People with gene variation are associated with an increased risk for developing Alzheimer’s disease also prone to changes in the flow around the brain and spine that are recognizable years before symptoms rise, according to a new study from Duke Health.
The work found that in people carrying the APOE4 gene variant, found in about 25 percent of the population, there are lower levels of specific inflammatory molecules in the cerebrospinal fluid. This raises the possibility that these inflammatory molecules may accumulate in the brain where they may damage synapses, rather than floating freely in the cerebrospinal fluid.
The findings, which were published online last month in the Journal of Alzheimer’s disease, provides a way to identify the earliest mechanisms occurring among APOE4 carriers that may contribute to Alzheimer’s disease before people develop memory problems or other symptoms of dementia.
Our work suggests a potential place for a long-studied molecule called C-reactive protein (CRP), which is usually elevated in the presence of inflammation, as a factor in the increased risk for Alzheimer’s disease seen in APOE4 carriers. “
Miles Berger, MD, Ph.D., Lead study author and Associate Professor, Department of Anesthesiology, Duke University Medical Center
Berger and colleagues analyzed data from targeted cerebrospinal fluid of Aluroer Disease Neuroimaging Institute research partners. Controlling the clinical status of Alzheimer’s disease, they identified differences in protein levels in the cerebrospinal fluid from individuals with a growing number of APOE4 gene mice. They found that people with more circulating APOE4 copies had lower CRP levels in their cerebrospinal fluid.
Berger stated that this is consistent with the current risk profile associated with APOE4 carriers. People with one APOE4 variant have about three to four times greater risk of developing Alzheimer’s disease, and those who carry two APOE4 variants have a greater than 10-fold risk.
“We found that people with the APOE4 allele have lower levels of spinal fluid CRP, before they ever develop depression or even brain weakness,” Berger said. “This suggests that CRP may be actively involved in damaging synapses. We believe that CRP does this in conjunction with inhibition of inflammatory proteins called fillers, which the one after another acting as a series of falling dominos.
“Altered filling activity was also found at autopsy in the brains of patients suffering from Alzheimer’s disease, and the filling pathway can both damage synapses and target them for destruction,” Berger said. “Our results raise the possibility that processes such as these may work over several years and even decades in APOE4 carriers leading to Alzheimer’s disease pathology and cognitive decline.”
Berger said there are other inflammatory diseases where CRP can be reduced rather than increased, especially lupus. He said medications used to control CRP for diseases such as rheumatoid arthritis and vasculitis could warrant screening for Alzheimer’s disease, but that further studies are needed to further clarify Duke team’s findings.
“Those with more APOE4 modifications may have eliminated too many synapses throughout their lives, until it reaches a point where the brain can no longer process information,” Berger said. “It would be like taking a book and deleting every 1000th letter at random. For a while, you could do that and the book would still make sense. But after a while, too many letters would be lost and lost. You think that’s the information in the book. We think that’s probably what’s happening in the brain. “
Source:
Duke University Medical Center
Magazine Reference:
Miles, B.,. et al. (2021) APOE4 Copy of Number-Dependent Proteomic Changes in the Cerebrospinal Fluid. Journal of Alzheimer’s disease. doi.org/10.3233/JAD-200747.