Regions of the brain where cortical tau is closely associated with the amount of tau in the entorhinal cortex. Image credit: Jenna N Adams (CC BY 4.0)
The changes in the brain that cause Alzheimer's disease begin up to 25 years before the first symptoms appear. During this long incubation period, two proteins accumulate in brain tissue: amyloid-β and tau. Amyloid-β forms clumps known as plaques, while tau forms structures called tangles. But whereas amyloid plaques accumulate evenly throughout the brain, this is not the case for tau. Instead tau accumulates first within a region called the entorhinal cortex, which is important for memory. Findings in animals suggest that tau then spreads out of the entorhinal cortex to other brain regions through neural connections.
The entorhinal cortex itself consists of two subregions, which each accumulate tau at different times. The anterolateral subregion (or alEC for short) develops tau first, followed by the posteromedial subregion (pmEC). These two subregions process different types of memory and so have connections to different areas of the brain. Does tau therefore spread to brain regions connected to the alEC before it spreads to regions connected to the pmEC?
To test this prediction, Adams et al. scanned the brains of healthy young adults to map their brain connectivity patterns. Young adults were chosen because the aging process itself can alter this connectivity. The brains of healthy older adults, aged 60 or more, were then scanned to measure amyloid-β and tau. None of the older adults had cognitive symptoms of Alzheimer's disease. Despite this, many showed deposits of amyloid-β and tau in their brains. As predicted, alEC-connected regions contained more tau than pmEC-connected regions. Indeed, the stronger the connection between a brain region and the alEC, the more tau that region contained.
These relationships occurred in older adults with and without amyloid-β in their brains. However, they were stronger in the individuals with amyloid-β. This adds to evidence suggesting that amyloid-β promotes the spread of tau. Future experiments should measure how tau spreads within an individual's network of connections over time. In the long run, researchers may even find that therapies that stop tau from spreading out of the alEC could help prevent Alzheimer's disease from taking hold.
