Update on sex-specific microglia contribution to early synaptic dysfunction in Alzheimer's disease

Women are twice as likely to develop Alzheimer's disease (AD) as men. Despite substantial progress in understanding the pathogenesis of sporadic AD, sex-specific mechanisms remain insufficiently explored, and preclinical research has historically been biased toward male subjects. Furthermore, there is often a delay of more than 10 years between the onset of neuropathological changes and clinical diagnosis. This latent pre-symptomatic period, during which pathological alterations may still be reversible, represents a promising window for therapeutic intervention. In this context, synaptic dysfunction and neuroinflammatory alterations are among the earliest detectable AD-associated impairments and have recently emerged as promising therapeutic targets. This mini-review summarizes the currently limited knowledge on sex-related differences in synaptic functions during pre-symptomatic stage of AD pathology in both pre-clinical and clinical studies. We further position sex as a critical biological variable impacting neuronal activity, either directly or indirectly through microglia-neuron crosstalk. Finally, we emphasize the importance and rationale for integrating sex-specific neuroimmune mechanisms into early-stage research to guide design of targeted, sex-tailored therapeutic strategies that modulate neuron-microglia interactions before clinical onset.