Cholesterol potential target for Alzheimer's disease, diabetes

A new study examined the role of cholesterol in both Alzheimer's disease and type 2 diabetes to identify a small molecule that may help regulate cholesterol levels in the brain, making it a potential new therapeutic target, according to the research published in the journal ACS Pharmacology and Translational Science.

Type 2 diabetes occurs when insulin becomes less efficient at removing glucose from the bloodstream, resulting in high blood sugar that can cause abnormal cholesterol levels. A similar situation occurs in Alzheimer's disease, but rather than affecting the body, the effects are localized in the brain, the researchers said.

When cholesterol rises, due to insulin resistance or other factors, the body starts a process known as reverse cholesterol transport, during which specific molecules carry excess cholesterol to the liver to be excreted. Apolipoprotein E (APOE) is one of the proteins involved in reverse cholesterol transport. APOE is also the strongest risk factor gene for Alzheimer's disease and related dementia, and an independent risk factor for type 2 diabetes and cardiovascular disease. Similarly, reduced activity of another cholesterol transporter, ATP-binding cassette transporter A1 (ABCA1), correlates with increased risk of cardiovascular disease, type 2 diabetes, and Alzheimer's disease, according to the study.

For the study, researchers honed in on a specific small molecule, CL2-57, due to its ability to stimulate ABCA1 activity with positive effects on liver and plasma triglycerides. The use of this compound showed improved glucose tolerance and insulin sensitivity, as well as reduced weight gain, among other beneficial effects.

Future research will seek to improve the properties of the small molecules to increase the levels in the brain, according to Gregory Thatcher, PhD, lead author of the study and a professor of pharmacology and toxicology. Their long-term goal is to understand which patients suffering from the cognitive and neuropsychiatric symptoms of Alzheimer's and dementia will benefit from the treatment, he said.

"During the [novel coronavirus (COVID-19)] pandemic, we hear about the mounting deaths in nursing homes and it's important to remember that Alzheimer's and related dementia is a major cause of the elderly moving to nursing homes," Thatcher said in a statement. "It would be good to think of a future in which healthspan was extended, especially a healthy brain. Maybe that's more important than lifespan."