2025 AD Strategic Fund: APOE Biology in Alzheimer's (ABA) (ABA)

Role of APOE in diabetes-related risk for AD

How do certain gene variations contribute to diabetes-linked risks for Alzheimer’s?

Florin Despa, Ph.D.
University of Kentucky Research Foundation
Lexington, KY - United States

Background

Amylin is a protein-like hormone secreted by the pancreas. It works along with insulin to help the body control blood sugar levels. In people with obesity or diabetes, amylin levels in the blood can be unusually high. Recently, research has shown that amylin can accumulate into toxic clumps in brain blood vessels, possibly contributing to brain damage and cognitive problems. In addition, amylin can clump together with beta-amyloid, a protein fragment known to play a role in Alzheimer’s disease.

Genes also play an important role in Alzheimer’s. The apolipoprotein E (APOE) gene provides instructions for making ApoE protein. There are several genetic variations of APOE, including APOE-e2, APOE-e3 and APOE-e4. In some populations, the APOE-e4 variation is thought to increase a person’s risk of developing Alzheimer’s, whereas APOE-e3 seems to have no impact on Alzheimer’s risk. 

There are other factors that may also play a role in a person’s risk. For instance, when diabetes is not controlled, too much sugar remains in the blood and over time, this can damage organs, including the brain. Scientists are finding more evidence that could link Type 2 diabetes with Alzheimer's disease, the most common cause of dementia. 

It is not known how APOE variations may relate to diabetes-linked risks for Alzheimer’s, including increased amylin levels or vascular diseases like vascular dementia. In preliminary research, Dr. Florin Despa and colleagues found that APOE-e4 was correlated to higher levels of amylin and beta-amyloid in genetically engineered Alzheimer’s-like mice.

Research Plan

Dr. Despa and colleagues have proposed a series of experiments to explore how APOE gene variations are linked to amylin accumulation and vascular disease. They will use genetically engineered mice with APOE gene variations to study the impact of these variations on amylin and beta-amyloid levels, as well as on the blood vessels of the brain. They will also study mice that have been genetically engineered to develop amylin deposits in their brain blood vessels to study if this leads to Alzheimer’s-like brain changes and memory problems in the mice.

Additionally, the research team will also study samples of brain tissue, blood and cerebrospinal fluid (the fluid that surrounds nerve cells in the brain) to measure amylin levels in individuals that had (1) diabetes and dementia, (2) only dementia or (3) only diabetes. They will determine how amylin levels in the blood relate to amylin build-up in the brain and how this relates to individuals’ APOE genes and whether they have diabetes or not.

Impact

This research may help explain how certain gene variations impact diabetes-related risk factors for Alzheimer’s. This work could also shed new light on the relationship between amylin and beta-amyloid in the brain, as well as help establish drug targets that could prevent amylin accumulation and brain injury in people at risk for Alzheimer’s disease.