Distinct Microglia States Associated with Alzheimer's Disease
Microglia are innate immune cells resident in the brain, responsible for defense against pathogens, destruction of senescent and potentially cancerous cells, and assistance with regeneration and tissue maintenance. In recent years, increasing attention has been given to changes in the behavior of microglia, particularly increased inflammatory signaling, as a contributing cause of age-related neurodegenerative conditions. Here, researchers make use of modern omics technologies to assess distinct states in subpopulations of microglia that associate with the presence or absence of Alzheimer's disease in older individuals. This sort of research sets the stage for later efforts to alter the behavior of microglia in order to improve brain function, such as via clearance of damaged or inflammatory microglia, or forcing overly inflammatory microglia into a more regenerative pattern of behaviors.
Alzheimer's disease (AD) is not an inevitable outcome of pathology but a dynamic process shaped by how brain cells respond to amyloid-β (Aβ) and tau. To disentangle these responses, we combined spatial transcriptomics and single-nucleus RNA sequencing of the superior frontal cortex from octogenarians living with or without dementia and from cognitively intact centenarians with comparable Aβ accumulation. We identified six distinct tissue domains representing a spatial pathological continuum of AD, with a key inflection point marked by a shift from Aβ-associated inflammatory changes to tau-associated cellular programs.
This transition was accompanied by a change in microglial states, from early inflammatory to late antigen-presenting phenotypes, termed early and late plaque-induced gene (PIG) programs. Resilient individuals showed distinct pathological patterns: octogenarians without dementia lacked late PIGs, whereas centenarians showed late PIG activation that was uncoupled from tau accumulation. Together, these findings highlight divergent resilience-associated mechanisms in human aging and position microglial state transitions at the Aβ-tau interface as candidate points of resilience with potential therapeutic relevance.