APOE Plasma Levels Predict Dementia Independent of Genotype

Daniel M. Keller, PhD

October 04, 2013

VIENNA, Austria — Association of the apolipoprotein E ε4 (APOE) allele and greatly elevated risk of developing Alzheimer's disease emerged 2 decades ago. But a recent study indicates that the level of APOE in plasma, independent of genotype, is also a marker of risk, in this case, greater risk with lower levels.

"There was no evidence of interaction between APOE level and APOE genotype in predicting Alzheimer's disease," Katrine Rasmussen, MD, from the Department of Clinical Biochemistry at the Rigshospitalet of the University of Copenhagen, Denmark, reported. "It was the same in each [APOE] genotype."

APOE, a product of astrocytes, has a major role in lipid transport and in neuronal repair. It carries cholesterol to APOE low-density lipoprotein receptors on neurons.

Speaking here at the XXI World Congress of Neurology (WCN), Dr. Rasmussen presented a study of 75,708 participants in the Copenhagen General Population Study and the Copenhagen City Heart Study to test the association of plasma APOE levels and APOE genotype with the development of dementia.

The researchers measured APOE levels and genotyped the samples for the rs429358 and rs7412 genes. These genes combine to produce 6 common APOE genotypes: ε22, ε32, ε42, ε33, ε43, ε44.

When the nearly 76,000 participants were divided into APOE tertiles, the cumulative incidence of Alzheimer's disease with age was significantly associated with APOE level.

"We found a 3-fold increased risk for the lowest tertile versus the highest tertile and a highly significant P [value] for trend, and the association remained after further adjustment for the APOE genotype," Dr. Rasmussen reported (log-rank trend P < .001).

APOE levels correlated with genotype (P < .001), but when multifactorial adjustment that included genotype was done, APOE level was found to be an independent risk predictor of Alzheimer's disease.

Compared with the highest tertile of APOE plasma level, the hazard ratio (HR) for the middle tertile was approximately 1.3 and for the lowest tertile approximately 1.6 (P for trend = .006).

As expected, the researchers found an association between APOE genotype and Alzheimer's disease, with the lowest risk seen with the ε22, ε 32, ε 42, and ε 33 genotypes (HR, approximately 1 after multifactorial adjustment including for APOE level; P for trend < .001).

The highest risks were seen with the ε43 and ε44 genotypes after the same adjustments (HR, approximately 3 and 7, respectively; P for trend < .001).

Even when low-risk genotypes (ε32 and ε33) were stratified by APOE level, the level was an independent risk factor for Alzheimer's disease (HR, approximately 1.9 for the lowest vs highest APOE tertile; P for trend = .001).

"We found that low plasma levels of APOE associate with risk of dementia, and we found that low plasma levels of APOE associate with risk of dementia independent of APOE gene type," Dr. Rasmussen concluded.

Session chair Jagjit Chopra, MD, PhD, professor emeritus of the Postgraduate Institute of Medical Education and Research in Chandigarh, India, who was not involved in the study, praised the study for its size and selection of populations to examine.

"This study was very good — 76,000 [participants]," he commented to Medscape Medical News. "This is not a small number of people that they looked into, and they were normal people, a normal population. That's the good part of it. They didn't say that we pick up only very elderly people."

Dr. Chopra suggested that there is a role for pharmaceutical companies to pursue the APOE finding as a possible contributor to a mechanism underlying Alzheimer's disease and a possible point of intervention leading to drug development.

There was no commercial funding for the study. Dr. Rasmussen and Dr. Chopra have disclosed no relevant financial relationships.

WCN 2013: XXI World Congress of Neurology: Free Papers Session 21. Presented September 24, 2013.

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