Estrogen-dependent hippocampal wiring as a risk factor for age-related dementia in women

Women are more prone than men to develop age-related dementia, such as Alzheimer’s disease (AD). This has been linked to the marked decrease in circulating estrogens during menopause. This review proposes to change this perspective and consider women’s vulnerability to developing AD as a consequence of sex differences in the neurobiology of memory, focusing on the hippocampus. The hippocampus of cognitively impaired subjects tends to shrink with age; however, in many cases, this can be prevented by exercise or cognitive training, suggesting that if you do not use the hippocampus you lose it. We will review the developmental trajectory of sex steroids-regulated differences on the hippocampus, proposing that the overall shaping action of sex-steroids results in a lower usage of the hippocampus in females, which in turn makes them more vulnerable to the effects of ageing, the “network fragility hypothesis”. To explain why women rely less on hippocampus-dependent strategies, we propose a “computational hypothesis” that is based on experimental evidence suggesting that the direct effects of estrogens on hippocampal synaptic and structural plasticity during the estrous-cycle confers instability to the memory-dependent hippocampal network. Finally, we propose to counteract AD with training and/or treatments, such as orienteering, which specifically favour the use of the hippocampus.