Findings suggest a potential "early warning" detection system for Alzheimer's disease

The findings suggest a potential "early warning" detection system for Alzheimer's disease, even in young and asymptomatic individuals.

Some of the most interesting - and useful - breakthroughs in science emerge from a combination of findings and techniques from different fields. That's certainly the case with a new paper in the journal Science, in which researchers used knowledge of genetic risk factors, neurocognitive testing, functional neuroanatomy and medical imaging to propose a new paradigm for early detection of Alzheimer's disease (AD).

Alzheimer's is a debilitating neurological disease with no current cure and few options for managing late-stage disease. Approximately half a million new cases are diagnosed each year, with a life expectancy post-diagnosis of about six years. Current treatments for AD are often ineffective, possibly because by the time patients become symptomatic, the disease has progressed too far to be reversed.

To explore potential new avenues for early diagnosis of AD, researchers from the German Center for Neurodegenerative Diseases (DZNE) and elsewhere performed a study comparing a "high-risk" AD group with a control group of volunteers. Both groups were comprised of young adults with no AD symptoms, but the high-risk cohort all carried an allele of the APOE gene that is known to confer at least a three-fold increased risk of developing the disease. The researchers asked whether they could detect any AD-relevant difference between the groups, even in the absence of any overt disease symptoms.

To do so, they leveraged previous AD research showing that early physical evidence of disease in AD sufferers is found in a region of the brain called the entorhinal cortex (EC). This is true even in young adults, and particularly in individuals carrying the APOE "AD risk" allele. In 2005, the EC region was discovered to contain cells known as "grid cells", a type of neuron (found in many species, including humans) responsible for maintaining spatial orientation and self-positioning.

Pulling these pieces together, the researchers used a virtual-environment object-location memory task to test the subjects' capacity to recall the position of an object and place it again appropriately. During these tests, the subjects were recorded using functional MRI (fMRI), to measure the associated signals and activity in their brains' EC regions. The researchers translated these signals into "grid-cell-like representations", patterns of activity that indicated the subjects were actively navigating using grid cell neurons.

Based on the fMRI data, there were clear differences between the two groups. The high-risk group was found to have significantly fewer grid-cell-like representations during the tests. This was true, even though no structural differences in the EC regions of the subjects' brains could be detected. High-risk subjects also showed measurable differences in "navigational preference"; in other words, the strategy employed during spatial orientation. The high-risk group showed a reduced preference for navigating in the center of the virtual environment, compared to the control group - possibly a compensation for reduced grid-cell function in these individuals.

In fact, even stronger evidence for such compensation emerged from a seemingly odd finding - despite the reduction in grid-cell-like representations among high-risk subjects, their performance in the object-location memory tests was comparable to the control group. Somehow, they were orienting as well, but apparently without the full use of their EC regions. Following up, the researchers found that the high-risk subjects showed increased activity during the tests in the hippocampus region of the brain, while the control subjects did not. While the hippocampus is known to be important for spatial memory, its recruitment to "assist" with impaired EC region navigation had not been seen before.

Together, the findings suggest a potential "early warning" detection system for Alzheimer's disease, even in young and asymptomatic individuals. The results also hint at a possible new target - grid-cell and EC region function - for AD therapy. Finally, this study provides intriguing data on adaptability in the brain, and the interplay between the EC region and the hippocampus in maintaining spatial orientation.