This new study offers a hopeful new path for the early detection and treatment of Alzheimer’s disease, even before symptoms begin to appear.
Dr. Rawan Tarawneh, a neurologist at the University of New Mexico, has discovered a novel biomarker that may help develop new diagnostic tests for the early identification of Alzheimer’s disease.
In a report published in November 2022 in the Annals of Clinical and Translational Neurology, Tarawneh and her colleagues found a novel protein in the cerebrospinal fluid that effectively detects endothelial injury—damage to the cells lining the brain’s small blood vessels—in Alzheimer’s disease.
Using this biomarker, Tarawneh and colleagues discovered that endothelium damage contributes significantly to cognitive impairment even in the absence of any other symptoms.
More than 6 million Americans have Alzheimer’s, including more than 43,000 New Mexicans aged 65 and up. These results give people with Alzheimer’s a glimmer of hope as they may lead to more research into drugs that could protect the brain endothelium from damage.
“These are novel and exciting findings,” remarks Tarawneh, who holds the position of associate professor in the UNM Department of Neurology and serves as both the director of the UNM Cognitive Neurology Section and the Memory & Aging Clinic.
“All of this is new.”
Researchers from UNM and the Knight Alzheimer’s Disease Research Center (ADRC) at Washington University in St. Louis, including Carlos Cruchaga, Ph.D., who is in charge of the Genomics Core, worked with Tarawneh to study 700 people who were cognitively normal but showed signs of Alzheimer’s disease through biomarkers.
The trial subjects, who were recruited at the Knight Washington ADRC, had thorough clinical, cognitive, MRI, and PET scans as well as biomarker evaluations that included assessing a new endothelial damage biomarker termed vascular-endothelial cadherin (VEC).
The study team found that even in the early stages of Alzheimer’s, before memory loss started, their cerebrospinal fluid levels of VEC were higher than in controls.
When added to known biomarkers for Alzheimer’s, like amyloid and tau, cerebrospinal fluid levels of VEC made it easier for these markers to spot early Alzheimer’s pathology.
According to Tarawneh’s research, endothelial damage seems to be a significant factor very early in the development of Alzheimer’s disease and is directly tied to memory, cognitive abilities, and synaptic plasticity.
Furthermore, even after controlling for imaging markers of small vessel disease, researchers discovered that VEC levels linked with cognitive outcomes to the same amount as amyloid and tau in these early preclinical phases.
These findings indicate that they can accurately assess endothelial damage in the brains of Alzheimer’s patients and that this damage is strongly linked to cognitive decline, just as amyloid and tau are. Additionally, they also show several mechanisms through which the blood vessel lining, or endothelium, influences memory and learning without involvement from amyloid and tau. These results confirm that the endothelium does indeed have a direct connection to cognitive impairment.
Neuroscientists have spent years studying microscopic alterations in brain tissue caused by the beta-amyloid protein and another protein called tau.
Among the many proteins found in the brain, beta-amyloid is the one that abnormally clumps together in Alzheimer’s patients to create the plaques that eventually accumulate between neurons and cause cell dysfunction.
Inside of neurons, a protein called tau assembles. Tau separates from the microtubules that support neurons structurally in Alzheimer’s disease and binds to other tau molecules to create dense tangles.
Researchers are still trying to figure out which of these changes are caused by Alzheimer’s and which are caused by it.
Endothelial damage was thought to be caused by amyloid and tau toxicity for a long time. But new studies are starting to show how important the endothelium and other parts of the blood vessels are in starting the chain of events that leads to Alzheimer’s disease.
According to the study, endothelium damage is caused by toxic levels of amyloid and aberrant accumulations of tau, but it is also possible that endothelial injury is the source of a rise in amyloid and tau levels.
“Now we’re seeing that maybe endothelial damage could be the inciting event,” Tarawneh adds, “and then amyloid and tau are secondary to that.”
Tarawneh speculates that endothelial cell injury in the capillaries leads to some kind of microcirculatory failure.
“Once endothelium is damaged, it causes aggregation of amyloid and tau. And then amyloid and tau cause further endothelial damage because they’re toxic,” she points out. “It’s a vicious cycle.”
Tarawneh’s grandma was given an Alzheimer’s disease diagnosis in the early 2000s. Tarawneh was inspired to pursue a career in neurology and study what happens to the brain in Alzheimer’s disease after being discouraged by the paucity of research in the subject.
Looking ahead Tarawneh said that she intends to do further study to determine how the endothelium affects Alzheimer’s disease.
“Maybe targeting it would be a way to treat the disease,” Tarawneh hopes. “It’s a new avenue for drug discovery.”
Tarawneh wants to keep looking into this. In order to confirm these findings and build upon earlier research, she said that her objective at UNM is to continually increase the number of individuals she can collect blood and cerebral fluid samples from.
Source: DOI: 10.1002/acn3.51685
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