How the APOE4 Alzheimer's gene affects your brain function as you get older

Scientists have already identified a gene which increases the risk of developing Alzheimer's disease. Now, they have shown how the brain activity of people who carry this specific APOE4 gene is affected as they get older.

What causes Alzheimer's disease is still not completely understood, although scientists know that a mix of genetic, environmental and lifestyle factors are involved.

Years of scientific research have failed to identify a specific gene which directly causes the disease, but scientists have identified APOE4 - a form of the apolipoprotein E (APOE) gene - as an important genetic risk factor. This means that having this form of the gene increases the probability of being diagnosed with the disease - but it does not mean people will definitely develop it.

In recent years, there has been renewed efforts to understand how this genetic risk factor affects brain function and cognitive skills in healthy adults. Scientists hope this can help improve the detection of people in the preclinical phase of the disease, before symptoms arise. So far, it is not entirely clear how having one or two copies of APOE4 affects brain function but researchers know it's crucial to learn more about this.

"The APOE 4 genetic variant is associated with 10 – 12 fold increase in the risk for Alzheimer's disease and this gene has an effect on brain function long before any cognitive decline is detectable. Importantly, this is not a genetic mutation, but a natural genetic variation in the population. Therefore, this is further evidence that individuals with this genetic make-up should be carefully and closely followed for early symptomatology of Dementia," Dr. Chris Foster, postdoctoral scientist at the University of Texas at Dallas Center for Vital Longevity, told IBTimes UK.

Distance judgement task

Foster is the first author of a study now published in The Journal of Neuroscience, which looks at healthy adults with APOE4 to see how they performed on a series of cognitive tasks and how this may help identify those most at risk of developing Alzheimer's Disease as they age.

A total of 31 adults who had either one or two copies of the APOE4 genes were included in this study, along with 31 controls who did not carry the APOE4 gene.

The participants went through a series of neuropsychological assessments, which included different memory tests. They then had to perform a task known as a 'distance judgement task' while their brain activity was measured using fMRI scans.

In the task, the participants were presented with a vertical reference line and with a horizontal bar. They were instructed to press a button to indicated whether a dot was "Nearer" to or "Farther" away from the horizontal bar than the length of the vertical reference line. This type of exercise tests spatial awareness and how people interpret information - two skills that are affected in Alzheimer's disease.

The task was repeated a number of times, with the difficulty increasing progressively. The researchers found that participants with the APOE4 gene seemed able to adjust their brain activity to the difficulty of the task just like non-APOE4 carrying adults of the same age, sex, and education level. However, this ability declined with age in the individuals with APOE4, but not in the controls. This resulted in them performing worse in the task.

The scientists say that these findings may help to inform the identification of individuals at increased risk of developing the disease by looking at their brain activity.

"The current findings suggest that changes in the ability of the brain to dynamically modulate in response to cognitive challenge may serve as an additional risk for future age-related cognitive decline. The clinical implication is that these functional brain differences may be an early sign of individuals who may go on to develop Alzheimer's disease," senior author Dr. Karen Rodrigue, an assistant professor of behavioural and brain Sciences at the University of Texas at Dallas Center for Vital Longevity added.

"While it would not be practical to use this experimental task for diagnostic purposes, it does provide new information about the types of brain changes associated with a genetic risk factor for AD. Therefore, this is further evidence that individuals with this genetic make-up should be carefully and closely followed for early symptomatology of Dementia".

The earliest possible detection of people who will go on to develop the disease is a major research priority. Many drugs have failed in clinical trials and it is thought that one reason for this is that they were given too late. If treatments were given earlier, before people start reporting the symptoms, these drugs might be more beneficial.

A blood test can identify which APOE alleles a person has, but cannot predict if he or she will develop Alzheimer's disease.