Dr Thomas WingoThomas S. Wingo, MD
Findings from a series of case studies suggest an association between early-onset Alzheimer disease and elevated levels of low-density lipoprotein cholesterol (LDL-C) free of the effects of APOE. Additionally, the data show the enhancement of rare coding variants of APOB in those with early-onset Alzheimer.1

The investigators, led by Thomas S. Wingo, MD, of the Division of Neurology, Atlanta Veterans Affairs Medical Center, and Departments of Neurology and Human Genetics, Emory University School of Medicine, noted that these APOB variants are a sign of the potential influence on plasma cholesterol levels, as the gene codes for the major protein of LDL-C—of which elevated levels indicate higher probability of early-onset disease.

“Two parallel lines of evidence suggest that circulating low-density lipoprotein cholesterol levels may play a role in the pathogenesis of early-onset Alzheimer disease, and future work should elucidate whether APOB influences the risk for early-onset Alzheimer disease by acting through plasma low-density lipoprotein cholesterol levels or through other mechanisms,” they wrote.

The group directly measured the plasma cholesterol levels in 267 samples from Emory University and the University of California San Francisco’s Alzheimer disease research centers, collected from 2009 to 2014. Underlying genetic variants—APOB, APP, PSEN1, and PSEN2—were sequenced from 2125 samples from the 2 aforementioned centers and comparative controls from 29 other centers from 1984 to 2015. In total, there were 654 patients with early-onset Alzheimer and 1471 controls.

The results revealed 13 known Alzheimer-causing genetic mutations in 3.4% of the samples (23 individuals); these included 2 sites in APP (n = 2), 10 sites in PSEN1 (n = 18), and 2 sites in PSEN2 (n = 3).

After a gene-based burden analysis was conducted, Wingo et al. noted that “only PSEN1 was significantly associated with [early-onset Alzheimer disease], although well-described pathogenic mutations were found in all 3 genes.” They added that once potential selection bias of known Alzheimer mutation carriers was accounted for, there was a weaker association found between PSEN1 and early-onset disease, in 2088 samples (effect size, 0.21; P = 2.60 × 10−3).

“A likely explanation of this finding [of stronger association with APOB than PSEN1] is ascertainment bias, that is, carriers with PSEN1 mutations are more likely to be recruited by an [Alzheimer disease center] because of their mutation status,” the investigators wrote. “In this case, we would expect to see attenuation in the association between known [Alzheimer]-causing mutations and [early-onset Alzheimer] after adjusting for [Alzheimer disease center] site, which is precisely what we observed.”

In total, APOE E4 accounted for 10.1% of the variance of early-onset Alzheimer disease. After controlling for this, early-onset Alzheimer cases had greater levels of total cholesterol (mean difference, 21.9 mg/dL [standard error (SE), 5.2]; P = 2.9 × 10−5), LDL-C (mean difference, 22.0 mg/dL [SE, 4.5]; P = 1.8 × 10−6), and plasma apolipoprotein B (ApoB; mean difference, 12.0 mg/dL [SE, 2.4]; P = 2.0 × 10−6) than the controls in 267 frozen samples.

After adjustments were made for a number of factors (sex, APOE E4, genetic principal components, center, and batch), the gene-based rare variant burden testing of 2066 samples showed that rare APOB coding variants were significantly more abundant in early-onset Alzheimer cases (effect size, 0.20; P = 4.20 × 10−4).

“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,” Wingo and colleagues wrote. They also noted that this association between higher LDL-C levels and early-onset disease was not fully explained by APOE E4 nor APOB, implying that additional genes and/or mechanisms contribute to those findings.

Wingo and colleagues did acknowledge a number of limitations, and in an accompanying editorial, Makoto Ishii, MD, PhD, noted that despite these limitations—including Alzheimer diagnoses being made without neuroimaging/cerebrospinal fluid biomarkers, an entirely white study population, and the multifaceted influence on plasma cholesterol—the study “highlights the usefulness of investigating [early-onset Alzheimer disease] to discover novel genetic coding variants that may underlie [Alzheimer] pathogenesis common to both [early-onset Alzheimer disease] and [late-onset Alzheimer disease].”

Ishii continued that in place of exclusion or ignorance of early-onset Alzheimer disease due to low prevalence or perceived differences from late-onset disease, “there should be a concerted effort to conduct large-scale comprehensive studies on [early-onset Alzheimer disease].” He wrote that this research could identify additional novel genetic candidates, as well as help in discerning differences between early- and late-onset disease.

“To this end, studies such as this one and the recently launched Longitudinal Early-Onset Alzheimer Disease Study are timely and will provide the foundation needed to answer many of these unresolved questions,” Ishii concluded.
REFERENCES
1. Wingo TS, Culter DJ, Wingo AP, 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.
2. Ishii M. Apolipoprotein B as a new link between cholesterol and Alzheimer disease. JAMA Neurol. Published online May 28, 2019. doi:10.1001/jamaneurol.2019.0212.