Microglial metabolism and immune function are pivotal factors in sexual dimorphism in Alzheimer’s disease

Age and sex are major risk factors in Alzheimer’s disease (AD) with a higher incidence of the disease in females. Chronic microglial activation and dysregulated neuro-inflammation are features of AD and may contribute to disease pathogenesis in a sexually dimorphic manner. We investigated sex differences in microglia in the APP/PS1 mouse model of Alzheimer’s disease and in post mortem brain tissue from patients with Alzheimer’s disease. Here we report elevated levels of activated, iron-laden and dystrophic microglia in the cortex and hippocampus of female APP/PS1 mice, and in post mortem tissue from female AD patients compared with males. These sex-related differences were paralleled by a metabolic shift to glycolysis in microglia from female APP/PS1 mice and increased production of inflammatory cytokines. These morphological, metabolic and immune-related changes were associated with impairments in microglial phagocytic function and greater Aβ plaque load in females. We propose that sex differences in microglia may underpin, at least in part, sexual dimorphism in the incidence and, potentially, clinical progression of Alzheimer’s disease.