Additionally, several questions that remain unanswered regarding the use of HA-E2 for the treatment of cognitive impairments: (1) whether HA-E2 administration results in a higher BBB penetration rate compared to E2 and the amount of HA-E2 that acts on the hippocampus and MS nucleus; (2) whether HA-E2 can reduce common pathological features of dementia, such as tau protein or β-amyloid; (3) whether long-term use of HA-E2 increases the risk of cardiovascular disease and breast cancer. This evidence concerns the gene MAPT and dementia.