High LDL linked to early-onset Alzheimer’s

Researchers with the Atlanta Veterans Affairs Medical Center and Emory University have 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 Dr. Thomas Wingo, lead author of the study, the results show that LDL cholesterol levels may play a causal role in the development of Alzheimer’s disease.

The results appear in the May 28, 2019, issue of JAMA Neurology.

“The big question is whether there is a causal link between cholesterol levels in the blood and Alzheimer’s disease risk,” says Wingo. “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.”

Wingo is a neurologist and researcher with the Atlanta VA and Emory University.

Elevated cholesterol levels have been linked to increased risk of Alzheimer’s later in life. This risk may be due to genetic factors tied to cholesterol. 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.

While late-onset Alzheimer’s–the 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.

Early-onset Alzheimer’s is a relatively rare form of the condition. The disease is considered “early-onset” when it appears before age 65. About 10% 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.

Three specific gene variants (dubbed APP, PSEN1, and PSEN2) are known to be related to early-onset Alzheimer’s disease. APOE E4 is also a risk factor in this form of the disease, as well. These gene variants explain about 10% of early-onset Alzheimer’s disease cases, meaning that 90% of cases are unexplained.

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 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.

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 did not find a link between HDL (high-density lipoprotein) cholesterol levels and early-onset Alzheimer’s, and only a very slight association between the disease and triglyceride levels.

The researchers 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, suggestion that other genes and mechanisms also increase disease risk.

While the study shines light on possible risk factors for early-onset Alzheimer’s disease, the 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 say.

In other cholesterol news:

New evidence: It’s not necessary to fast before complete cholesterol test

A new study adds to the growing body of evidence that it is unnecessary for most patients to fast before having bloodwork done to measure lipid levels to determine risk of future cardiovascular events. Since the 1970s, studies have suggested that fasting and nonfasting before a complete cholesterol test, otherwise known as lipid level testing, may make little difference in assessing who is at risk for a future heart attack, stroke or other cardiovascular event. But most of these studies were conducted by comparing groups of people at a population level rather than in the same individuals. This left a lingering question about how well nonfasting lipid levels can predict future events for patients. A large study led by investigators at Brigham and Women’s Hospital, Harvard Medical School, and Imperial College provides robust evidence that nonfasting lipid levels were similar to fasting lipid levels in the same individuals, predicting cardiovascular risk just as well. The results are published in JAMA Internal Medicine.

“We hope this study will be the final nail in the coffin, providing strong evidence that, within the same person, fasting or not before a lipid level test doesn’t matter for predicting cardiovascular risk,” said corresponding author Samia Mora, MD, MHS, a cardiovascular medicine specialist and director of the Center for Lipid Metabolomics in the Divisions of Preventive and Cardiovascular Medicine at the Brigham and an associate professor at Harvard Medical School. “This should reassure health care providers and patients that it doesn’t make a difference if you fast or don’t fast if the goal is to predict your cardiovascular risk.”

To conduct their study, Mora and colleagues conducted a post hoc prospective follow-up study of participants from the Anglo-Scandinavian Cardiac Outcomes Trial-Lipid Lowering Arm (ASCOT-LLA), a randomized clinical trial. Fasting and nonfasting lipid levels for more than 8,000 participants were measured four weeks apart with no intervention in between. Patients were followed for a median of 3.3 years for major coronary events (heart attacks, fatal coronary heart disease) and atherosclerotic cardiovascular disease (heart attacks, stroke, and related deaths).

The team found that risk associations of nonfasting lipid levels with coronary events were similar to those for fasting lipid levels measured four weeks later. When patients were not fasting, they had modestly higher triglyceride levels but similar cholesterol levels compared to when they were fasting.

“We spend most of our lives in a nonfasting state. And for some patients, especially those who are elderly or have diabetes, it can be risky to fast before lipid testing,” said Mora. “Health care providers held back because of concerns of variability within individuals, but the data here is so convincing. It should allow people to feel more comfortable with nonfasting lipid testing for cardiovascular risk assessment, including when taking a statin.”

Mora and colleagues note some important limitations to the study. ASCOT-LLA involved European participants, and while they represent multiple European countries, the majority were white and male. The researchers expect that the findings will be relevant to more diverse populations but note that future research should assess potential ethnic and/or racial differences.

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