Microglia play a part in protein clearance and synaptic pruning. This latter process is re-activated in Alzheimer disease (AD) and promoted by amyloid-β (Aβ). A screen of 18 AD-associated genes revealed that loss of the DNA–RNA binding protein TDP43 led to a considerable increase in phagocytic clearance of Aβ by microglia. Selective knockout of TDP43 from microglia in a mouse model of AD resulted in increased Aβ clearance but, unexpectedly, increased synapse loss. Consistent with this, people with TDP43 pathology had lower Aβ load and a lower risk of AD but showed a small cognitive deficit. Therefore, microglial dysfunction could contribute to AD pathology.