Hormonal treatment, mild cognitive impairment and Alzheimer's disease

Abstract

A plethora of in vitro and in vivo studies have supported the neuroprotective role of estrogens and their impact on the neurotransmitter systems implicated in cognition. Recent hormonal replacement therapy (HRT) trials in non-demented postmenopausal women suggest a temporary positive effect (notably on verbal memory), and four meta-analyses converge to suggest a possible protective effect in relation to Alzheimer's disease (reducing risk by 29 to 44%). However, data from the only large randomized controlled trial published to date, the Women's Health Initiative Memory Study, did not confirm these observations and have even suggested an increase in dementia risk for women using HRT compared to controls. Apart from methodological differences, one key shortcoming of this trial has probably been the focus on late-onset (postmenopausal) hormonal changes, i.e. at a time when the neurodegenerative process has already begun and without taking into account individual lifetime exposure to hormone variability. Multifactorial models based on an exhaustive view of all hormonal events throughout the reproductive life (rather than on a specific exposure to a given steroid) together with other risk factors (notably genetic risk factors related to estrogen receptor polymorphisms) should be explored to clarify the role of hormonal risk factors, or protective factors for cognitive dysfunction and dementia.

Fig. 1. Effects of HT on specific cognitive function in non-demented menopausal women as a function of age and type of HT

Twenty one RCTs were performed over the last 20 years using estradiol (E2) or CEE opposed or not with progestins and administered either to “young” menopausal women (i.e. younger man 65) or to “old” women of 65 years and more. The number of RCTs under each condition is indicated between brackets. Black, grey, and white bars correspond respectively to the % of RCTs where HT was found to have a negative, a positive, or no effect, on at least one cognitive task. The studies on global cognitive functioning (MMSE,…) or those with ultra-low-dose estradiol were not considered.