Trained immunity in microglia, driven by epigenetic reprogramming (e.g., increased H3K4me1 and H3K27ac), exacerbates cerebral β-amyloidosis in Alzheimer’s disease, particularly through HIF-1α and mammalian target of rapamycin (mTOR) pathways. Here, MTOR is linked to early-onset autosomal dominant Alzheimer disease.