Plasma ApoE Protein Concentration Correlates With Brain Amyloid Burden

Megan Brooks

December 29, 2010

December 29, 2010 — The apolipoprotein E (ApoE) concentration in blood correlates with brain amyloid burden in nondemented elderly individuals, according to new data from the National Institute on Aging's Baltimore Longitudinal Study on Aging (BLSA).

"To the best of our knowledge, this is the first study to link plasma ApoE protein concentration with brain amyloid deposition in cognitively normal older individuals," Madhav Thambisetty, MD, PhD, from the National Institute on Aging's Clinical Research Branch in Baltimore, Maryland, told Medscape Medical News.

The study was published online December 20 in the Journal of Alzheimer's Disease.

According to Dr. Thambisetty, the team's next step is "to relate changes in plasma ApoE protein concentration over time to brain amyloid deposition."

"We think that looking at changes in plasma ApoE levels over time (compared to a single measurement) may be more informative in predicting which individuals might eventually develop greater amyloid deposition in the brain. We hope that these studies might eventually allow us to identify cognitively normal elderly people who are at risk for accumulating greater brain amyloid burden," he said.

The current findings are based on studies involving 57 BLSA participants who were in their late 60s at baseline and their late 70s at the time of positron emission tomography (PET) scans.

With the goal of identifying a peripheral signature of brain amyloid burden, the researchers performed discovery-phase proteomic experiments using plasma samples collected 10 years before PET using Pittsburgh Compound B fluorescent tracer, which binds to fibrillar amyloid-beta.

Two-dimensional plasma gel electrophoresis identified a panel of 18 plasma protein "spots" that effectively discriminated between individuals with high and low brain amyloid-beta, including a "prominent signal" from plasma ApoE protein.

The researchers focused on this protein in subsequent validation studies, "given the large body of evidence implicating both the APOE gene and ApoE protein in [Alzheimer's disease (AD)] risk and amyloid-beta metabolism."

They performed quantitative enzyme-linked immunosorbent assay (ELISA) assays of plasma ApoE concentration in a separate set of plasma samples obtained within 1 year of the corresponding PET scans.

Again, plasma ApoE protein concentration was strongly associated with the extent of amyloid deposition, particularly in the medial temporal lobe — the site of early neuropathological changes in AD. "Targeted voxel-based analysis localized this association to the hippocampus and entorhinal cortex," the authors write.

APOE e4 carriers also showed greater amyloid beta levels in several AD-associated brain regions relative to noncarriers. The average plasma ApoE protein concentration was significantly higher in APOE e4 carriers relative to noncarriers (175.4 vs 146.8 μg/mL; P = .004).

There was a significant correlation between amyloid burden in the medial temporal cortex and plasma ApoE concentration — an association that appeared to be driven primarily by APOE e4 noncarriers. Higher plasma ApoE protein concentrations were associated with greater amyloid burden in the hippocampus and entorhinal cortex.

"Together with previous evidence for a role of the ApoE protein in amyloid-beta deposition and clearance, these results indicate that plasma ApoE concentration may be a biologically relevant peripheral marker of in vivo amyloid deposition in brain regions vulnerable to AD pathology," the researchers write.

"We are planning similar studies with plasma clusterin concentration (also known as apolipoprotein-J, or ApoJ) because we reported earlier this year a similar finding, where we related plasma clusterin concentration to brain amyloid burden in the same group of BLSA participants," Dr. Thambisetty told Medscape Medical News.

"We know from studies done by other groups in animal models of AD that both these proteins (ApoE and ApoJ) might be important in binding to and clearing amyloid-beta from the brain."

Dr. Thambisetty noted that focusing on cognitively normal older individuals for this study and the planned follow-up experiments will help researchers identify blood biomarkers that predict brain pathology in nondemented individuals who are at risk for subsequent disease.

"This 'at-risk' group might benefit the most from early disease-modifying treatments, and also [be] the group that could be targeted in clinical trials of emerging treatments," he said.

Another strength of the study is the longitudinal design of the BLSA, which helps to track changes in candidate biomarkers over time, which is likely to be more informative than observations at single time points. The relatively small sample size is a limitation of the current study.

"We now await independent replication/confirmation of the results by other groups. This is a necessary next step," Dr. Thambisetty said.

Reached for outside comment, John Q. Trojanowski, MD, PhD, codirector of the Alzheimer's Disease Neuroimaging Initiative Biomarker Core at the University of Pennsylvania, Philadelphia, who was not involved in the study, called it a "very solid study."

"The researchers used a proteomic approach and then followed up with confirmatory ELISA studies," he continued. "Often when people do proteomic studies they stop there, which only really gives you a spot — a band — to identify and correlate with either normal or some other status, but this group has gone and done confirmatory ELISA in a separate set of samples, so I think it is a solid study," Dr. Trojanowski added.

The study was supported in part by the National Institute on Aging, National Institutes of Health, National Institute for Health Research Biomedical Research Centre for Mental Health at the South London and Maudsley National Health Service Foundation Trust and Institute of Psychiatry, King's College London, United Kingdom. Partial support was also through a research and development contract with MedStar Research Institute. Dr. Thambisetty is listed as an inventor on a patent application filed by King's College London based on his previous work on proteomic analyses of plasma from patients with AD. A complete list of author disclosures can be found on the journal's Web site. Dr. Trojanowski has disclosed no relevant financial relationships.

J Alzheimers Dis. Published online December 20, 2010.

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