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Variants in APOB May Be Associated With Early-Onset Alzheimer’s Disease

Key clinical point: Variants in APOB, the gene that influences circulating levels of low-density lipoprotein, may be important in the pathogenesis of early-onset Alzheimer’s.

Major finding: Rare coding variants in the APOB gene were significantly more common in early-onset Alzheimer’s disease (EOAD) cases than in controls (5.0% vs. 1.7%).

Study details: The three-cohort study comprised 2,125 patients with EOAD.

Disclosures: This research was supported by grants from the Veterans Health Administration, the National Institutes of Health, the To Remember Foundation, the Douglas French Alzheimer’s Foundation, and a contract with the State of California Department of Health Services. Several authors reported financial ties to pharmaceutical companies outside of this work.

Citation:

Wingo TS et al. JAMA Neurol. 2019 May 28. doi: 10.1001/jamaneurol.2019.0648.

Commentary:

This important study provides the first evidence that rare genetic coding variants of apolipoprotein B may contribute to the risk of early-onset Alzheimer’s disease, Makoto Ishii, MD, PhD, wrote in an accompanying editorial (JAMA Neurol. 2019 May 28. doi: 10.1001/jamaneurol.2019.0212).

But the study by Wingo et al. doesn’t tell the entire tale, he wrote.

The results from this study “found that there are likely to be additional contributing factors independent of APOB and APOE. 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 913 or factors known to modulate circulating LDL cholesterol levels, such as thyroid hormones.”

Although intriguing, “Clearly, additional studies looking at these factors are needed to fully elucidate the association between LDL cholesterol and EOAD. Furthermore, 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 EOAD. Identifying such a protective coding variant of APOB would greatly strengthen the link between APOB and AD pathogenesis.”

Prior studies of circulating APOB levels in humans have reached disparate conclusions. A large population-based study found no association between APOB levels and incident dementia or Alzheimer’s, he noted.

“Therefore, whether these findings can be verified in individuals with late-onset AD remains to be determined.”

Dr. Ishii is with the Feil Family Brain and Mind Research Institute in the department of neurology at Cornell University, New York. He has no relevant disclosures.