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Cognitive aging in midlife women: is it real?

20 March, 2017

Cognitive aging has become an important issue because of increased life expectancy in women. Cognitive complaints are common during midlife, as part of the climacteric syndrome. By using data from a longitudinal observational study in 2124 participants from the Study of Women's Health Across the Nation, Karlamangla and colleagues [1] attempted to demonstrate that cognitive aging is present in midlife women, irrespective of menopausal transition and its associated symptoms. Moreover, their study design tried to avoid the so-called practice effects deriving from the ability to learn from repeat testing in younger women. Average age at baseline (third cognition testing visit) was 54 years and the majority of the women were postmenopausal, with half the cohort being 2 or more years beyond the final menstrual period. There were 7185 cognition assessments (processing speed, verbal episodic memory [immediate and delayed], and working memory) with median follow-up time of 6.5 years. By adjusting for practice effects, retention, menopause symptoms (depressive, anxiety, vasomotor, and sleep disturbance), and covariates, they found a mean decline in cognitive speed of 0.28 per year (95% confidence interval, CI 0.20–0.36) or of 4.9% in 10 years, and a mean decline in verbal episodic memory (delayed testing) of 0.02 per year (95% CI 0.00–0.03) or of 2% in 10 years.


Menopausal transition may represent a time of cognitive vulnerability [2] and the intensity of psychological, vasomotor and combined climacteric symptoms may predict cognitive performance in postmenopausal women [3]. A recent meta-analysis of studies of cognition and depression across stages of the menopausal transition concluded that postmenopausal women perform worse than perimenopausal women on phonemic verbal fluency and delayed verbal memory tests. Moreover, perimenopausal and postmenopausal women are more likely to have significant depressive symptoms compared to premenopausal women [4]. Neurological symptoms that emerge during perimenopause are indicative of disruption in multiple estrogen-regulated systems and affect multiple domains of cognitive function [5]. However, cognition is a complex function originating in several areas of the brain and the hormonal environment is only one of the multitude of factors influencing cognitive symptoms (without cognitive impairment), which cannot be considered an early sign of future dementia in healthy midlife and older women [6]. Therefore, large-scale prospective studies of midlife women are strongly needed to better demonstrate the trajectory of cognition across reproductive senescence and the relationship with other aspects of mental well-being. In spite of the undoubted role of estrogens in cognition throughout a wide range of mechanisms [7], MHT should not be used to enhance cognitive function in women with natural menopause, but the initiation during midlife is associated with reduced risk of Alzheimer’s disease and dementia, according to IMS guidelines (level of evidence A and B, respectively) [8]. Indeed, individually modifiable risk factors, other than the use of MHT, may be implicated in ameliorating cognitive aging in healthy midlife and older adults [9]. Interestingly enough, a neuroimaging study has recently demonstrated that age-related reductions in context memory may reflect a shift in the type of information on which the brain focuses during memory formation and retrieval, rather than a decline in cognitive function at midlife. During a memory task, activation of the visual cortex was increased in young adults in comparison with middle-aged and older adults, whereas, in middle-aged and older adults, activation was greater in the prefrontal cortex [10]. Whether such specific age-related changes in midlife memory reflect adaptive purposes of the aging brain needs further investigation.

Rossella E. Nappi

Research Centre for Reproductive Medicine, Gynaecological Endocrinology and Menopause, IRCCS San Matteo Foundation, Department of Clinical, Surgical, Diagnostic and Paediatric Sciences, University of Pavia, Pavia, Italy


  1. Karlamangla AS, Lachman ME, Han W, Huang M, Greendale GA. Evidence for cognitive aging in midlife women: Study of Women's Health Across the Nation. PLoS One 2017;12(1):e0169008
  2. Epperson CN, Sammel MD, Freeman EW. Menopause effects on verbal memory: findings from a longitudinal community cohort. J Clin Endocrinol Metab 2013;98:3829-38
  3. Triantafyllou N, Armeni E, Christidi F, et al. The intensity of menopausal symptoms is associated with episodic memory in postmenopausal women. Climacteric 2016;19:393-9
  4. Weber MT, Maki PM, McDermott MP. Cognition and mood in perimenopause: a systematic review and meta-analysis. J Steroid Biochem Mol Biol 2014;142:90-8
  5. Brinton RD, Yao J, Yin F, Mack WJ, Cadenas E. Perimenopause as a neurological transition state. Nat Rev Endocrinol 2015;11:393-405
  6. Maki PM, Henderson VW. Cognition and the menopause transition. Menopause 2016;23:803-5
  7. Li R, Cui J, Shen Y. Brain sex matters: estrogen in cognition and Alzheimer's disease. Mol Cell Endocrinol 2014;389:13-21
  8. Baber RJ, Panay N, Fenton A; IMS Writing Group. 2016 IMS Recommendations on women's midlife health and menopause hormone therapy. Climacteric 2016;19:109-50
  9. Lehert P, Villaseca P, Hogervorst E, Maki PM, Henderson VW. Individually modifiable risk factors to ameliorate cognitive aging: a systematic review and meta-analysis. Climacteric 2015;18:678-89
  10. Ankudowich E, Pasvanis S, Rajah MN. Changes in the modulation of brain activity during context encoding vs. context retrieval across the adult lifespan. Neuroimage 2016;139:103-13

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