Lymphoid-like Suppressive Microglia in Alzheimer’s Disease: A New Neuroimmune Regulatory Axis?

Microglia are central regulators of Alzheimer’s disease pathogenesis, but their roles cannot be reduced to a simple protective-versus-harmful dichotomy. Genetic, single-cell, and spatial studies have shown that Alzheimer ’s-associated microglia occupy diverse disease-linked states shaped by amyloid plaques, tau pathology, lipid stress, complement activation, astrocyte signaling, aging, and immune genetic risk. Among the regulatory nodes controlling these states, SPI1, which encodes the myeloid transcription factor PU.1, has emerged as a key determinant of microglial identity and disease responsiveness. Human genetic studies suggest that reduced SPI1 expression may be protective, whereas experimental data indicate that excessive PU.1 suppression can impair essential microglial functions. This review examines the emerging concept that partial, plaque-associated reduction in PU.1 may enable a distinct lymphoid-like immunoregulatory microglial program marked by CD28 expression. Recent evidence suggests that PU.1-low CD28-positive microglia may restrain neuroinflammation and amyloid pathology, raising the possibility that Alzheimer’s plaques induce not only inflammatory and phagocytic microglial responses, but also endogenous suppressive programs that limit tissue damage. We discuss this proposed PU.1/CD28 regulatory axis in relation to disease-associated microglia, TREM2–APOE signaling, complement-mediated synapse loss, antigen-presentation pathways, plaque-niche biology, and therapeutic microglial reprogramming. We also highlight major unresolved questions, including whether PU.1-low CD28-positive microglia are present and functional in human Alzheimer’s disease, whether they are specific to amyloid-rich niches or extend to tau and mixed pathologies, and how such states could be safely manipulated without disrupting essential immune surveillance. We propose that lymphoid-like suppressive microglia represent a promising but still unproven framework for understanding protective neuroimmune regulation in Alzheimer’s disease and for developing state-specific microglial therapies.