colleagues will develop iPSCs that possess a genetic variation of AKAP9 associated with Alzheimer’s and determine whether the variation impacts levels of abnormal tau in the nerve cells. They will use additional techniques to investigate how this genetic variation may impact nerve cell structure and organization. 

The team will also use iPSCs to create brain organoids, three-dimensional brain-like structures that can be grown in a laboratory dish to more closely resemble human brain tissue. They will study how the MAPT genetic variation associated with FTD impacts nerve cell structure and organization and the accumulation of abnormal tau.


The results of this study may shed light on how genetic variations contribute to the accumulation of abnormal tau in Alzheimer’s, FTD, and other neurodegenerative diseases.

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