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University of Cambridge researchers find Alzheimer’s disease progresses much differently than previously thought

According to the new study, the replication of aggregates in distinct areas of the brain, rather than the dissemination of aggregates, is the mechanism that controls the rate of advancement in Alzheimer’s disease. This is the first study to use human data to figure out which pathways affect Alzheimer’s disease development over time. (Image: GerryShaw/Wikimedia Commons)

Researchers have utilized human data for the first time to measure the pace of key processes that contribute to Alzheimer’s disease, and they discovered that it develops in a fundamentally different way than previously understood. Their findings might have a big impact on the development of future medications.

Instead of starting from a single place in the brain and triggering a chain reaction that results in the death of brain cells, the multinational research led by the University of Cambridge discovered that Alzheimer’s disease spreads quickly across the brain. The rate at which the illness kills cells in these areas by producing toxic protein clusters is a limiting factor in how rapidly the disease advances overall.

The researchers tracked the aggregation of tau, one of two major proteins linked in Alzheimer’s disease, using post-mortem brain tissues from Alzheimer’s patients as well as PET scans from living individuals ranging from moderate cognitive impairment to full-blown Alzheimer’s disease.

Tau and another protein called amyloid-beta clump together to form tangles and plaques, which cause brain cells to die and the brain to atrophy in Alzheimer’s disease. Memory loss, behavioral changes, and trouble carrying out regular tasks are all symptoms of this condition.

The researchers discovered that the mechanism controlling the rate of progression in Alzheimer’s disease is the replication of aggregates in individual regions of the brain, rather than the spread of aggregates from one region to another, by combining five different datasets and applying them to the same mathematical model.

The findings, published in the journal Science Advances, provide fresh insights into the progression of Alzheimer’s disease and other neurodegenerative disorders, as well as novel avenues for future therapy development.

For many years, phrases like ‘cascade’ and ‘chain reaction’ have been used to describe the mechanisms in the brain that lead to Alzheimer’s disease. It’s a challenging condition to investigate since it takes decades to develop and a clear diagnosis can only be made after reviewing brain tissue samples after death.

For years, scientists have studied the illness mostly using animal models. The harmful protein clusters colonize diverse areas of the brain, suggesting that Alzheimer’s disease spreads swiftly in mice.

“The thinking had been that Alzheimer’s develops in a way that’s similar to many cancers: the aggregates form in one region and then spread through the brain,” said Dr Georg Meisl from Cambridge’s Yusuf Hamied Department of Chemistry, the paper’s first author. “But instead, we found that when Alzheimer’s starts there are already aggregates in multiple regions of the brain, and so trying to stop the spread between regions will do little to slow the disease.”

This is the first time human data has been utilized to determine which pathways influence Alzheimer’s disease progression over time. It was made feasible in part by developments in PET scanning and increases in the sensitivity of other brain measures, as well as the chemical kinetics technique pioneered at Cambridge over the last decade, which allowed the processes of aggregation and dissemination in the brain to be simulated.

“This research shows the value of working with human data instead of imperfect animal models,” said co-senior author Professor Tuomas Knowles, also from the Department of Chemistry. “It’s exciting to see the progress in this field – fifteen years ago, the basic molecular mechanisms were determined for simple systems in a test tube by us and others; but now we’re able to study this process at the molecular level in real patients, which is an important step to one day developing treatments.”

The researchers discovered that tau aggregation replication is unexpectedly sluggish, taking up to five years. “Neurons are surprisingly good at stopping aggregates from forming, but we need to find ways to make them even better if we’re going to develop an effective treatment,” said co-senior author Professor Sir David Klenerman, from the UK Dementia Research Institute at the University of Cambridge. “It’s fascinating how biology has evolved to stop the aggregation of proteins.”

The researchers believe this strategy might aid in the discovery of therapies for Alzheimer’s disease, which affects an estimated 44 million people globally, by focusing on the most crucial processes that occur when people develop the condition. The technology might also be used to study other neurodegenerative disorders, such as Parkinson’s disease.

“The key discovery is that stopping the replication of aggregates rather than their propagation is going to be more effective at the stages of the disease that we studied,” said Knowles.

The study was published in Science Advances, on October 29th, 2021.

Abstract. Both the replication of protein aggregates and their spreading throughout the brain are implicated in the progression of Alzheimer’s disease (AD). However, the rates of these processes are unknown and the identity of the rate-determining process in humans has therefore remained elusive. By bringing together chemical kinetics with measurements of tau seeds and aggregates across brain regions, we can quantify their replication rate in human brains. Notably, we obtain comparable rates in several different datasets, with five different methods of tau quantification, from postmortem seed amplification assays to tau PET studies in living individuals. Our results suggest that from Braak stage III onward, local replication, rather than spreading between brain regions, is the main process controlling the overall rate of accumulation of tau in neocortical regions. The number of seeds doubles only every ∼5 years. Thus, limiting local replication likely constitutes the most promising strategy to control tau accumulation during AD.

Meisl, G., Hidari, E., Allinson, K., Rittman, T., DeVos, S. L., Sanchez, J. S., Xu, C. K., Duff, K. E., Johnson, K. A., Rowe, J. B., Hyman, B. T., Knowles, T., & Klenerman, D. (2021). In vivo rate-determining steps of tau seed accumulation in Alzheimer’s disease. Science advances, 7(44), eabh1448.

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