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What is the relationship between cholesterol and Alzheimer’s disease, and when might that connection lead to disease-limiting medications?

New research funded by Cure Alzheimer’s Fund has helped advance these questions in a significant way. 

For more than a decade now, researchers have been aware of important links between cholesterol and Alzheimer’s disease. Studies have shown that cholesterol levels are a significant risk factor in developing the disease, and that cholesterol-limiting statins might lower this risk. Further investigation has revealed that cholesterol somehow regulates the production of the toxic protein fragment Abeta, a central player in Alzheimer’s. 

But researchers have been struggling to define the precise cholesterol-Alzheimer’s relationship. How does cholesterol assist or instigate the production of Abeta? 

One step closer to a potential drug

A new study by Dora Kovacs, Ph.D., Raja Bhattacharyya, Ph.D., and Cory Barren, M.Sc., at Massachusetts General Hospital provides a specific answer, and brings us one step closer to a potential drug that might interrupt the disease process. 

This is not the first important contribution to this issue by Dr. Kovacs and colleagues. In 2001, they identified a specific enzyme in the cholesterol pathway, abbreviated as ACAT, involved in the production of Abeta. By inhibiting ACAT, they demonstrated that Abeta production also can be reduced.

In a newly published paper in the Journal of Neuroscience, they identify a specific mechanism of action that accounts for this relationship between ACAT and Abeta production. The process, known as “palmitoylation,” involves the attachment of fatty acids to pieces of a membrane protein.

The team also used two known ACAT inhibitors previously designed to reduce cholesterol to actually reduce Abeta production. They conclude that using these inhibitors “would appear to be a valid strategy for prevention and/or treatment of Alzheimer’s disease.”

This careful work points to more potential therapies for Alzheimer’s disease through the use of existing or future cholesterol-lowering drugs. “Our hope,” Dr. Kovacs said, “is that one or more ACAT inhibitors currently in clinical trials for cardiovascular disease can be used for Alzheimer’s disease in the near future.”

Breakthrough research

In recent decades, targeting cholesterol has helped to radically advance the prevention and treatment of heart disease. This accumulation of research suggests we might be on the cusp of achieving the same thing with Alzheimer’s.

“This is exactly the sort of groundbreaking research we set out to support,” said Cure Alzheimer’s Fund Chairman Jeff Morby. “In fact, Dr. Kovacs’ earlier cholesterol research was the very first project supported by Cure Alzheimer’s Fund. Alzheimer’s research is arduous, but having persevered and followed the facts, we’re now one important step closer to a useful treatment.”