The Effect of Cumulative Lifetime Estrogen Exposure on Cognition in Depressed versus Non-Depressed Older Women

Introduction There are sex differences in the prevalence and age-matched incidence of Alzheimer's Disease (AD), with women constituting up to two-thirds of individuals living with AD in the United States. Symptoms of depression and anxiety are also higher in women and can increase dementia risk. Additionally, the decline in estrogen level impacts cognitive function, often leading to difficulties with memory, attention, and concentration. Estrogen withdrawal during menopause also precipitates an increase in depressive symptoms and cognitive decline. Cumulative lifetime estrogen exposure (CLEE), estimated by variables known to influence estrogen levels across the life span, has been correlated with cognitive function later in life. In particular, higher levels of CLEE are associated with improvement in memory performance in older women. Our report is the first to examine how CLEE relates to depression and cognitive function in older women with depression compared to non-depressed controls. Methods A total of 135 participants aged 60 years and older were included in the analysis. Sixty-four clinically depressed women (mean age 69.1 (SD 6.4) years) were compared to 71 non-depressed age-matched controls (mean age 66.1 (SD 8.3) years) using a lifetime estrogen exposure questionnaire. Depressed participants were included with the 24-item Hamilton Rating Scale for Depression (HAMD) score of > 14 at baseline. CLEE was defined by combining the reproductive span (age of menopause minus age of menarche) and any post-menopausal hormone replacement therapy use. Participants were divided into higher versus lower CLEE groups based on a median of 480 months of estrogen exposure. Participants completed a comprehensive neuropsychological test battery that evaluated learning (California Verbal Learning Test-II [Trial 1 through 5 Total] or Hopkins Verbal Learning Test [Total Recall], Rey–Osterrieth Complex Figure Test [3-minute recall]); delayed recall (California Verbal Learning Test-II [long delayed free recall] or Hopkins Verbal Learning Test [Delayed Recall], Rey–Osterrieth Complex Figure Test [30-minute delayed recall]); and executive functioning (Trail Making Test B, Controlled Oral Word Association test [FAS]).We transformed raw scores to z-scores for each test score for each participant. Z-scores were reversed when necessary so that high z-scores represented good performance for all measures. These z-scores were averaged within each neuropsychological domain to produce composite scores.General linear models were used to examine whether cognitive domain scores were associated with CLEE in depressed and non-depressed women, controlling for age, educational level and ethnicity. Results Depressed and non-depressed women had significantly different levels of CLEE: 448.6 (SD 66.0) vs. 487.3 (SD 108.6), t(133) = 2.52, p = .01. CLEE was not associated with cognitive performance in the combined sample of depressed and non-depressed participants, controlling for depression status. However, amongst non-depressed participants, higher CLEE group was significantly associated with better performance on delayed recall (F(1,60) = 5.45, p=0.02; effect size = .64). Conclusions Consistent with previous findings, higher CLEE was associated with better performance on delayed recall, though we found this effect only among non-depressed participants. This suggests an enduring protective role of estrogen on memory in non-depressed older postmenopausal women. CLEE was not associated with cognitive function in older women with depression. Further research should examine the role of the CLEE in older women in depression, treatment response and in cognitive decline. Funding K24 AT009198 R01 AT008383 (NCCIH) R01 AT008383-04S (NCCIH)