Scientists have, for the first time, they say, used human data to quantify the speed of different processes that lead to Alzheimer’s disease (AD). The international research team, headed by scientists at the University of Cambridge, used post-mortem brain samples from AD patients, as well as PET scans from living patients, who ranged from exhibiting mild cognitive impairment, to those with full-blown Alzheimer’s disease, to track the aggregation of tau, one of two key proteins implicated in AD.
Their results indicated that AD develops in a very different way to that previously thought, and rather than starting from a single point in the brain and initiating a chain reaction that leads to the death of brain cells, the disease reaches different regions of the brain early. But how quickly the disease kills cells in these regions, through the production of toxic protein clusters, limits how quickly the disease progresses overall.
The findings open up new ways of understanding the progress of AD and other neurodegenerative diseases, and could have important implications for the development of potential treatments. The researchers say their methodology could be used to help the development of treatments for Alzheimer’s disease, which affects an estimated 44 million people worldwide, by targeting the most important processes that occur when humans develop the disease. In addition, the methodology could be applied to other neurodegenerative diseases, such as Parkinson’s disease.
“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 Georg Meisl, PhD from Cambridge’s Yusuf Hamied Department of Chemistry “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.”
Meisl is first author of the team’s published paper in Science Advances, which is titled, “In vivo rate-determining steps of tau seed accumulation in Alzheimer’s disease.”
Alzheimer’s disease, similarly to other aggregation-associated neurodegenerative diseases, is characterized by a progressive decline in health over the course of years, with symptoms often only becoming apparent years after the onset of pathological changes, the authors explained. In AD, tau and another protein, called amyloid-beta (Aß) accumulate into neurofibrillary tangles (NFTs) and plaques—known collectively as aggregates—causing brain cells to die and the brain to shrink. This results in memory loss, personality changes and difficulty carrying out daily functions. “However, the rates of these processes are unknown and the identity of the rate-determining process in humans has therefore remained elusive,” the team wrote.
For many years, these processes within the brain that result in Alzheimer’s disease have been described using terms like ‘cascade’ and ‘chain reaction’. “It is believed that the patterns of location and abundance of tau NFTs observed in postmortem AD brains, which form the basis for the classification of AD into Braak stages, arise from the spread of tau seeds along well-established connections through the brain,” the team explained. “If the rate of this spread is slow enough, and assuming that aggregation begins in a single location, it has been proposed that spreading from one brain region to the next could be a key limiting factor in disease progression.”
However, AD is a difficult disease to study, since it develops over decades, and a definitive diagnosis can only be given after examining samples of brain tissue after death. So, for years, researchers have relied largely on animal models to study AD. Results from mice suggested that Alzheimer’s disease spreads quickly, as the toxic protein clusters colonize different parts of the brain.
By combining five different datasets and applying them to the same mathematical model, the researchers have now observed that the mechanism controlling the rate of progression in Alzheimer’s disease is the replication of aggregates in individual regions of the brain, and not the spread of aggregates from one region to another. “We develop a general model by considering the different fundamental classes of processes and grouping together similar phenomena into one effective term,” they wrote. “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.”
The researchers say the study is the first to use human data to track which processes control the development of Alzheimer’s disease over time. It was made possible in part by the chemical kinetics approach developed at Cambridge over the last decade, which allows the processes of aggregation and spread in the brain to be modeled, as well as advances in PET scanning and improvements in the sensitivity of other brain measurements.
“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 co-senior author Tuomas Knowles, PhD, also from the Department of Chemistry. “This research shows the value of working with human data instead of imperfect animal models. 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 found that the replication of tau aggregates is surprisingly slow – taking up to five years. “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,” the authors noted. “Thus, limiting local replication likely constitutes the most promising strategy to control tau accumulation during AD”
“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, FRS FMedSc, 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 are now planning to look at the earlier processes in the development of the disease, and extend the studies to other diseases such as Frontal temporal dementia, traumatic brain injury and progressive supranuclear palsy where tau aggregates are also formed during disease. “We envisage that the models developed here will form the basis for determining the rate-limiting processes and quantifying their rates for a wide range of other tauopathies and aggregation-related neurodegenerative diseases in general,” they concluded.