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Center for Cognitive Health

Understanding Why Tangles Spread in Alzheimer’s Disease: Part I

             As discussed in our previous blogs, the study of Alzheimer’s disease (AD) concentrates on its two primary biomarkers: phosphorylated Tau protein (p-tau), that reflects neurofibrillary tangles (NFTs), and amyloid beta (Aβ), that forms amyloid plaques. The give and take between plaques and NFTs complicate the understanding of how AD develops and spreads, as it is hypothesized that Aβ accumulation activates the phosphorylation of tau (i.e., p-tau) therefore instigating NFT formation. Clinically, as NFTs proliferate through the brain, a person’s cognition declines in correspondence with the rate and location where NFTs are spreading. However, it is unclear how this process is controlled and how plaques stimulate it, causing difficulty in finding a successful therapy, or cure, for AD.

             A rise in phosphorylated tau is indicative of plaque formation; p-tau181, p-tau217, and p-tau231 are the most telling isoforms. Research has found that p-tau217 mediates the interplay between plaques and tangles. One study compared regional plaque accumulation and p-tau217 thresholds to understand which has a stronger influence on the spread of tangles. Findings show that p-tau217 was the main predictor for the spread of NFTs. However, the association between p-tau217 and NFTs decreased as the disease progressed. Plaque load and p-tau tend to plateau in those with AD, but tangles continue to spread. With these findings, perhaps p-tau217 is the initial spark that induces tangles, but once the NFTs have made a prominent presence, tangles themselves take over the continuity of spreading. This indicates that p-tau217 could be a therapeutic target for AD, but only in the early stages.

             Taking the focus of AD pathology a step earlier in the process, another study sought out how plaques give rise to p-tau to begin with. Research has labeled sTREM2, a microglial activation marker, as a connection to rising p-tau. Microglia are the immune scavenger cells in the brain. This study compared three groups of people: amyloid-negative controls, early amyloid accumulators, and late amyloid accumulators to dissect the association of plaques and p-tau. Results found that plaques and increased sTREM2 and p-tau181 correlated, but differed between the stages of AD. In early accumulators, plaques were found to instigate microglia in a way to activate the phosphorylation of p-tau181, allowing it to increase. However, in late accumulators, sTREM2 appeared to weaken p-tau181’s effect. Nonetheless, these results have been found reversed in other research, making it difficult to understand the connection of microglia’s role in brain atrophy.

             Phosphorylated tau may have a role in the progression of NFTs as described above, but how can these higher concentrations of p-tau, and its eventual plateau, explain the patterns that tangles spread throughout the brain? Stay tuned for Part II of this blog, where we discuss how location and higher neuronal firing in areas could propagate the spread of NFTs and how this associates with the occurrence and rate of cognitive decline.



Alzforum. (2022, September 08). What drives tangles to spread? answers start rolling in. Alzforum: Networking for a cure. https://www.alzforum.org/news/conference-coverage/what-drives-tangles-spread-answers-start-rolling