People who have a gene variant associated with an increased risk of developing Alzheimer’s disease also tend to have changes in the fluid around their brain and spinal cord that are detectable years before symptoms arise, according to new research from Duke Health. This could be a route to early detection of problems that could arise in the future and a possible basis for early intervention.
The work found that in people who carry the APOE4 gene variant, which is found in roughly 25 percent of the population, the cerebrospinal fluid contains lower levels of certain inflammatory molecules.
The findings, which were published online last month in the Journal of Alzheimer’s Disease, provide a potential means to identify the earliest mechanisms occurring among APOE4 carriers that might contribute to Alzheimer’s disease before people develop memory problems or other symptoms of dementia. This could be a basis of the development of novel therapies for Alzheimer’s and other forms of dementia.
“Our work suggests a potential role for a long-studied molecule called C-reactive protein, which is typically elevated when there’s inflammation, as a factor in the increased Alzheimer’s disease risk seen in APOE4 carriers,” said lead author Miles Berger, M.D., Ph.D., associate professor in Duke’s Department of Anesthesiology.
Berger and colleagues analyzed data from targeted cerebrospinal fluid of Alzheimer’s Disease Neuroimaging Institute research participants.
Controlling for Alzheimer’s disease clinical status, they identified protein level variations in the cerebrospinal fluid from people with an increasing number of APOE4 gene variant copies. They found that people with more APOE4 copies had lower CRP levels circulating in their cerebrospinal fluid.
Berger said this is consistent with the current risk profile associated with APOE4 carriers. People with a single APOE4 variant have about a three- to four-fold increased risk of developing Alzheimer’s disease, while those who carry two APOE4 variants have a greater than 10-fold 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,” Berger said.
“Altered complement activity has also been found at autopsy in the brains of patients who suffered from Alzheimer’s disease, and the complement pathway can both damage synapses and target them for destruction,” Berger said.
“Our results raise the possibility that processes like these operating over many years and even decades in APOE4 carriers could eventually result in Alzheimer’s disease pathology and cognitive decline.”