A University of Pittsburgh (Pitt) School of Medicine-led team has identified neuroinflammation as the key driver of the spread of pathologically misfolded proteins in the brain, and a cause of cognitive impairment in patients with Alzheimer’s disease. Using positron emission tomography imaging, the researchers have, for the first time, shown in living patients that neuroinflammation—activation of the brain’s resident microglial immune cells—is not merely a consequence of disease progression but, rather, it is a key upstream mechanism that is a requisite for disease development.

The study findings suggest that targeting neuroinflammation might be beneficial for people with early-stage Alzheimer’s disease and that the approach might help to reverse or at least slow down the accumulation of pathologic tau protein in the brain and stave off dementia. “Our research suggests that combination therapy aimed to reduce amyloid plaque formation and limit neuroinflammation might be more effective than addressing each pathology individually,” said Tharick Pascoal, MD, PhD, assistant professor of psychiatry and neurology at Pitt.

Assistant professor of psychiatry and neurology, University of Pittsburgh School of Medicine.[Tharick Pascoal]
Pascoal, and Pedro Rosa-Neto, MD, PhD, of McGill University, are senior and co-corresponding authors of the international team’s published paper in Nature Medicine, which is titled, “Microglial activation and tau propagate jointly across Braak stages.” The authors include researchers from McGill University; University of Gothenburg, Sweden; University of Antwerp, Belgium; University of Toronto, Canada; Imperial College London, U.K.; Sahlgrenska University Hospital, Mölndal, Sweden; and Cornell University.


Alzheimer’s disease is characterized by the accumulation of amyloid plaques—protein aggregates lodged between nerve cells of the brain—and clumps of disordered protein fibers, called tau tangles, forming inside the nerve cells. Although studies in cultured cells and animal models have generated ample evidence that microglial activation drives the spread of tau fibers in Alzheimer’s disease, this process has never been proven in humans. “Compelling experimental evidence suggests that microglial activation is involved in the spread of tau tangles over the neocortex in Alzheimer’s disease …” the authors wrote. “Rather than merely being an inflammatory epiphenomenon, recent studies in animal models suggested that microglial activation drives tau pathology. These animal studies suggested microglial activation as a key player in the progression of tau pathology in the living human brain leading to dementia.”

And while postmortem studies have suggested that the accumulation of tau tangles in AD follows a stereotypical pattern known as Braak stages, no previous study has tested whether microglial activation plays a role in the stereotyped spread of tau in Braak stages in patients with AD, the researchers pointed out.

To determine the mechanism by which disordered tangles of tau protein fibers and amyloid plaques spread across the brain and lead to dementia, the investigators used positron emission tomography (PET) brain imaging to assess microglial activation, amyloid-beta, and tau pathologies, in 130 individuals across the aging and AD clinical spectrum. “In this study, using a PET agent selective for microglial activation, applying recent advances in brain molecular network analysis, using a large cohort of genetically screened individuals to optimize the signal of microglia activation imaging and a tau imaging agent capable of capturing early and late Braak stages, we studied the association between microglial activation and tau propagation.”

Both younger and elderly people have lower degree of neuroinflammation (red) than patients with Alzheimer’s disease. [Adapted from Pascoal et al., Nature Medicine]
The researchers found that neuroinflammation was more prevalent in older people and that it was even more pronounced in patients with mild cognitive impairments and those with Alzheimer’s disease-associated dementia. Bioinformatics analysis confirmed that tau propagation depended on microglial activation—it is a key element that links the effects of amyloid plaque aggregation to tau spread and, ultimately, cognitive impairment and dementia.


“… our results suggest a close link between microglial activation, AD hallmark biomarkers and dementia symptoms, supporting that microglial activation may be a key element associated with AD progression with the potential to be incorporated in the biological definitions of the disease,” the team concluded. “Our findings also support that Aβ potentiates the effects of microglial activation on tau spreading … we found evidence suggesting that when these three pathologies are present in the human brain concomitantly, they synergistically interact with each other to determine dementia.”

“Many elderly people have amyloid plaques in their brains but never progress to developing Alzheimer’s disease,” said Pascoal. “We know that amyloid accumulation on its own is not enough to cause dementia—our results suggest that it is the interaction between neuroinflammation and amyloid pathology that unleashes tau propagation and eventually leads to widespread brain damage and cognitive impairment.”

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