Candice M Roux, Slavica Krantic
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.