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With June being Alzheimer’s and Brain Awareness Month, a new international study has revealed a key biological tipping point in Alzheimer’s disease
This tipping point may help to explain why some people develop dementia while others remain mentally sharp despite having the same disease-related brain changes.
Researchers from VIB, KU Leuven, the UK Dementia Research Institute, and Muna Therapeutics analysed brain tissue from older adults with and without cognitive decline, as well as from cognitively healthy older adults.
The research showed important differences in how the brain’s immune cells respond to Alzheimer’s pathology.
Alzheimer’s disease affects more than 55 million people worldwide and is typically characterised by the buildup of amyloid-beta plaques and tau tangles in the brain.
But researchers have long wondered why some individuals remain cognitively healthy even when the usual signs of the disease are present.
The brain’s immune cells
The study focused on microglia, specialised immune cells that help protect and maintain the brain. Researchers believe that these cells play an important part in determining whether Alzheimer’s disease progresses to dementia.
Using advanced techniques such as spatial transcriptomics and single-cell sequencing, the research team examined brain tissue at an unprecedented level of detail. They identified six distinct stages, or tissue domains, representing different phases of Alzheimer’s disease progression.
The researchers discovered that a biological transition occurs between the early stages, which are dominated by amyloid-beta plaques, and the later stages, marked by tau pathology and neurodegeneration.
During the early phase of the disease, microglia entered an inflammatory state associated with amyloid plaques. As the disease advanced, these cells underwent a dramatic transformation, switching to an antigen-presenting state associated with the emergence of tau pathology.
Researchers believe this shift may represent a crucial turning point that determines whether Alzheimer’s pathology progresses toward dementia.
The findings suggest that it is not simply the presence of plaques and tangles that drives cognitive decline, but also how the brain’s immune system responds to these changes.
Two paths to resilience
The research also showed that resilience to Alzheimer’s disease can arise from two distinct biological mechanisms.
Among cognitively healthy individuals in their eighties who had accumulated amyloid plaques, researchers observed the early microglial response but found little evidence of the later immune transition associated with disease progression. This suggests that preventing the shift in microglial behaviour may help protect against dementia.
However, centenarians showed a different pattern. While they are activated, the later microglial program, this response appeared largely independent of tau accumulation.
In these individuals, a cellular state typically associated with neurodegeneration appeared to occur without triggering cognitive effects. This suggests that resilience is not just due to the absence of disease-related changes in the brain, but may instead depend on the brain’s ability to adapt to those changes.
Opportunities for treatment
This research could help develop more targeted Alzheimer’s therapies. Instead of focusing on removing amyloid plaques, future treatments can now look to preserve beneficial microglial responses or influence the transition between different microglial states.
Researchers also highlighted pathways such as TREM2 as promising therapeutic targets. Interventions aimed at maintaining protective immune responses may be most effective before later stages of disease become established.
During Alzheimer’s and Brain Awareness Month, this study could help develop new pathways for treatments that delay or even prevent the onset of dementia.