Researchers from the VIB-KU Leuven Center for Neuroscience, the UK Dementia Research Institute, and Muna Therapeutics have discovered a biological transition that occurs in Alzheimer’s disease (AD) that may influence whether the accumulation of amyloid-β plaques and tau pathology progresses to dementia. Using human brain tissue from octogenarians with and without dementia as well as cognitively healthy centenarians, the team found that a shift in the behavior of microglia occurs at a critical point between amyloid-driven inflammation and tau-associated neurodegeneration. The research, published in Nature Medicine, point to these microglial transitions as a potential new target for treating the disease.
“This has been an exciting journey with many partners,” said co-senior author Bart De Strooper, MD, PhD, a professor at VIB-KU Leuven Center for Neuroscience, Belgium. “The study, entirely based on human donor material, provides insight into one type of resilience mechanism in the progression of AD to dementia.”
Alzheimer’s disease affects more than 55 million people worldwide, but prior research has not been able to fully explain why some people with AD remain cognitively healthy despite having significant amounts of amyloid plaques and tau tangles in their brains. Current models of AD progression have assumed a linear path from amyloid accumulation to tau pathology, neurodegeneration, and cognitive decline. However, observations of cognitively intact older adults with substantial pathology have indicated there may be other biological factors that influence dementia development.
“AD is not an inevitable outcome of pathology but a dynamic process shaped by how brain cells respond to amyloid-β (Aβ) and tau,” the researchers wrote, adding that “Clinical symptoms may thus arise only when these compensatory mechanisms fail, crossing inflection points that shift the brain from adaptation to degeneration.”
Previous studies using single-cell and spatial transcriptomics had shown that microglia, astrocytes, oligodendrocytes, and neurons undergo stage-specific changes in response to amyloid accumulation. Those findings, combined with observations that some centenarians maintain cognition despite extensive pathology, suggested that immune-cell responses might influence disease outcomes and were the underpinnings of the current research.
To further understand these mechanisms, the investigators examined 24 well-characterized octogenarian brains and 20 brains from cognitively intact centenarians enrolled in the Dutch 100-plus Study. Using spatial transcriptomics, single-nucleus RNA sequencing, and in situ hybridization to tissue from the superior frontal gyrus, the team was able to analyze gene activity at single-cell resolution while preserving the spatial relationships between cells and pathological features in the brain.
Their analysis identified six distinct tissue domains representing a continuum of Alzheimer’s disease progression. Within this “spatial pathological” continuum of AD the researchers found a “key inflection point marked by a shift from Aβ-associated inflammatory changes to tau-associated cellular programs.”
This transition coincided with a significant change in microglial behavior. Early in the disease process, microglia adopted inflammatory states associated with amyloid plaques. Later, they shifted into antigen-presenting states linked to emerging tau pathology. The researchers described these as early and late plaque-induced gene, or PIG, programs.
Data from the study indicated that resilience to disease progression involved different microglial responses in the different groups studied. Octogenarians who accumulated amyloid plaques but remained free of dementia mounted the early inflammatory microglial response but did not progress to the later antigen-presenting state. This compared with cognitively intact centenarians in which the later microglial program was activated, but this activation occurred without the corresponding buildup of tau pathology typically associated with neurodegeneration.
“Resilient individuals showed distinct pathological patterns: octogenarians without dementia lacked late PIGs, whereas centenarians showed late PIG activation that was uncoupled from tau accumulation,” the researchers wrote.
According to the investigators, these findings indicate that resilience to development of dementia in AD is not simply a matter of avoiding pathology, but may depend on how the brain regulates the cellular consequences of AD pathology.
The research also revealed clues about how microglia might be targeted therapeutically. The researchers suggest that preserving beneficial early microglial functions involved in amyloid clearance and synaptic maintenance while preventing chronic antigen-presenting activation associated with tau pathology could help slow disease progression. Potential targets include pathways involving TREM2, CSF1R, and molecules associated with microglial state transitions.
“These findings open new opportunities to target microglial states—especially pathways such as TREM2—and extend resilience rather than simply focusing on plaque removal,” said co-senior author Niels Plath, PhD, chief scientific officer of Muna Therapeutics. “We are excited to continue this journey and understand the causal role of microglial transitions leading to the identification of novel therapeutic approaches to delay or prevent disease progression.”
Continued research will look to determine the causal mechanisms that drive these microglial state transitions and identifying the genetic, immune, or aging-related factors that allow some individuals to remain resilient despite significant Alzheimer’s pathology.
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