Lower Amyloid Burden in Elderly With Alzheimer's Gene

Pam Harrison

October 04, 2012

October 4, 2012 — The burden of brain amyloid in nondemented elderly persons is lower among those who carry a newly identified gene for late-onset Alzheimer's disease (AD) compared with noncarriers, new research shows.

Madhav Thambisetty, MD, PhD, from the National Institute on Aging, National Institutes of Health, Baltimore, Maryland, and colleagues found that the mean level of amyloid burden in elderly persons who carry the complement component receptor–1 (CR1) gene variant was statistically significantly less in many areas of the brain than in those who did not carry the same risk allele.

Furthermore, the investigators found that CR1 interacts with APOE, the most robust genetic risk factor for AD, to influence brain amyloid deposition.

"Our main interest was to look at the effect of this novel genetic risk factor for AD on brain amyloid and to ask if it might influence brain amyloid during aging," Dr. Thambisetty told Medscape Medical News.

"What we found was that individuals in the main study sample who carry the risk allele of CR1 surprisingly had lower amounts of brain amyloid than those who did not carry this risk allele. So we need to understand mechanisms other than those that increase brain amyloid as well as important interactions between AD risk genes better."

The study was published online October 1 in Biological Psychiatry.

Widespread Decrease

For the study, investigators recruited 57 cognitively normal individuals (mean age, 78.5 years) from the Baltimore Longitudinal Study of Aging (BLSA).

Participants underwent C-Pittsburgh compound-B positron emission tomography (PET) amyloid imaging scans and genome-wide genotyping.

Researchers also evaluated identical PET data from 22 cognitively normal individuals in the Alzheimer's Disease Neuroimaging Initiative (ADNI).

Analyses revealed that of the 57 BLSA participants, 17 carried the risk allele of the rs38188361 single nucleotide polymorphism in the CR1 gene.

Genome-wide association studies have clearly implicated the CR1 gene as a major risk factor for AD.

Among ADNI participants, 4 out of 22 also carried the variant.

Carriers of the risk allele were referred to as AA/AG, and noncarriers were termed GG.

"We observed widespread and statistically significant decreases in brain amyloid burden among carriers of the risk allele (AA/AG) of rs3818361 relative to noncarriers (GG)," investigators write.

Risk Unrelated to Amyloid Burden

Statistically significant differences were also observed in many different areas of the brain.

Findings were replicated in the separate cohort of 22 ADNI patients as well.

"We also observed a statistically significant increase in variability in brain amyloid burden in risk noncarriers (GG) of rs3818361 relative to the risk group (AG/AA)," they add.

Again, these differences were observed in many different areas of the brain.

Researchers also investigated factors that might be responsible for the increased variability in brain amyloid deposition in noncarriers of the CR1 risk allele.

Here, they found significant interactions between APOE genotype and the CR1 group in several brain regions — "indicating differential effects of APOE genotype on amyloid burden for risk versus nonrisk groups in these regions," they observed.

Specifically, among participants who did not carry the risk allele, APOE ε4 carriers showed greater brain amyloid burden than APOE ε4 noncarriers.

In contrast, amyloid burden was similar for APOE ε4 carriers and noncarriers to carriers of the rs3818361 risk allele.

Findings were replicated in the separate cohort of 22 ADNI patients as well.

"These findings were in nondemented elderly patients, so this is an important caveat to remember in drawing implications at this time," Dr. Thambisetty cautioned.

"But the findings suggest to us that the CR1 risk factor gene, if it contributes to Alzheimer's disease, does it in a way unrelated to increasing amyloid burden."

Complex Disease

Heather Snyder, PhD, senior associate director of medical and scientific relations with the Alzheimer's Association in Chicago, Illinois, told Medscape Medical News that the study underscores just how complex AD is and the fact that it probably does have multiple causes.

"The genetics of AD are also multifactorial," she added, "so I think this type of research is essential to try and understand the different mechanisms that may be playing a role in the disease."

She did caution that it was a relatively small study group and that, as Dr. Thambisetty himself observed, more research and additional evidence is needed before they can reach any decisive conclusion about these types of interactions.

Nevertheless, as genome-wide association studies uncover ever more genetic risk factors for AD, "we need to understand what the mechanisms and interactions are before we understand what is happening in this disease."

Dr. Thambisetty is a named inventor on a patent application related to blood biomarkers for Alzheimer's disease, filed by his previous employer, Kings College London. Dr. Snyder has disclosed no relevant financial relationships. The study was supported in part by the Intramural Research Program, the National Institute on Aging, and the National Institutes of Health.

Biol Psychiatry. Published online October 1, 2012. Abstract