Brain and spinal fluid changes indicate Alzheimer’s years before onset

Brain and spinal fluid changes indicate Alzheimer’s years before onset
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New research has revealed that 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.

The research team at Duke Health found that in people who carry the APOE4 gene variant, which is found in roughly 25% of the population, the cerebrospinal fluid contains lower levels of certain inflammatory molecules. The researchers say that this raises the possibility that these inflammatory molecules may be collecting in the brain where they may be damaging synapses, rather than floating freely in the cerebrospinal fluid.

The findings have been published in the Journal of Alzheimer’s Disease.

Spinal fluid

The team analysed data from targeted cerebrospinal fluid of Alzheimer’s Disease Neuroimaging Institute research participants, identifying 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 c-reactive protein (CRP) levels circulating in their cerebrospinal fluid.

The finding could offer potential means to identify the earliest mechanisms that might contribute to Alzheimer’s disease as it develops.

Miles Berger, M.D., Ph.D., associate professor in Duke’s Department of Anaesthesiology, said: “Our work suggests a potential role for a long-studied molecule called C-reactive protein (CRP), which is typically elevated when there’s inflammation, as a factor in the increased Alzheimer’s disease risk seen in APOE4 carriers.

“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 might be actively involved in damaging synapses. We think CRP is doing this together with a cascade of inflammatory proteins called complement, which sequentially activate each other like a row of dominos falling.

“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. 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.”

He added: “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 1,000th 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.”

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