Elevated Levels of ‘Bad’ Cholesterol Linked to Early-Onset Alzheimer’s Disease

A study published in the journal JAMA Neurology suggests that levels of low-density lipoprotein (LDL) cholesterol, sometimes referred to as ‘bad’ cholesterol, play a causal role in the development of Alzheimer’s disease.

Lipoprotein structure (chylomicron): ApoA, ApoB, ApoC and ApoE – apolipoproteins; T – triacylglycerol, CEo – cholesterol ester, green – phospholipids. Image credit: Xvaz Quez / CC BY-SA 3.0.

Early-onset Alzheimer’s disease 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 studies have shown that the condition is largely genetics-based, meaning it is likely to be inherited if a parent has it.

Four specific gene variants — dubbed APP, PSEN1, PSEN2 and APOE E4 — are known to be related to early-onset Alzheimer’s disease. APOE E4 is known to raise levels of circulating cholesterol, particularly LDL.

“The big question is whether there is a causal link between cholesterol levels in the blood and Alzheimer’s disease risk,” said Dr. Thomas Wingo, a neurologist with the Atlanta Veterans Affairs Medical Center and the Emory University School of Medicine.

To test whether early-onset Alzheimer’s disease is linked to cholesterol and identify the genetic variants that might underlie this possible association, Dr. Wingo and colleagues sequenced specific genomic regions of 2,125 people, 654 of whom had early-onset Alzheimer’s and 1,471 of whom were controls.

The researchers 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.

They 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 scientists 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 team 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 study authors 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.

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,” Dr. Wingo and co-authors said.

“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.”

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Thomas S. Wingo et al. Association of Early-Onset Alzheimer Disease With Elevated Low-density Lipoprotein Cholesterol Levels and Rare Genetic Coding Variants of APOB. JAMA Neurol, published online May 28, 2019; doi: 10.1001/jamaneurol.2019.0648