Researchers have found a new gene associated with Alzheimer’s diseases called BCHE. The team, led by scientists at the Indiana University School of Medicine, used genetic data combined with brain imaging to identify genes associated with the amyloid plaque deposits found in Alzheimer’s disease patients. In addition to uncovering the new gene, their study also identified the APOE gene, long associated with development of Alzheimer’s.
The team believes this research is the first to implicate variations in the BCHE gene in plaque deposits visualized in living individuals who have been diagnosed with Alzheimer’s disease or are at risk for developing the disease. The enzyme coded by the BCHE gene has previously been studied in post-mortem brain tissue and is known to be found in plaques. The researchers also believe this is the first genome-wide association study of plaque deposits using a specialized PET scan tracer that binds to amyloid.
The BCHE gene finding “brings together two of the major hypotheses about the development of Alzheimer’s disease,” says Andrew J. Saykin, Psy.D., Raymond C. Beeler Professor of Radiology and Imaging Sciences at IU and principal investigator for the genetics core of the Alzheimer’s Disease Neuroimaging Initiative.
Scientists have long pointed to the loss of an important brain neurotransmitter, acetylcholine, which is depleted early in the development of the disease, as a key aspect of the loss of memory-related neurons. The BCHE gene is responsible for an enzyme that breaks down acetylcholine in the brain. The other major Alzheimer’s hypothesis holds that the development of amyloid plaques is the primary cause of the disease’s debilitating symptoms. As it turns out, the enzyme for which the BCHE gene codes is also found in significant quantities in those plaques.
“This study is connecting two of the biggest Alzheimer’s dots,” says Dr. Saykin. “The finding that BCHE gene variant predicts the extent of plaque deposit in PET scans among people at risk for Alzheimer’s disease is likely to reinvigorate research into drugs that could modify the disease by affecting the BCHE enzyme or its metabolic pathway.” Some existing drugs inhibit this enzyme, but it is unclear whether this influences plaque deposits. Results from this study appear to offer scientists new potential targets for drugs to slow, reverse, or even prevent the disease.
The study makes use of an imaging agent, florbetapir, that allows physicians to see the level of plaque buildup in a patient’s brain, something that previously could be determined only with an autopsy.
The researchers conducted PET scans of 555 participants in the Alzheimer’s Disease Neuroimaging Initiative, a long-term public-private research project that includes people at risk for Alzheimer’s disease and patients who have been diagnosed with the disease as well as participants with no symptoms. The imaging data was combined with analyses of DNA collected from the participants to determine whether particular gene variants were found more often among patients with higher levels of plaque deposits.
The analysis found that a variant in BCHE was significantly associated with the levels of plaque deposits. The effect of BCHE was independent of APOE, but the effects of the two genes were additive—people with the suspect variants of both genes had more plaque deposits than people who had only one of the variants associated with plaque development.
“The findings could recharge research efforts studying the molecular pathways contributing to amyloid deposits in the brain as Alzheimer’s disease develops and affects learning and memory,” says Vijay K. Ramanan, the paper’s first author and an M.D./Ph.D. student at the IU School of Medicine. The study is published online in Molecular Psychiatry in an article titled “APOE and BCHE as modulators of cerebral amyloid deposition: a florbetapir PET genome-wide association study”.