May 30, 2019
2 min read

Circulating cholesterol tied to early-onset Alzheimer’s disease

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Study findings indicated that higher levels of cholesterol was associated with early-onset Alzheimer’s disease independently of apolipoprotein E 4 allele, APOE E4.

“Data suggest that cholesterol is a risk factor for [Alzheimer’s disease] independent of APOE; however, the role of cholesterol in [early-onset Alzheimer’s disease (EOAD)] and of other cholesterol-related genes in EOAD is not known,” Thomas S. Wingo, MD, from the department of neurology, Emory University School of Medicine, and colleagues wrote in JAMA Neurology.

In this case series, researchers examined the link between circulating cholesterol levels and early-onset Alzheimer’s disease as well as genetic variants underlying this possible link. They measured clinical diagnosis, age at diagnosis, plasma cholesterol measures—including total cholesterol, cholesterol, cholesterol, triglycerides and apolipoprotein B—and sequenced the genetic variants APOE, APP, PSEN1, PSEN2, and APOB in samples from 2125 early-onset Alzheimer’s disease cases and controls.

Overall, APOE E4 explained 10.1% of the variance in liability to early-onset Alzheimer’s disease. After controlling for APOE E4, analysis indicated that with early-onset Alzheimer’s disease exhibited higher levels of total cholesterol (mean difference = 21.9 mg/dL; P = 2.9 × 105), LDL (mean difference = 22 mg/dL; P = 1.8 × 106), and plasma apolipoprotein B (mean difference = 12 mg/dL; P = 2 × 106) compared with controls.

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Wingo and colleagues estimated that LDL explained 7.6% of the variance in liability to early-onset Alzheimer’s disease independent of APOE E4. Additional regression analyses stratified byAPOEE3/3 orAPOEE3/4genotype confirmed that Alzheimer’s had significantly higher LDL levels compared with controls independently of APOEE3/3 in 153 samples (mean difference = 25.6 mg/dL; P = 2 × 105) or APOEE3/4 in 82 samples (mean difference = 19.8 mg/dL; P = .02).

In addition, rare APOB coding variants were significantly more abundant in early-onset cases independently of APOE (effect size = 0.2; P = 4.2 × 104), according to the results.

“Our findings suggest an important role of cholesterol metabolism in pathogenesis,” Wingo and colleagues wrote. “The APOB variants we found do not fully explain the association between elevated LDL levels and EOAD, indicating that further studies are needed to identify additional genetic variants underlying the contribution of lipid metabolism to pathogenesis.”

These findings emphasize the importance of investigating early-onset Alzheimer’s disease to find novel genetic coding variants that could underlie disease pathogenesis common to both early- and late-onset Alzheimer’s (LOAD), Makoto Ishii, MD, PhD, from the Feil Family Brain and Mind Research Institute at Weill Cornell Medicine, wrote in a related comment.

“Instead of excluding or ignoring EOAD owing to its low prevalence or perceived differences from LOAD, there should be a concerted effort to conduct large-scale comprehensive studies on EOAD,” Ishii wrote. “This may ultimately result in not only the identification of additional novel candidate genes involved in but also the discernment of any differences between EOAD and LOAD that may eventually lead to better management and care of patients with EOAD.” – by Savannah Demko

Disclosures: Wingo reports grants from the National Institute of Aging, the NIH and the VA. Please see the study for all other authors’ relevant financial disclosures. Ishii reports grant support from the NIH and owning stock in Regeneron Pharmaceuticals.