Recent findings suggest that people who carry the 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. These changes are detectable years before symptoms arise.
Alzheimer’s disease (AD) is a progressive brain disorder that causes a slow decline in memory, thinking and reasoning skills. The ɛ4 polymorphism of the apolipoprotein E gene is the best described genetic contributor to late onset AD. Individuals carrying a single APOE4 allele copy have a ∼3-fold increased risk of developing AD, whilst those carrying two APOE4 alleles have a greater than 10-fold risk of developing AD. Due to its pleiotropic effects, APOE4 carriers live ~4.2 years less than non-APOE4 carriers. Our understanding of the mechanisms that explain how APOE4 contributes to AD risk and causes worse outcomes is still unclear.
One mechanism suggests that the link between APOE4 and AD is neuroinflammation. In humans, neuroinflammation is a key contributor to AD pathogenesis. As neurodegeneration in AD itself associates with inflammation, it is important to study the effect of APOE4 on the central nervous system of older adults who have not yet presented with dementia and neurodegeneration due to AD.
Characterisation of cerebrospinal fluid
In this study, published in the Journal of Alzheimer’s Disease, researchers analysed targeted CSF proteomic data from Alzheimer’s Disease Neuroimaging Institute research subjects. The team adjusted for age, sex and APOE4 copy number as well as AD clinical status.
They found that increasing APOE4 copy number was associated with a significant decrease in C-reactive protein (CRP) levels. It also resulted in increased CSF ALDOA, CH3L1 and FABH levels. These findings raise the possibility that these inflammatory molecules may be collecting in the brain where they may be actively involved in damaging synapses. Specifically, the team think CRP is doing this together with a cascade of complement proteins. Experts have found altered complement activity during autopsy in the brains of patients who suffered from AD.
Miles Berger, lead author, stated:
“Maybe those with more APOE4 variants have excessive deletion of synapses throughout life, until it gets to point where the brain can’t process information anymore.
It would be like taking a book and randomly deleting every 1000th letter. For a while, you could do that, and the book would still make sense. But after time, too many letters would be gone, and you would lose the information in the book. We think that might be what’s happening in the brain.”
There are several other notable inflammatory diseases for which CRP can be present at lower levels, e.g., lupus. The team suggest that it might be worth investigating therapies that control CRP in these diseases for use in AD.
Image credit: By sbtlneet – pixabay.