New research has found a link between high LDL cholesterol levels and early-onset Alzheimer’s disease.
The results could help doctors understand how the disease develops and what the possible causes are, including genetic variation, according to researchers with the Atlanta Veterans Affairs Medical Center and Emory University.
According to Dr. Thomas Wingo, a neurologist and researcher with the Atlanta VA and Emory University, the results show that LDL cholesterol levels may play a causal role in the development of Alzheimer’s disease.
“The big question is whether there is a causal link between cholesterol levels in the blood and Alzheimer’s disease risk,” said Wingo, lead author of the study. “The existing data have been murky on this point.
“One interpretation of our current data is that LDL cholesterol does play a causal role. If that is the case, we might need to revise targets for LDL cholesterol to help reduce Alzheimer’s risk. Our work now is focused on testing whether there is a causal link.”
High cholesterol levels have been linked to an increased risk of Alzheimer’s later in life. This risk may be due to genetic factors tied to cholesterol, researchers believe.
Past research has shown that a major risk factor for Alzheimer’s disease is a specific mutation in a gene referred to as APOE. It is the largest known single genetic risk factor for Alzheimer’s disease. This APOE variant, called APOE E4, is known to raise levels of circulating cholesterol, particularly low-density lipoprotein (LDL). This type of cholesterol is sometimes referred to as “bad cholesterol” because high LDL levels can lead to a build-up of cholesterol in the arteries, the researchers explain.
While late-onset Alzheimer’s — the most common form of the disease — appears to be linked to cholesterol, little research has been done on a possible connection between cholesterol levels and early-onset Alzheimer’s risk, according to the researchers.
Early-onset Alzheimer’s is a relatively rare form of the condition, appearing before the age of 65. About 10 percent of all Alzheimer’s cases are early-onset. Past research has shown that the condition is largely genetics-based, meaning it is likely to be inherited if a parent has it, according to the scientists.
Three specific gene variants — APP, PSEN1, and PSEN2 — are known to be related to early-onset Alzheimer’s. APOE E4 is also a risk factor in this form of the disease. These gene variants explain only about 10 percent of early-onset Alzheimer’s disease cases, meaning that 90 percent of cases are unexplained, the researchers noted.
To test whether early-onset Alzheimer’s disease is linked to cholesterol and identify the genetic variants that might underlie this possible association, the researchers sequenced specific genomic regions of 2,125 people, 654 of whom had early-onset Alzheimer’s and 1,471 who didn’t. They also tested blood samples of 267 participants to measure the amount of LDL cholesterol.
They found that APOE E4 explained about 10 percent of early-onset Alzheimer’s, which is similar to estimates in late-onset Alzheimer’s disease.
The researchers also tested for APP, PSEN1, and PSEN2. About 3 percent of early-onset Alzheimer’s cases had at least one of these known early-onset Alzheimer’s risk factors, the study discovered.
After testing blood samples, the researchers found that participants with elevated LDL levels were more likely to have early-onset Alzheimer’s disease, compared with patients with lower cholesterol levels. This was true even after the researchers controlled for cases with the APOE mutation, meaning cholesterol could be an independent risk factor for the disease, regardless of whether the problematic APOE gene variant is present, the researchers explained.
The researchers did not find a link between high-density lipoprotein (HDL) cholesterol levels and early-onset Alzheimer’s, and only a very slight association between the disease and triglyceride levels.
The researchers report they also found a new possible genetic risk factor for early-onset Alzheimer’s disease.
Early-onset Alzheimer’s cases were higher in participants with a rare variant of a gene called APOB. This gene encodes a protein that is involved in the metabolism of lipids, or fats, including cholesterol.
The finding suggests a direct link between the rare APOB mutation and Alzheimer’s disease risk, according to the researchers.
However, the link between LDL-C level and early-onset Alzheimer’s was not fully explained by APOE or APOB, suggesting that other genes and mechanisms also increase disease risk, the researchers said.
Researchers say that more research is needed to fully explain the connection between the disease and cholesterol. The relative rarity of early-onset Alzheimer’s disease presents a challenge in finding enough samples to perform large genetic studies on the condition, they add.
The study was published in JAMA Neurology.
Source: Veterans Affairs
Photo: Drs. Thomas Wingo and Aliza Wingo (foreground) lead a lab at the Atlanta VA and Emory University dedicated to understanding the genetic basis of Alzheimer’s disease and psychological well-being and resilience. Credit: Lisa Pessin.