These findings offer mechanistic insight into how microglial signaling interfaces with neuronal and oligodendrocyte function in AD and suggest that targeting microglial DAP12 signaling, potentially in combination with tau-directed therapies, may offer a promising strategy to mitigate neurotoxicity, demyelination, and cognitive decline in Alzheimer’s disease and related tauopathies. Here, TYROBP is linked to early-onset autosomal dominant Alzheimer disease.