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Coding variants in apolipoprotein B may be associated with early-onset Alzheimer’s disease

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APOB could be one of many contributing factors

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.



Variants in the apolipoprotein B gene (APOB), which creates the main protein in low-density and very low-density cholesterol, may be associated with early-onset Alzheimer’s disease, Thomas Wingo, MD, and his colleagues have determined.

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The finding may help fill out the genetic risk picture for early-onset Alzheimer’s disease (EOAD), said Dr. Wingo of the Atlanta Veterans Affairs Medical Center. The study found that the already-known genetic markers for EOAD – mutations of the presenilin (PSEN) 1 and 2 genes and amyloid precursor protein (APP) – account for just a small fraction of cases.

“To place the genetic association between APOB and EOAD in context, we note that only 3.4% of all EOAD cases in our combined data set showed a known pathogenic mutation, and we found a stronger association between EOAD and rare coding variants in APOB, compared with PSEN1 in our fully adjusted analysis,” the team wrote. However, “approximately 5.0% of patients with EOAD and 1.7% of controls were found to harbor a rare coding polymorphism in APOB that is likely to disrupt the structure, functions, or abundance of ApoB protein.”

The team conducted genetic analysis on plasma samples from 2,125 EOAD and control subjects included in several research cohorts. They first determined the association between cholesterol and EOAD, and then the frequency of variants in apolipoprotein E epsilon 4 (APOE e4), APP, PSEN1, PSEN2, and ApoB. Gene sequencing revealed that 3.4% of samples showed mutations in APP, PSEN1, or PSEN2.

“Given the strong associations between APOE e4 and EOAD and elevated circulating LDL cholesterol levels, we expected individuals with EOAD to have elevated LDL levels,” the team said. But an analysis of 267 of the samples for lipid levels found that, even after the researchers controlled for APOE e4, EOAD cases had higher total cholesterol, low-density cholesterol, and plasma ApoB, compared with controls. However, they found no association between EOAD and high-density lipoprotein or triglycerides.

“Because total cholesterol largely consists of LDL-C, and ApoB is the main lipoprotein of LDL-C, these findings are consistent with one another.

“From these data, we estimated that LDL-C explains 7.6% of the variance in liability to EOAD, independently of APOE e4 ... These results demonstrate that elevated levels of LDL-C [and ApoB] were significantly associated with increased EOAD risk, and this effect was only partially mediated by APOE e4 genotype.”

The results also raised a question: What was driving the association between LDL and EOAD? Because variants of the ApoB gene can either raise or lower LDL, the team examined variants associated with coding changes. These variants were significantly more common in EOAD cases than in controls (5.0% vs. 1.7%).

“Two affected individuals ... were compound heterozygotes, with the remainder being heterozygotes,” the researchers wrote. “Each compound heterozygote case was heterozygous for two different rare coding sites ... Of these four variants, only [one] has been previously described.”

“Our finding of a significant association between rare coding variants in APOB and EOAD independently of APOE is novel, important, and consistent with multiple genome-wide association studies that revealed strong associations between late-onset AD and common intron markers of genes involved in brain cholesterol metabolism [ABCA7, BIN1, CLU, and SORL1]. Furthermore, mice overexpressing ApoB show hyperlipidemia, neurodegeneration, increases in APP, accumulation of amyloid plaques, and cognitive impairment similar to mice overexpressing wild-type human APP. Collectively, these studies and our findings suggest an important role of cholesterol metabolism in AD pathogenesis.”

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.

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

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