There is evidence that the brain changes associated with Alzheimer’s disease begin many years before clinical symptoms like memory loss and mental decline emerge. With this in mind, biomarkers of these changes could be valuable ways to identify individuals at the “preclinical” stage, which is early enough for brain-preserving treatment to be effective.
Now, a new study by researchers from the US and Australia, who examined members of families with a genetic form of the disease, shows that spinal fluid concentrations of three biomarkers proposed for Alzheimer’s reverse once symptoms of the disease emerge – the biomarker levels are higher during the preclinical stage.
Such information could be very important for people developing diagnostics and treatments for Alzheimer’s disease, says senior author Anne Fagan, research professor of neurology at Washington University School of Medicine in St. Louis, MO.
“We’re not sure why this reversal occurs, but understanding it may be very important for clinical trials of drugs to treat or prevent Alzheimer’s,” she says, explaining that:
“Changes in the levels of these biomarkers likely will be among the criteria we use to assess the success or failure of Alzheimer’s drugs, so we need to know how these biomarkers normally behave in the absence of treatment.”
She and her colleagues report their findings in the journal Science Translational Medicine.
Studying families with gene mutations that predispose them to Alzheimer’s disease offers unique and powerful ways to research biomarker changes during the period before symptoms emerge.
For their study, Prof. Fagan and colleagues studied data from people taking part in a multinational research project led by Washington University, called the Dominantly Inherited Alzheimer’s Network (DIAN).
All the participants belong to families carrying genetic mutations that cause rare inherited forms of Alzheimer’s. Affected members can develop symptoms of mental decline as early as their 30s.
Tests on spinal fluid to look for biomarkers are among the variety of exams that participants undergo as members of the DIAN study.
For this latest study, the researchers were interested in three biomarkers in particular: two structural proteins called tau and p-tau, and a neuronal calcium sensor called VILIP-1.
Levels of all three biomarkers go up when brain cells are injured and are linked to mental decline. Previous studies have suggested they are released by dying cells and washed into the spinal fluid.
The team examined results of spinal fluid tests carried out at regular intervals in 26 DIAN participants. All of the participants carried a mutation known to cause a genetic, or “autosomal-dominant” form of Alzheimer’s.
There was no surprise when the researchers found the biomarker levels went up over time in participants who did not yet show signs of dementia.
But they were very surprised when they found in most of those who had started developing signs of dementia, the biomarker levels went down over time. The drop was small, but nonetheless consistent and statistically significant, they noted.
Prof. Fagan says they found this to be “very interesting, particularly given that previous studies have shown that other indicators of Alzheimer’s disease, such as brain shrinkage, continue after the onset of dementia.”
She suggests perhaps the levels peak before dementia sets in because there is an intense stage of cell death in the preclinical phase, and this eases off as symptoms emerge.
Another equally plausible reason could be because of the reduction in the number of brain cells that are left, she adds.
The researchers acknowledge this is only a small study with a few participants, and they are now enrolling new participants in the DIAN study, as well as continuing to follow those in the current study.
Prof. Fagan says they need to collect more data on more participants over a longer period of time to firm up these preliminary conclusions.
They also want to find out if the biomarker levels show a similar pattern in people who do not have the genetic form of Alzheimer’s and who are typically diagnosed much later in life.
Funds from several sources helped finance the study, including the National Institutes of Health (NIH), the National Institute on Aging, the Dominantly Inherited Alzheimer’s Network, and the DIAN Pharma Consortium.
But Medical News Today recently learned of a new study that found the Alzheimer’s death toll is higher than reported, and suggested the disease belongs in the CDC’s top three list of killers. The researchers blamed incorrect identification of the disease as the reason for its lower position in the list.