Potential Biomarkers for Alzheimer’s Disease Early Diagnosis

Alzheimer’s disease is a neurodegenerative disorder characterized by cognitive and behavioral problems. It is the most common form of dementia in the elderly with patients initially experiencing memory loss and confusion that gradually leads to behavior and personality changes, a decline in cognitive abilities and ultimately to severe loss of mental function. Alzheimer’s disease is characterized by the loss of neurons responsible for memory and learning, and brain formation of amyloid plaques (containing sticky beta-amyloid proteins) and tangles (twisted strands of a protein called tau).

It is thought that Alzheimer’s disease starts developing long before the individual experiences clinical symptoms, therefore biomarkers that can identify the disease in an early stage, potentially allowing an earlier intervention and improved clinical outcome, would be extremely valuable.

Researchers at the University of Kentucky’s Sanders-Brown Center on Aging are currently searching for such biomarkers. One of them is Dr. Mark Lovell, who believes that a proper biomarker must be able to predict the disease and be easily identified by a physician at a clinical setting.

“Multiple studies show alterations in levels of the proteins associated with AD [Alzheimer’s disease] – tau and beta amyloid – in cerebrospinal fluid [CSF], but a spinal tap to obtain that fluid is often a hard sell for patients” explained Dr. Lovell in a news release. “Furthermore, there appears to be variability in the data connecting the levels of these proteins in CSF and the diagnosis of AD, which has limited the use of beta amyloid and tau clinically.”

In the search for alternative biomarkers, Dr. Lovell and his team sorted proteins present in CSF according to their molecular weight. Two proteins in particular called the researchers’ attention – transthyretin and prostaglandin-d-synthase. “We were able to tease out that these two proteins, when subjected to oxidative damage, tended to stick together and fractionate at a higher molecular weight than expected,” said Dr. Lovell.

Researchers found that these two proteins may signal dysfunction in the choroid plexus, a brain region responsible for the production of CSF. Since such dysfunction is characteristic of Alzheimer’s disease, researchers suggested them as potential biomarkers. Remarkably, the presence of both proteins was also detected in blood samples. “I’ve historically been skeptical that blood can be as strong a predictor of Alzheimer’s disease as CSF, but I was pleasantly surprised to see that there was a reasonable correlation in samples of CSF and blood taken from the same patients,” said Dr. Lovell, who believes that Alzheimer’s disease will ultimately be diagnosed through a set of three or four biomarkers.

Dr. Brian Gold, on the other hand, is focused on brain imaging tools in the search for non-invasive Alzheimer’s disease biomarkers that correlate with microstructural brain changes. “We’ve instead been focusing on microstructural brain changes detectable with a form of MRI [magnetic resonance imaging] called diffusion tensor imaging (DTI), which assesses the diffusion of water molecules in the brain.” explained Dr. Gold. “As cellular structures begin to degenerate, tissue barriers degenerate as well, allowing for increased water diffusion DTI-based changes in the brain are thus somewhat analogous to hairline cracks in a house’s foundation that precede visible structural damage.” Dr. Gold published last year the finding that the microstructure of white matter in the brain is associated with CSF biomarkers of Alzheimer’s disease.

Finally Drs. Dick Kryscio and Erin Abner are involved in the management of the Alzheimer’s Disease Center (ADC) database, which has clinical information and several samples from more than 1,300 individuals. The two researchers carefully analyzed the database in the search of factors that might represent an early sign of the disease. Interestingly, both researchers have published studies showing that there is a link between self-reported memory complaints and the development of cognitive impairment later in life. “In other words, people usually are the best judges of their own memory — they can detect subtle problems years before there are more obvious symptoms,” said Dr. Abner.

Overall, independently of the approach taken, the common goal of researchers at Sanders-Brown Center on Aging is to detect Alzheimer’s disease at its earliest stages.