Susan Jeffrey

November 19, 2013

DALLAS, Texas — Plasma levels of apolipoprotein E (APOE) are associated with the risk for Alzheimer's disease (AD) and dementia, independent of APOE genotype, a new study shows.

Using 2 large general population cohorts, Danish researchers found that low plasma levels of APOE were associated with significantly higher risks of AD and of all dementia, but not with cerebrovascular disease, regardless of the presence or absence of the APOE ε4 genotype that is already associated with increased AD risk.

"These things suggest that plasma levels of APOE may be a new preclinical plasma biomarker for dementia, and again, this is the first plasma biomarker for predicting future dementia," said Ruth Frikke-Schmidt, from Rigshospitalet, Copenhagen University Hospital in Copenhagen, Denmark.

She speculated that low levels of plasma APOE reflect APOE activity in the brain. "So, low APOE in plasma mirrors low APOE production in the brain, which probably is not good, because less β-amyloid is cleared," she concluded.

Dr. Frikke-Schmidt reported their findings here at the American Heart Association (AHA) Scientific Sessions 2013.

Established Risk

APOE plays a major role in lipid transport and in neuronal repair, the authors note. In the circulation, it's associated with…and serves as a ligand for receptors in the liver, clearing triglyceride-rich lipoproteins. "But in the brain, it's another situation," Dr. Frikke-Schmidt said. Astrocytes produce APOE, and there it's responsible for the clearance of β-amyloid, the "sticky" protein associated with the senile plaques seen in AD and other forms of dementia.

The strong association between an APOE genetic variant, ε4, and dementia, particularly AD, was established in 1993 and "has been validated globally," she said. Later, APOE ε4 was also linked to a moderate increased risk for cerebrovascular disease.

In this study, they set out to test whether plasma levels of APOE are similarly related to risk for AD, dementia or cerebrovascular disease, independent of APOE genotype. "This is important because we do not have any biomarkers for dementia, and only a few for cerebrovascular disease," she said.

The population studied included 76,386 participants in the Copenhagen General Population Study (CGPS) and the Copenhagen City Heart Study (CCHS). They measured plasma APOE levels and calculated the risk for disease according to age- and sex-adjusted percentile groups of plasma APOE concentrations, creating the following tertiles: 0% to 33%, 34% to 66%, and 67% to 100%.

They also genotyped participants for rs429358 and rs7412, which combine into 6 common APOE genotypes: ε22, ε32, ε42, ε33, ε43, and ε44. The latter is the highest-risk allele for AD.

In the combined studies, they found that participants in the lowest tertile for plasma APOE had a higher cumulative incidence of dementia compared with those in the intermediate and highest tertiles (log-rank trend, P = 4.4 × 10–12). "If you look at the age, at approximately the age of 86, there was a cumulative incidence of 8% in those with the lowest levels compared to 3% in those with the highest levels of APOE," Dr. Frikke-Schmidt noted.

In the individuals with the lowest levels vs the highest levels, the risk for dementia was 3-fold higher in the group with the lowest APOE levels. "This remained significant even after adjustment for the very strong ε4 APOE genotype," she noted.

Most people carry the ε33 genotype, and using these carriers as the control, the researchers found that carriers of the ε44 genotype had a 10-fold increased risk for dementia. "In all populations, it's 10-fold," she noted, "a 1000% increase, and 3% of us carry this." This risk remained unchanged after adjustment for APOE levels.

They then plotted APOE levels by APOE genotype in each population separately and found in both the CGPS and the CCHS populations almost identical proportions, with the ε22 carriers having the highest levels, declining steadily down the groups to the ε44 carriers, a highly significant trend.

"This association with the ε22 carriers is well known, way back in biology, because these individuals are receptor defective, and they do not bind to LDL [low-density lipoprotein] receptors in the liver, so there are high levels of APOE in plasma," Dr. Frikke-Schmidt noted.

Dissecting the Risk

APOE genotype explains 26% of the variation in APOE, Dr. Frikke-Schmidt said, "so when there is this strong association between genotype and plasma levels, how do we dissect the risk of dementia conferred by plasma APOE levels from the risk conferred by the strong APOE genotype?" To look at this, they stratified APOE levels into tertiles within just the low-risk carriers (ε32 and ε33) and just the high-risk carriers (ε43 and ε44), and saw similar results (P for trends = .001 and 3.1 × 10–4, respectively).

"I think this is the strongest evidence that APOE levels, the effect of that on dementia is independent of genotype," she said. This is further substantiated by the fact there was no evidence of interaction between APOE levels and APOE genotype in predicting dementia, she added.

There was no association between plasma APOE and cerebrovascular disease, but there was an association between APOE genotype and cardiovascular disease. There was a slight increased risk of all cardiovascular disease for ε44 carriers that was most pronounced for hemorrhagic stroke, she noted, and the associations remained significant after adjustment for other lipids and proteins, including APOE.

Dr. Frikke-Schmidt pointed to a recent paper in Nature showing in a mouse model that the ε44 allele and a lack of APOE was associated with an inflammatory response in the pericytes of the neurovascular unit, leading to a defect in the blood-brain barrier and access of neurotoxic substances into the brain tissue, starting the process of AD.

The authors have disclosed no relevant financial relationships.

American Heart Association (AHA) Scientific Sessions 2013. Abstract #17377. Presented November 18, 2013.

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