Risk gene for Alzheimer's associated with lower brain amyloid
A variation in the complement receptor-1 (CR1) gene, a newly identified gene associated with risk for late-onset Alzheimer's disease, is associated with lower levels of beta amyloid—a brain protein involved in Alzheimer's—in cognitively healthy older people, according to a study published online Sept. 27 in Biological Psychiatry. The findings suggest that a mechanism other than one related to beta amyloid accumulation may influence disease risk associated with the gene.

Previous research has shown that the rs3818361 single nucleotide polymorphism in complement component (3b/4b) CR1 is associated with increased risk of Alzheimer's disease (AD), according to the researchers. Although this novel variant is associated with a small effect size and is unlikely to be useful as a predictor of AD risk, it might provide insights into AD pathogenesis.

Thus, Madhav Thambisetty, MD, PhD, chief of the Clinical and Translational Neuroscience Unit in the Laboratory of Behavioral Neuroscience of the National Institute for Aging's Intramural Research Program, National Institutes of Health, in Baltimore, and colleagues examined the association between rs3818361 and brain amyloid deposition in non-demented older individuals.

The researchers used 11C-Pittsburgh Compound-B PET to quantify brain amyloid burden in 57 non-demented older individuals (mean age 78.5 years) in the neuroimaging substudy of the Baltimore Longitudinal Study of Aging (BLSA). In a replication study, they analyzed 11C-Pittsburgh Compound-B PET data from 22 cognitively normal older individuals (mean age 77.1 years) in the Alzheimer's Disease Neuroimaging Initiative dataset.

Of the 57 BLSA participants, 17 carried the Alzheimer’s risk variant of the CR1 gene, while four of the 22 ADNI participants carried the variant.

They found that risk allele carriers of rs3818361 have lower brain amyloid burden relative to noncarriers. “There is a strikingly greater variability in brain amyloid deposition in the noncarrier group relative to risk carriers, an effect explained partly by APOE genotype,” the study authors wrote.

In noncarriers of the CR1 risk allele, APOE E4 individuals showed significantly higher brain amyloid burden relative to APOE E4 noncarriers, according to Thambisetty et al, who also independently replicated the observation of lower brain amyloid burden in risk allele carriers of rs3818361 in the Alzheimer's Disease Neuroimaging Initiative sample.

“We found that brain amyloid burden in the group with the CR1 risk variant was lower than in the group without it. This difference in brain amyloid between the two groups is statistically significant in several brain regions,” Thambisetty said in a NIH press release. “That suggests 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.

“The findings suggest that the increased risk of Alzheimer's associated with CR1 is not driven by an increase in amyloid in the brain and that we may also need to consider multiple genetic risk factors in combination," Thambisetty continued. "It may be possible that CR1 acts through other mechanisms, distinct from those that increase amyloid deposition in the brain. These may include influencing inflammation in the brain, but further research is needed to identify what these other mechanisms might be.”

“The prevailing hypothesis has implicated factors increasing beta amyloid in the brain as an integral element of Alzheimer's disease pathology,” NIA Director Richard J. Hodes, MD, said in the press release. “This study indicates the importance of exploring and understanding other distinct mechanisms that may be at work in this disease.”