A major study led by researchers at the University of Oslo has shown that changes in the brain’s cortical thickness can be detected years before amyloid-beta plaques reach detectable levels on scans, challenging the long-held view that amyloid buildup is the first event in Alzheimer’s disease. The research, published in Nature Neuroscience, was guided by James M. Roe and Yunpeng Wang and draws on data from three large longitudinal studies of cognitive ageing.
Alzheimer’s disease is characterised by amyloid-beta plaques, and the traditional model holds that plaque accumulation comes first and drives subsequent brain shrinkage. A 2010 study framed this timeline, and later work has shown that high amyloid levels accelerate brain volume loss even before symptoms appear. Earlier reviews noted that the brain’s outer cortex can temporarily thicken in the earliest genetic forms of the disease.
In the Oslo-led study, researchers used MRI to track cortical thickness over time and PET scans to measure amyloid-beta. The final sample included 4,570 MRI scans from 1,051 people, of whom 691 also had amyloid PET data available.
They looked back from each participant’s first positive amyloid scan, focusing on scans taken between one and ten years before this threshold. By excluding scans near the moment of positivity, the team aimed to reveal the brain’s baseline trajectory prior to amyloid detection.
The analysis showed that those who would later develop high amyloid levels possessed a thicker cerebral cortex in advance of positivity, and they also exhibited a slower rate of age-related cortical thinning.
The thickening was most evident in the frontal regions of the brain. When the researchers accounted for the precise continuous amyloid levels measured in early scans, many of the thickness differences remained, suggesting the cortical changes are at least partly independent of early amyloid accumulation.
Moreover, the spatial pattern of cortical thickening aligned with areas typically prone to amyloid deposition, and the timing mirrored the spread of plaques. Regions that thickened earlier tended to be the ones where amyloid began to accumulate first.
The authors caution that the time markers were tied to when a person first tested positive on PET, not the exact biological moment of positivity, and scans were taken at intervals. They used statistical modelling to predict positivity age, but the results held under these assumptions.
The study involved cognitively healthy older adults and did not measure tau, another protein linked to Alzheimer’s, which the authors say is unlikely to drive the seven-year pre-positivity changes. They call for further research to uncover what causes the early cortical thickening, which could reflect inflammation or glial changes rather than neuronal addition.
Led by Roe and Wang, and published with colleagues including several other researchers, the paper invites a rethink of the early brain changes that precede amyloid positivity by years. The findings suggest that structural alterations in the cortex may emerge long before amyloid detection, offering new avenues for understanding the disease’s timeline.
