Tau replication in local brain regions, not spread between regions, drives Alzheimer’s pathology

Reuters Health - 03/11/2021 - Using mathematical modeling, researchers found that tau accumulation in local brain regions, rather than spread between regions, drives pathology in Alzheimer's disease, and that the amount of tau "seeds" replicated in the brain doubles about every five years.

"The model suggests that replication and spreading are two distinct features of the propagation process, and that local replication is the main process controlling the overall rate of accumulation of tau in neocortical regions," Dr. Bradley Hyman of Massachusetts General Hospital in Boston told Reuters Health by email.

"The number of tau seeds doubles about every five years, consistent with the time course of the disease in most patients of a decade or longer," he said. "The model suggests that even modest therapeutic interventions that increase the doubling time may make a major change in the life course of patients with dementia."

As reported in Science Advances, Dr. Hyman and colleagues used an approach called chemical kinetics to model the tau aggregation and spread processes in the brain, as well as advanced PET scanning and other brain measurement tools.

Notably, to track tau aggregation, they analyzed post-mortem brain samples from Alzheimer's patients, as well as PET scans from living patients with mild cognitive impairment through full-blown disease.

By combining five different datasets and applying them to the same mathematical model, the team determined that the mechanism controlling the rate of Alzheimer's disease progression is the replication of aggregates in individual neocortical brain regions, not the spread of aggregates from one region to another, particularly in later stages of the disease (from Braak stage III onward).

Therefore, the authors conclude, "limiting local replication likely constitutes the most promising strategy to control tau accumulation during AD."

Dr. Rebecca Edelmayer, the US Alzheimer's Association Senior Director of Scientific Engagement, commented on the study in an email to Reuters Health. "Tau isn't the primary cause of Alzheimer's, but it is thought to be the most closely correlated with the cascade of changes associated with the disease, including cognition."

"The authors suggest that tau spreading from cell to cell may not be the prime driver of tau accumulation, but rather through multiple 'seeding' points across the brain, tau builds up over time in various regions," she said. "This research is particularly informative for tau-targeting drug development. For example, a drug that blocks the buildup of tau in multiple regions of the brain may be more effective than a drug trying to prevent the spread of tau from cell-to-cell."

"Because of its contributions to the neurodegenerative process, tau is one of the major areas of focus for therapy development," she noted. "But Alzheimer's is a complicated disease, and we will likely need multiple treatments that target the various aspects of the disease. This includes amyloid, tau, and possibly others."

"The next step for this research is to understand the tau accumulation mechanism in other tau-driven neurodegenerative diseases ('tauopathies')," she added. "The Tau Pipeline Enabling Program (T-PEP; https://bit.ly/3bGimRP), a jointly funded program by the Alzheimer's Association and Rainwater Charitable Foundation, is actively funding research in this area."

SOURCE: https://bit.ly/3wbbg1j Science Advances, online October 29, 2021.

By Marilynn Larkin



Posted on 3 November 20219 November 2021