ENC Health Currents: Fibrinogen Leads To Cognitive Decline In Alzheimer's Patients

Mar 6, 2019

Brain from patient with Alzheimer's disease with fibrinogen (red) and tortuous blood vessels (green).
Credit Mario Merlini

Alzheimer’s disease is a debilitating neurodegenerative disorder affecting around 170,000 seniors in North Carolina and more than 5 million people in the U.S.  According to the Alzheimer’s Association, the number of people with the disease will more than triple by the year 2050. The cost to care for patients is estimated to climb to over a trillion dollars.  This growing problem along with advances in technology have led to an increase in Alzheimer’s research as scientists look for ways to treat the disease or delay its progression.  A recent study published in the scientific journal “Neuron” give researchers a better understanding of what causes Alzheimer’s and what contributions vascular pathology make to the progression of the disease.

A team of researchers led by senior investigator Dr. Katerina Akassoglou with Gladstone Institutes in San Francisco showed for the first time that a blood-clotting protein called fibrinogen can destroy connections between neurons in the brain and result in cognitive decline.  Researchers used advanced imaging technology to study both human and mouse brains to observe how the disease progressed and how the blood clotting protein fibrinogen affected cognitive decline. 

“We were very surprised to find that there was this elimination of neurological connections around the fibrinogen deposits.  Up to that point, amyloid had been considered the main source that is inducing this elimination of the neurological connections,” said Akassoglou.

The researchers found that when fibrinogen crosses the blood-brain barrier, it creates toxic signals which cause immune cells to destroy neurons.  The study showed that even small quantities of fibrinogen injected into a healthy brain caused a loss of synapses and immune cells to activate.

“If there’s a new culprit in the brain that can contribute to the elimination of neurological connections, what it could mean is that it is possible this could be a new avenue to target this factor, this blood-derived factors.  And by protecting the blood-brain barrier and targeting fibrin, you can protect these neurological connections.  And this could be a pathway that could be additive to other mechanisms.  So I think it sheds the light how targeting vascular pathways to neurodegeneration might be really important to achieve maximum protection from memory loss and cognitive decline.”

Katerina Akassoglou and the study's first author, Mario Merlini.
Credit Gladstone Institutes

Akassoglou, who is also the Professor at the Department of Neurology at the University of California San Francisco, and her colleagues developed an antibody that neutralizes the ability of fibrinogen to interact with a molecule on the brain’s immune cells. 

“We hope that the antibody will be a tool that can selectively suppress this toxic effect of fibrin in the brain and protect from neurodegeneration. In a private study, we presented pre-clinical evidence in animal models of multiple sclerosis because obviously, this suppresses inflammation, and also in animal models of Alzheimer’s disease as it suppresses neurodegeneration that is derived from this pathogenic inflammation,” said Akassoglou. 

The results from the study help scientists understand previous research that found Alzheimer’s patients with amyloid pathology and patients with vascular pathology both had similar rates of cognitive decline.  But when both types of pathology were present, the effect resulted in more severe memory loss. 

“I think these are very interesting observations that we want to continue in the context of Alzheimer’s disease, but other neurological diseases,” said Kassoglou.  “We have studies to further understand the mechanisms of how this happens in the brain, developing imaging probes to be able to monitor these pathologies better, and in the context of therapies of how can we turn this pathogenic inflammation into a protective mechanism in the brain and protect from cognition and memory loss.”

Credit Alzheimer's Association