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2024 Alzheimer's Association Clinician Scientist Fellowship (AACSF)

The Amygdala as Gateway and Gatekeeper to Lewy Body Co-pathology

How do misfolded proteins accumulate in the brain and nervous system during neurodegenerative diseases?

David Fischer, M.D.
The Regents of the University of California, San Francisco
San Francisco, CA - United States


A major hallmark of neurodegenerative diseases is the accumulation of misfolded proteins in the brain and nervous system. One protein, called alpha-synuclein, can accumulate inside nerve cells to form what is known as Lewy bodies. Studies have shown that Lewy bodies may originate in the amygdala region of the brain before affecting the broader nervous system. Lewy bodies in the amygdala may contribute to changes in thinking or other cognitive symptoms. Many people with Alzheimer’s also have Lewy bodies predominantly in this brain region.

Recently, a technique has allowed researchers to measure alpha-synuclein in a person’s cerebral spinal fluid (CSF), which is the fluid that surrounds the spinal cord. This could represent a new biological marker, or biomarker, to understand a person’s risk of having Lewy bodies in their brain. Preliminary research by Dr. David Fischer and colleagues also shows that detecting alpha-synuclein in a person’s CSF may indicate Lewy bodies have expanded beyond the amygdala region of the brain and into the broader nervous system.

Research Plan

In their current study, Dr. Fischer’s team will study connections between alpha-synuclein levels in a person’s CSF and Lewy bodies in their amygdala. First, the researchers will use specialized microscopes to label misfolded alpha-synuclein in brain tissue donated by people who had Lewy body-associated dementia. They will then use computer algorithms to help count the number of nerve cells containing misfolded proteins in different brain regions that all lead to the spinal cord. This will help Dr. Fischer understand how the disease physically progresses beyond the amygdala. Dr. Fischer will also compare the results between people who did and did not have alpha-synuclein detected in their CSF. Together, these experiments will help Dr. Fischer determine the pattern of how alpha-synuclein, and even other misfolded proteins, may expand from the brain to the broader nervous system during neurodegenerative diseases.

In a second part of the study, Dr. Fischer will measure the levels of all the genes inside nerve cells containing misfolded alpha-synuclein. This advanced genetics technique will help Dr. Fischer understand what other biological processes may contribute to alpha-synuclein misfolding and Lewy body formation in the brain.


This study will provide a deeper understanding of whether alpha-synuclein in CSF might be a viable biomarker of Lewy bodies in the brain. A CSF test for alpha-synuclein could represent a non-invasive way to better understand a person’s risk of developing certain neurodegenerative diseases, including those often associated with Alzheimer’s.

Funding support for this project has been made possible by the Fred A. and Barbara M. Erb Family Foundation. This awardee is recognized as the Fred A. Erb Clinical Research Science Fellow for the Alzheimer's Association.

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