SAN DIEGO – Earlier age at surgical menopause may be associated with a steeper decline in cognitive function and increased Alzheimer’s disease–related neuropathologic scores, preliminary results from two longitudinal studies have shown.
"Our findings support a growing literature on the impact of surgical menopause on cognitive function, and add granularity to these outcome measures," Dr. Riley M. Bove said at the annual meeting of the American Academy of Neurology. "In light of the sometimes conflicting and sometimes controversial findings related to modifying factors such as hormone replacement therapy [HRT], we believe that ongoing investigations are warranted."
Doug Brunk/IMNG Medical Media
Dr. Riley Bove
In an effort to determine the impact of reproductive decline on the spectrum of cognitive decline, Dr. Bove, a neurologist at Brigham and Women’s Hospital, Boston, and her associates studied 1,884 women enrolled in two ongoing longitudinal studies: the Memory and Aging Project (MAP), a study of older men and women in assisted living facilities that was launched in 1997, and the Religious Orders Study (ROS), a study of Catholic priests, nuns, and brothers that was launched in 1994.
"Observational studies have noted that the loss of estrogen associated with menopause, including surgical menopause, may be associated with cognitive decline," Dr. Bove said. "In animal models estrogen has been found to be neuroprotective. However, in humans the evidence is a lot more complex. The results of the Womens Health Initiative Memory Study a decade ago did find adverse effects of hormone replacement therapy initiated in women in their 60s. Since then a window of opportunity hypothesis has emerged, according to which HRT perimenopausally may be protective, but following this window, it may be neutral or even harmful. We aimed to look at longitudinal changes in cognition, risk of an Alzheimer’s diagnosis, and neuropathologic measures related to Alzheimer’s disease. Our hypothesis was that earlier surgical menopause is associated with earlier risk of cognitive decline."
Study participants, who have been followed for up to 19 years, underwent a baseline clinical and reproductive history, annual clinical and cognitive evaluations, and annual blood draws. The researchers examined the association between age at menarche and menopause, number of cycling years, and ever use and duration of HRT.
During annual cognitive tests, the researchers evaluated five composite domains that were weighted toward memory and categorized by factor analysis. The domains include episodic memory (seven tests), semantic memory (three tests), working memory (three tests), perceptual speed (two tests), and visuospatial ability (two tests). They also established a global cognition composite score, which was a sum of the 17 individual tests.
Dr. Bove and her associates considered a clinical diagnosis of Alzheimer’s based on clinical criteria and neuropathologic measures. The three Alzheimer’s disease–associated measures were neuritic plaques, neurofibrillary tangles, and diffuse plaques, as well as a global AD pathology score, which was an average of these three measures. Age at menopause was a continuous variable. All models controlled for age, smoking, and years of education.
Of the total women studied, all were free of dementia at enrollment, their mean age was 78 years, and 91% were non-Hispanic white. On average, compared with women in the ROS study, those in the MAP study were older (79.6 vs. 75.9 years, respectively); were less educated (14.1 vs. 17.9 years); were more likely to smoke (38% vs. 8%); had an earlier age at menarche (12.8 vs. 13.1); had a later age at menopause (47.3 vs. 46.6); and had a slightly higher number of cycling years (34.5 vs. 33.4).
Of the 1,884 women, 1,277 reported having natural menopause, and 607 reported having surgical menopause. More women in the surgical menopause group reported HRT use (53% vs. 27%, respectively). "Approximately 90% of HRT use was oral, so we collapsed all of the different forms of HRT use into one group," she explained.
Among women who had undergone surgical menopause, early age at menopause was associated with a faster decline in global cognition (P = .0007), as well as faster declines in episodic memory (P = .0003) and semantic memory (P = .0022). "We did not find the similar association in the natural menopause group," Dr. Bove said.
However, the researchers observed no significant association between age at surgical menopause and risk of clinical Alzheimer’s (P = .093) nor in the pathologic diagnosis of Alzheimer’s (P = .053). Early age at surgical menopause was associated with significantly lower scores in global AD pathology (P = .038) and neuritic plaques (P = .013) but not in neurofibrillary tangles (P = .138) or diffuse plaques (P = .490).