A thickening cortex preceded known markers of Alzheimer’s disease by up to seven years

Brain imaging could reveal early changes linked to Alzheimer’s disease.

MRI scans show that the thickness of the outermost layer of the brain changes before the onset of the disease, detectable up to seven years prior, researchers reported August 19 in Nature Neuroscience. Though the differences are too subtle to use as a diagnostic tool, they could help researchers understand the early stages of Alzheimer’s.

Alzheimer’s disease is the most common form of dementia and can cause memory loss, disorientation and behavior shifts. But changes in the brain can occur long before these cognitive symptoms appear. Sticky protein fragments called amyloid-beta build up in the brains of people who go on to develop Alzheimer’s. These bundles, along with tangles of another protein called tau, slowly kill off brain cells and shrink the brain.

Under the current criteria, spotting A-beta buildups via positron emission tomography scans, or PET scans, is enough for an Alzheimer’s diagnosis even in the absence of cognitive symptoms. But most people do not receive PET scans without symptoms, so they won’t get diagnosed until later.

To better understand how the disease takes shape, Alzheimer’s researcher Yunpeng Wang and colleagues wanted to test whether they could spot brain changes before patients developed A-beta buildups.

The team examined MRI scans from over a thousand participants in long-term studies that track brain changes with aging. Wang and colleagues compared changes in the thickness of the cortex — the outermost layer of the brain, which averages around 2.5 millimeters thick — between people who later showed high A-beta levels and people who did not.

People who went on to develop high A-beta levels had thicker cortices than people who did not. Differences in thickness of a few hundredths of a millimeter were visible up to seven years before the participants were deemed to have high A-beta levels based on their PET scans. The cortices of people in both groups thinned naturally with age, but those of people who later developed high A-beta thinned less overall. The researchers didn’t observe any link between the thickness of the cortex and memory problems at this early stage of the disease.

The findings imply that “the trajectory of cortical changes is not [as] simplistic as we used to think,” says Victor Montal, a degenerative diseases researcher at the Barcelona Supercomputing Center who was not involved in the work. Rather than assuming the cortex thins consistently due to atrophy as the disease progresses, researchers will need to account for slower thinning in the early stages when studying Alzheimer’s, he says.

The relative thickening of the cortex might come from inflammation that occurs as A-beta first starts to accumulate, says Wang, of the University of Oslo. But MRIs can’t determine the cause of the thickening directly.

“I don’t think that this cortical thickness is something you’re going to use clinically,” says Frederik Barkhof, a neuroradiologist at University College London who was not involved in the study. The changes in cortex thickness are too subtle to use as individual diagnostic tools, he says, but they could help researchers understand the mechanisms behind Alzheimer’s disease and emerging treatments.

For example, some existing Alzheimer’s treatments remove A-beta but don’t stop the volume loss in the brain. The new findings could indicate that the current treatments reduce inflammation and not that a patient is losing excess brain tissue despite treatment, he says.