Unique Biomarker Could Lead to Diagnostic Tests for Detection of Early-Stage Alzheimer’s

Patients with Alzheimer’s disease experience endothelial injury, or damage to the cells lining the tiny blood vessels in the brain. Previous research has focused on changes visible in brain tissue under a microscope including the beta-amyloid protein and another protein, called tau. Beta-amyloid is a naturally occurring protein that clumps together in abnormal levels among patients with Alzheimer’s to form plaques which get collected between neurons and disrupt cell function. Tau is a protein that collects inside neurons. In patients with Alzheimer’s, tau detaches from the microtubules that act as structural supports for neurons and sticks to other tau molecules to form dense tangles. Researchers are yet to determine which of these changes causes Alzheimer’s and could be due to the disease. For some time now, endothelial damage has been considered secondary to amyloid and tau toxicity, although recent research has begun to shed light on the significant role played by the endothelium and other vascular constituents in setting off the cascade of events that lead to Alzheimer’s disease.

Researchers at University of New Mexico (Albuquerque, NM, USA) have now identified a new protein in the cerebrospinal fluid that can reliably detect endothelial injury in patients with Alzheimer’s disease. Using this biomarker, they found that endothelial injury is a key contributor to cognitive impairment during the earliest pre-symptomatic stages of the disease as well. The findings raise hope for millions of people with Alzheimer’s, as they could pave the way for further research into drug interventions for preventing damage to the brain endothelium.

The researchers conducted a study involving 700 cognitively normal participants who had biomarker evidence of Alzheimer’s disease and had undergone detailed clinical, cognitive, MRI and PET scans and biomarker assessments including measurement of vascular-endothelial cadherin (VEC), a novel marker of endothelial injury. The research team discovered elevated cerebrospinal fluid levels of VEC as compared to controls in even the earlier stages of Alzheimer’s, prior to the onset of memory loss. Upon combining with established Alzheimer’s biomarkers, such as amyloid and tau, the cerebrospinal fluid levels of VEC enhanced the ability of these markers to detect early Alzheimer’s pathology. The researchers also found that the VEC levels correlated with cognitive outcomes to the same extent as amyloid and tau in these early preclinical stages, even after adjusting for imaging measures of small vessel disease.

The research suggests that toxic levels of amyloid and abnormal accumulations of tau cause endothelial injury, while increased amyloid and tau levels may be owing to endothelial injury. The researchers hypothesize that some form of microcirculatory failure occurs that begins in the capillaries, where the endothelial cells are damaged. Going forward, the team plans to conduct further research to understand how the endothelium is involved in Alzheimer’s disease. Their work could pave the way for further research into drug intervention for preventing and/or healing endothelial injury.

“Our study suggests that endothelial damage plays an important role very early in the course of Alzheimer’s disease, and is directly linked to memory, cognitive functions and synaptic plasticity,” said University of New Mexico neurologist Rawan Tarawneh, MD. “We found that we could measure endothelial injury reliably in the brain of Alzheimer’s disease patients and that endothelial injury actually correlates with cognitive outcomes, to a similar degree as amyloid and tau. We have also identified several pathways by which the endothelium influences memory and learning independently of amyloid and tau. So, this is proving that, yes, endothelium – the lining of the blood vessels – has a direct correlation with cognitive impairment.”

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