Ageing primes the expression of Alzheimer’s disease (AD) risk genes expressed by microglia. Amyloid induces a protective “Disease-Associated” state in microglia. Exhaustion of this protective microglial state permits the development of Tau pathology, in an APOE-dependent manner. AD progression is associated with interferon signalling pathways and distinct neuronal subpopulations related to Tau spread and neuronal death.