The results, published online last month in the Journal of Alzheimer Disease, offer a potential means of identifying the earliest mechanisms that may appear in APOE4 carriers and contribute to Alzheimer’s disease before people develop memory problems or other symptoms of dementia .
Our work suggests a possible role for a long-studied molecule called C-reactive protein (CRP), which is typically elevated in inflammation, as a factor in the increased risk of Alzheimer’s disease that occurs in APOE4 carriers.
Lead Author Miles Berger, MD, Ph.D., Associate Professor in the Duke’s Department of Anaesthesiology.
Berger and colleagues analyzed data from the targeted cerebrospinal fluid of research participants at the Alzheimer’s Disease Neuroimaging Institute. Under monitoring of the clinical status of Alzheimer’s disease, they identified variations in protein levels in human cerebrospinal fluid with increasing numbers of copies of APOE4 gene variants. They found that people with more APOE4 copies had lower levels of CRP that circulated in their cerebrospinal fluid.
Berger said this is consistent with the current risk profile of the APOE4 carriers. People with a single APOE4 variant have a three to four times higher risk of developing Alzheimer’s disease, while people with two APOE4 variants have a more than tenfold risk.
We found that spinal fluid CRP levels are lower in people with the APOE4 allele before they ever develop dementia or even mild cognitive impairment. This suggests that CRP may be actively involved in synapse damage. We believe that CRP does this along with a cascade of inflammatory proteins called complement that activate one after another like a series of falling dominoes. Altered complement activity has also been found at autopsy in the brains of patients suffering from Alzheimer’s disease, and the complement pathway can both damage synapses and target them for destruction. Our results suggest that processes like these, which take place over many years and even decades in APOE4 carriers, may ultimately lead to Alzheimer’s disease pathology and cognitive decline.
Berger said there are other inflammatory conditions that are more likely to decrease rather than increase CRP, particularly lupus. He said therapies to control CRP in conditions like rheumatoid arthritis and vasculitis might warrant an investigation into Alzheimer’s disease, but additional studies are needed to shed light on the Duke team’s findings.
Perhaps those with more APOE4 variants have synapses over-clearing throughout life until it comes to a point where the brain can no longer process information. It would be like taking a book and randomly erasing every 1000th letter. You could do that for a while and the book would still make sense. But after a while, too many letters would be gone and you would lose the information in the book. We think this could be what’s going on in the brain.
In addition to Berger, the study’s authors include Mary Cooter, Alexander S. Roesler, Stacey Chung, John Park, Jennifer L. Modliszewski, Keith W. VanDusen, J. Will Thompson, Arthur Moseley, Michael J. Devinney, Shayan Smani and Ashley Hall , Victor Cai, Jeffrey N. Browndyke, Michael W. Lutz, David L. Corcoran, and Alzheimer Disease Neuroimaging Initiative.
The study was supported by the National Institutes of Health (P30AG028716, UH2AG056925, U01 AG024904), the Alzheimer’s Drug Discovery Foundation, the first Ann Bussel Award from the Ruth K. Broad Foundation at Duke University, and the Duke Anaesthesiology Department. A full list of supporting funding can be found in the study.
See press release