High levels of LDL cholesterol has been linked to an increased risk of early-onset Alzheimer’s disease, regardless of the genetic risk factor. Therefore, cholesterol could be an independent risk factor for dementia. In addition, while the scientists were researching this link, they ended up identifying a potential new genetic risk factor for early-onset Alzheimer’s, a rare variant of the APOB gene.
The study was conducted by researchers from the Atlanta Veterans Affairs Medical Center and Emory University. Their results could help doctors understand how the disease develops and what the possible causes are, including genetic variation. The research appears in the May 28, 2019, issue of JAMA Neurology.
LDL cholesterol levels may play a causal role in the development of Alzheimer’s disease, according to Dr. Thomas Wingo, lead author of the study. He said:
The big question is whether there is a causal link between cholesterol levels in the blood and Alzheimer’s disease risk. 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 LDC cholesterol to help reduce Alzheimer’s risk. Our work now is focused on testing whether there is a causal link.
An increased risk of Alzheimer’s later in life has already been linked to elevated cholesterol levels. Yet, this risk may be due to genetic factors tied to cholesterol. But there is a specific mutation in a gene referred to as APOE that is known to be a major risk factor for Alzheimer’s disease. It is the largest known single genetic risk factor for Alzheimer’s disease. This APOE variant, called APOE E4, raises levels of circulating cholesterol, particularly low-density lipoprotein (LDL), aka “bad cholesterol” because high LDL levels can lead to a build-up of cholesterol in the arteries.
Late-onset Alzheimer’s is the common form of the disease, which appears to be linked to cholesterol. Early-onset Alzheimer’s is quite a rare form of the condition so less is known about it. The disease is considered “early-onset” when it appears before age 65. Around 10% of all Alzheimer’s cases are early-onset. Very little research has been done on a possible connection between cholesterol levels and the risk of Early-onset Alzheimer’s. All they really know is that the condition is largely genetics-based, meaning it is likely to be inherited if a parent has it.
Of the 10% explainable early-onset Alzheimer’s disease cases, there are three specific gene variants (dubbed APP, PSEN1, and PSEN2) linked. These gene variants are related to early-onset Alzheimer’s disease. APOE E4 is also a risk factor in this form of the disease, as well. The rest of the 90% of cases are unexplained. That’s why the researchers wanted to test whether early-onset Alzheimer’s disease is linked to cholesterol and they wanted to identify the genetic variants that might underlie this possible association.
To do this, the researchers sequenced specific genomic regions of 2,125 people, 654 of whom had early-onset Alzheimer’s and 1,471 of whom were controls. They also tested blood samples of 267 participants to measure the amount of LDL cholesterol. They found that APOE E4 explained about 10% 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% of early-onset Alzheimer’s cases had at least one of these known early-onset Alzheimer’s risk factors.
Then they checked cholesterol levels and 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. Therefore, cholesterol could be an independent risk factor for the disease, regardless of whether the problematic APOE gene variant is present.
The researchers also found a new possible genetic risk factor for early-onset Alzheimer’s disease – a rare variant of a gene called APOB. This gene was higher in participants with early-onset Alzheimer’s. This gene encodes a protein that is involved in the metabolism of lipids, or fats, including cholesterol.
More research is needed to fully explain the connection between the disease and cholesterol but the study does shine some light on possible risk factors for early-onset Alzheimer’s disease. The difficulty lies in the relative rarity of early-onset Alzheimer’s disease which presents a challenge in finding enough samples to perform large genetic studies on the condition.
