New research into the genetic underpinnings of Alzheimer's disease offers fresh evidence that the devastating brain disorder may gain a foothold years before dementia sets in, and takes a key step toward earlier detection of the disease.
In a study that scoured the genes of healthy young people for the presence of variants linked to Alzheimer's disease, researchers have found that those who carried many of the telltale gene variations had a smaller hippocampus -- a brain structure that is crucial to memory-formation – than did their peers with few of the genetic variations.
While statistically significant, the association was somewhat weak. But it was clearly detectable in cognitively healthy study participants who were still very young-- between 18 and 36 years old.
When a large population of older study participants without dementia underwent the same broad genetic query, the test was able to distinguish those with poorer memory and cognitive function from those whose mental faculties were still strong.
On average, researchers found that the more Alzheimer's disease genetic variants an older study participant carried, the smaller his hippocampus and the greater was the presence in his brain of beta-amyloid protein –the sticky stuff that forms brain plaques in those with Alzheimer's disease.
The new study was published Wednesday in the journal Neurology.
The genetic test, which queried the genome at several thousand sites that have been linked to Alzheimer's disease, also detected with some accuracy participants who, over a three-year follow-up period, would go on to be diagnosed with Alzheimer's.
The genetic test used in the latest study is unlikely at any point soon to be a useful predictor of who will develop Alzheimer's and who won't, said experts. For now, its principal use may be to identify people who are at unusually high risk of developing symptoms of dementia as they age. Those people might then be enrolled in clinical trials of therapies that could delay or disrupt the onset of Alzheimer's disease's most telling symptom -- progressive loss of memory and cognitive function.
Heredity is believed to play a powerful role in Alzheimer's risk. Certain variations in one gene, called APOE, appear to account for some of Alzheimer's inherited risk – about 6%. Studies that look for common patterns of genetic variation in large populations of people with the same disease—so-called genome-wide association studies – have found many other gene variants linked to Alzheimer's, but no one of those seems very powerful.
The latest study does little to zero in on gene variants that play a clear role in conferring Alzheimer's disease risk. In fact, its findings suggest instead that in determining an individual's risk of developing Alzheimer's disease, the interaction among genes, and between genes and environment, is likely very complex.
When the researchers applied a genetic test that looked for only 18 variants known to be associated with dementia risk, they failed to find patterns that separated people on the basis of cognitive function, or hippocampal volume, or beta-amyloid levels in the brain. Those patterns only emerged when they queried their population's genomes at thousands of sites and assigned each participant a "polygenic risk score" based on his or her results.
"This result suggests that there is still a lot of undetected genetic variation underlying the risk of Alzheimer's disease," said Boston University neurologist Sudra Seshadri, who was not involved with the study. That's consistent with other research, she added, and underscores that developing a truly predictive test of an individual's Alzheimer's disease risk will be a daunting task.
Still, the latest effort at early detection is "an important first attempt," said Johns Hopkins University's Dr. Dimitrios Avramopoulos, who studies genes and mental illness and was not involved in the study. As genome-wide association studies become larger, and researchers' gain confidence in identifying the true risk variants for Alzheimer's Disease, "prediction will improve," Avramopoulos added.
Until such tests are in hand, he said, the new findings support the notion that the processes leading to Alzheimer's disease start early and progress for a long time before symptoms of dementia are clearly evident. That long run-up "underlines the importance of accurate predictions, which can allow early lifestyle modifications or treatments," Avramopoulos said. "Genetic risk scores will certainly have a place in these predictions."
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