Researchers at John Hopkins University School of Medicine report they can predict when people will develop cognitive impairment associated with Alzheimer’s disease years before the first symptoms appear.
They say they can do that by measuring levels of certain proteins in cerebrospinal fluid (CSF).
These biomarkers could help guide the earlier use of potential drug treatments to prevent or halt the progression of Alzheimer’s while people are still cognitively normal, the researchers speculate.
Medications designed to stop the brain damage related to Alzheimer’s have failed in clinical trials, possibly because they are given to patients who already have symptoms and too much damage to overcome, according to the researchers.
“When we see patients with high blood pressure and high cholesterol, we don’t say we will wait to treat you until you get congestive heart failure. Early treatments keep heart disease patients from getting worse, and it’s possible the same may be true for those with pre-symptomatic Alzheimer’s,” said Marilyn Albert, Ph.D., a professor of neurology and primary investigator of the study.
“But it has been hard to see Alzheimer’s disease coming, even though we believe it begins developing in the brain a decade or more before the onset of symptoms.”
For the new study, the Hopkins research team used CSF collected between 1995 and 2005 for the Biomarkers for Older Controls at Risk for Dementia (BIOCARD) project from 265 middle-aged healthy volunteers. About 75 percent of the group had a close family member with Alzheimer’s disease, a factor putting them at higher than normal risk of developing the disorder, the researchers reported.
During the 10 years, and again in 2009, researchers gave the participants a battery of neuropsychological tests and a physical exam.
They found that particular baseline ratios of two proteins — phosphorylated tau and beta amyloid found in CSF — were a harbinger of mild cognitive impairment, often a precursor to Alzheimer’s, more than five years before symptoms appeared.
The researchers also found that the rate of change over time in the ratio was also predictive. The more tau and the less beta amyloid found in the spinal fluid, the more likely that symptoms would develop, according to the study. And, according to Albert, the more rapidly the ratio of tau to beta amyloid goes up, the more likely that symptoms will develop.
Researchers have known that these proteins were in the spinal fluid of patients with advanced disease. “But we wondered if we could measure something in the cerebral spinal fluid when people are cognitively normal to give us some idea of when they will develop difficulty,” Albert said. “The answer is yes.”
Alzheimer’s disease disrupts critical metabolic processes that keep neurons healthy. These disruptions cause neurons to stop working, lose connections with other nerve cells, and finally die.
The brains of people with Alzheimer’s have an abundance of two abnormal structures — amyloid plaques and “tangles” made of tau, the researchers explain.
The plaques are sticky accumulations of beta-amyloid that build up outside of the neurons, while the tangles form inside the neurons. When there are too many tangles inside the cells, the cells start to die. In a normal brain, tau helps the skeleton of the nerve cell maintain itself. When too many phosphate groups attach themselves to tau, too much of the protein develops and tangles form.
According to Albert, researchers believe that the relative amount of beta-amyloid in the spinal fluid decreases as Alzheimer’s progresses because it is getting trapped in the plaques and, therefore, isn’t entering the fluid.
Though the BIOCARD study has been going on for nearly two decades, this is some of the first predictive data to come out of it, according to Albert. She said that’s due to the length of time it takes for even high-risk middle-aged people to progress to dementia.
Only 53 of the original patients have progressed to mild cognitive impairment or dementia, giving a sample size just large enough to draw some preliminary conclusions, she said. These first symptoms include memory disruptions, such as repeating oneself, forgetting appointments and forgetting what others have said.
Albert cautions that the biomarker ratio is not accurate enough at this point to precisely predict whether a particular individual is progressing to dementia. Further analysis of information about those in the study group is needed over time, she noted.
However, if the findings prove valid, they could guide the use of early treatments with drugs that become available, she said. The findings also may be used to help test new drugs by seeing if they alter the rate at which the proteins change over time, she concluded.
The study was published in journal Neurology.
Source: Johns Hopkins Medicine