Patients with elevated levels of low-density lipoprotein (LDL-C) may have a higher likelihood of developing early-onset Alzheimer’s disease. A study in JAMA Neurology found an association between high LDL-C levels and gene variants known to influence cholesterol levels, including the rare apolipoprotein B (APOB) variant. However, the presence of these variants could not fully explain the connection between this neurological disorder and LDL-C, suggesting that other factors may be contributing to neurologic disease.

Apolipoprotein E ε4 (APOE E4), a gene variant associated with elevated levels of circulating cholesterol, LDL-C in particular, is a known risk factor for Alzheimer’s. APOE, along with other gene variants APP, PSEN1, and PSEN2, have been linked to about 10% of all early-onset cases. Multiple studies have shown an association between high cholesterol and late-stage Alzheimer’s, yet no research has ever established a definitive causal link between early-onset Alzheimer’s risk and high cholesterol.

“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,” said the study’s lead author Thomas Wingo, MD, an assistant professor at Emory University School of Medicine, in a statement. The goal of the study was to examine the relationship between circulating cholesterol levels and early-onset Alzheimer’s disease and any underlying genetic factors that might be influencing disease pathogenesis.

Wingo and colleagues from the Atlanta Veterans Affairs Medical Center and Emory University sequenced specific genomic regions from the blood samples of 2,125 patients, 654 of which had early-onset Alzheimer’s and 1,471 individuals with normal cognitive function, to examine the link between early-onset disease and known Alzheimer’s variants APP, PSEN1, PSEN2, and APOE E4. In another step, they measured plasma cholesterol levels in 267 samples to assess any connections between cholesterol and early-onset Alzheimer’s.

Similar to estimates in late-onset Alzheimer’s, APOE E4 explained about 10% of early-onset Alzheimer’s. Even after controlling for those cases with the APOE E4 variant, researchers found that patients with higher LDL-C levels were more likely to have early-onset disease compared with those with lower cholesterol levels—suggesting that cholesterol could serve as a risk factor independent of the APOE gene variant.

“Because of the strong association between elevated plasma LDL cholesterol levels and [early-onset Alzheimer’s disease] that was at least partly independent of APOE E4, the authors hypothesized that genetic variants in the gene for apolipoprotein B (APOB), the major lipoprotein of LDL cholesterol, could be involved,” observed Makoto Ishii, MD, PhD, in a related editorial. After adjusting for various factors such as APOE E4 status and sex, the researchers found that the prevalence of the rare APOB coding variant was higher in early-onset cases. “Five percent of patients with [early-onset disease] carried an allele, in comparison with 1.7% of controls,” the researchers reported.

In other findings, early-onset Alzheimer’s disease risk factors such as APP, PSEN1, and PSEN2 showed up in at least 3% of the early-onset cases. Negligible or no associations were found between early-onset disease and higher triglyceride and high-density lipoprotein cholesterol levels.

Neither APOE E4 nor APOB were able to fully explain the association between early-onset disease and elevated LDL-C levels. As an example, some of the noncarriers of APOB exhibited a strong link between these two variables, suggesting that factors other than this rare variant might be influencing cholesterol levels in patients with early-onset disease, Ishii noted.

The study provides breakthrough evidence that a link between rare genetic coding variants of APOB and early-onset Alzheimer’s exist, Ishii continued. “As the authors of this study note, it is not known if there are protective variants of APOB that would decrease the risk for developing [early-onset Alzheimer’s disease]. Identifying such a protective coding variant of APOB would greatly strengthen the link between APOB and [Alzheimer’s disease] pathogenesis.”

Although it represents just 5% of cases, studying early-onset disease is crucial, not just in helping affected patients, but also for providing insights that might lead to breakthroughs for the majority of patients who have late-onset Alzheimer’s—and determining whether other factors independent of APOB/APOE might contribute to Alzheimer’s, Ishii noted. “These may include rare variants in other genes involved directly in LDL cholesterol metabolism, such as the LDL receptor and proprotein convertase subtilisin/kexin type 9 or factors known to modulate circulating LDL cholesterol levels, such as thyroid hormones,” he offered.