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Female Sex and Alzheimer’s Risk: The Menopause Connection

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Abstract

Along with advanced age and apolipoprotein E (APOE)-4 genotype, female sex is a major risk factor for developing late-onset Alzheimer’s disease (AD). Considering that AD pathology begins decades prior to clinical symptoms, the higher risk in women cannot simply be accounted for by their greater longevity as compared to men. Recent investigation into sex-specific pathophysiological mechanisms behind AD risk has implicated the menopause transition (MT), a midlife neuroendocrine transition state unique to females. Commonly characterized as ending in reproductive senescence, many symptoms of MT are neurological, including disruption of estrogen-regulated systems such as thermoregulation, sleep, and circadian rhythms, as well as depression and impairment in multiple cognitive domains. Preclinical studies have shown that, during MT, the estrogen network uncouples from the brain bioenergetic system. The resulting hypometabolic state could serve as the substrate for neurological dysfunction. Indeed, translational brain imaging studies demonstrate that 40–60 year-old perimenopausal and postmenopausal women exhibit an AD-endophenotype characterized by decreased metabolic activity and increased brain amyloid-beta deposition as compared to premenopausal women and to age-matched men. This review discusses the MT as a window of opportunity for therapeutic interventions to compensate for brain bioenergetic crisis and combat the subsequent increased risk for AD in women.

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References

  1. Farrer, L.A., et al., Effects of age, sex, and ethnicity on the association between apolipoprotein E genotype and Alzheimer disease. A meta-analysis. APOE and Alzheimer Disease Meta Analysis Consortium. JAMA, 1997. 278(16): p. 1349–56.

    Article  PubMed  CAS  Google Scholar 

  2. Alzheimer’s, A., 2016 Alzheimer’s disease facts and figures. Alzheimers Dement, 2016. 12(4): p. 459–509.

    Article  Google Scholar 

  3. Stopping Alzheimer’s Disease and Related Dementias: Advancing Our Nation’s Research AgendaNIH Bypass Budget Proposal for Fiscal Year 2018 N.I.o. Health, Editor. 2018.

  4. Vina, J. and A. Lloret, Why women have more Alzheimer’s disease than men: gender and mitochondrial toxicity of amyloid-beta peptide. J Alzheimers Dis, 2010. 20 Suppl 2: p. S527–33.

    Article  PubMed  CAS  Google Scholar 

  5. Brinton, R.D., et al., Perimenopause as a neurological transition state. Nat Rev Endocrinol, 2015. 11(7): p. 393–405.

    Article  PubMed  CAS  Google Scholar 

  6. Sperling, R.A., J. Karlawish, and K.A. Johnson, Preclinical Alzheimer diseasethe challenges ahead. Nat Rev Neurol, 2013. 9(1): p. 54–8.

    Article  PubMed  CAS  Google Scholar 

  7. Nelson, H.D., Menopause. Lancet, 2008. 371(9614): p. 760–70.

    Article  PubMed  Google Scholar 

  8. Mosconi, L., et al., Perimenopause and emergence of an Alzheimer’s bioenergetic phenotype in brain and periphery PLoS One, 2017. in press: p. e0193314.

    Google Scholar 

  9. Mosconi, L., et al., Sex differences in Alzheimer risk Brain imaging of endocrine vs chronologic aging. Neurology, 2017. 89(13): p. 1382–1390.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  10. Harlow, S.D., et al., Executive summary of the Stages of Reproductive Aging Workshop + 10: addressing the unfinished agenda of staging reproductive aging. Menopause, 2012. 19(4): p. 387–95.

    Article  PubMed  PubMed Central  Google Scholar 

  11. Cray, L., N.F. Woods, and E.S. Mitchell, Symptom clusters during the late menopausal transition stage: observations from the Seattle Midlife Women’s Health Study. Menopause, 2010. 17(5): p. 972–7.

    Article  PubMed  Google Scholar 

  12. Brinton, R.D., Estrogen-induced plasticity from cells to circuits: predictions for cognitive function. Trends Pharmacol Sci, 2009. 30(4): p. 212–22.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  13. Nilsson, S., K.F. Koehler, and J.A. Gustafsson, Development of subtypeselective oestrogen receptor-based therapeutics. Nat Rev Drug Discov, 2011. 10(10): p. 778–92.

    Article  PubMed  CAS  Google Scholar 

  14. McEwen, B.S., et al., Estrogen effects on the brain: actions beyond the hypothalamus via novel mechanisms. Behav Neurosci, 2012. 126(1): p. 4–16.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  15. Maki, P.M., The timing of estrogen therapy after ovariectomy—implications for neurocognitive function. Nat Clin Pract Endocrinol Metab, 2008. 4(9): p. 494–5.

    Article  PubMed  Google Scholar 

  16. Yao, J. and R.D. Brinton, Estrogen regulation of mitochondrial bioenergetics: implications for prevention of Alzheimer’s disease. Adv Pharmacol, 2012. 64: p. 327–71.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  17. Liu, F., et al., Activation of estrogen receptor-beta regulates hippocampal synaptic plasticity and improves memory. Nat Neurosci, 2008. 11(3): p. 334–43.

    Article  PubMed  CAS  Google Scholar 

  18. Yin, F., et al., The perimenopausal aging transition in the female rat brain: decline in bioenergetic systems and synaptic plasticity. Neurobiol Aging, 2015. 36(7): p. 2282–95.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  19. Yao, J., et al., Ovarian hormone loss induces bioenergetic deficits and mitochondrial beta-amyloid. Neurobiol Aging, 2012. 33(8): p. 1507–21.

    Article  PubMed  CAS  Google Scholar 

  20. Ding, F., et al., Early decline in glucose transport and metabolism precedes shift to ketogenic system in female aging and Alzheimer’s mouse brain: implication for bioenergetic intervention. PLoS One, 2013. 8(11): p. e79977.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  21. Rettberg, J.R., et al., Identifying postmenopausal women at risk for cognitive decline within a healthy cohort using a panel of clinical metabolic indicators: potential for detecting an at-Alzheimer’s risk metabolic phenotype. Neurobiol Aging, 2016. 40: p. 155–63.

    Article  PubMed  PubMed Central  Google Scholar 

  22. Mattson, M.P. and T. Magnus, Ageing and neuronal vulnerability. Nat Rev Neurosci, 2006. 7(4): p. 278–94.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  23. Ungar, L., A. Altmann, and M.D. Greicius, Apolipoprotein E, gender, and Alzheimer’s disease: an overlooked, but potent and promising interaction. Brain Imaging Behav, 2014. 8(2): p. 262–73.

    Article  PubMed  PubMed Central  Google Scholar 

  24. Fleisher, A., et al., Sex, apolipoprotein E epsilon 4 status, and hippocampal volume in mild cognitive impairment. Arch Neurol, 2005. 62(6): p. 953–7.

    Article  PubMed  Google Scholar 

  25. Damoiseaux, J.S., et al., Gender modulates the APOE epsilon4 effect in healthy older adults: convergent evidence from functional brain connectivity and spinal fluid tau levels. J Neurosci, 2012. 32(24): p. 8254–62.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  26. Swerdlow, R.H., J.M. Burns, and S.M. Khan, The Alzheimer’s disease mitochondrial cascade hypothesis. J Alzheimers Dis, 2010. 20 Suppl 2: p. S265–79.

    Article  PubMed  CAS  Google Scholar 

  27. Walsh, D.M. and D.J. Selkoe, A critical appraisal of the pathogenic protein spread hypothesis of neurodegeneration. Nature Reviews Neuroscience, 2016. 17(4): p.251.

    Article  PubMed  CAS  Google Scholar 

  28. Benzinger, T.L., et al., Regional variability of imaging biomarkers in autosomal dominant Alzheimer’s disease. Proc Natl Acad Sci U S A, 2013. 110(47): p. E4502–9.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  29. Bove, R., et al., Age at surgical menopause influences cognitive decline and Alzheimer pathology in older women. Neurology, 2014. 82(3): p. 222–9.

    Article  PubMed  PubMed Central  Google Scholar 

  30. Craig, M.C., P.M. Maki, and D.G. Murphy, The Women’s Health Initiative Memory Study: findings and implications for treatment. The Lancet Neurology, 2005. 4(3): p. 190–194.

    Article  PubMed  Google Scholar 

  31. Menopause & Hormones, FDA, Editor. 2014.

  32. Investigators, W.G.f.t.W.s.H.I., Risks and benefits of estrogen plus progestin in healthy postmenopausal women: principal results from the Women’s Health Initiative randomized controlled trial. Jama, 2002. 288(3): p. 321–333.

    Article  Google Scholar 

  33. Shumaker, S.A., et al., Estrogen plus progestin and the incidence of dementia and mild cognitive impairment in postmenopausal women: the Women’s Health Initiative Memory Study: a randomized controlled trial. Jama, 2003. 289(20): p. 2651–2662.

    Article  PubMed  CAS  Google Scholar 

  34. LaCroix, A.Z., et al., Health outcomes after stopping conjugated equine estrogens among postmenopausal women with prior hysterectomy: a randomized controlled trial. Jama, 2011. 305(13): p. 1305–1314.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  35. Shufelt, C.L., et al., Timing of hormone therapy, type of menopause, and coronary disease in women: data from the National Heart, Lung, and Blood Institute-sponsored Women’s Ischemia Syndrome Evaluation. Menopause (New York, NY), 2011. 18(9): p. 943–950.

    Article  Google Scholar 

  36. Rasgon, N.L., et al., Prospective randomized trial to assess effects of continuing hormone therapy on cerebral function in postmenopausal women at risk for dementia. PLoS One, 2014. 9(3): p. e89095.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  37. Maki, P.M. and S. M. Resnick, Longitudinal effects of estrogen replacement therapy on PET cerebral blood flow and cognition. Neurobiol Aging, 2000. 21(2): p. 373–83.

    Article  PubMed  CAS  Google Scholar 

  38. Rocca, W.A., et al., Increased risk of cognitive impairment or dementia in women who underwent oophorectomy before menopause. Neurology, 2007. 69(11): p. 1074–1083.

    Article  PubMed  CAS  Google Scholar 

  39. Mielke, M.M., P. Vemuri, and W.A. Rocca, Clinical epidemiology of Alzheimer’s disease: assessing sex and gender differences. Clinical epidemiology, 2014. 6: p.37.

    Article  PubMed  PubMed Central  Google Scholar 

  40. Shao, H., et al., Hormone therapy and Alzheimer disease dementia New findings from the Cache County Study. Neurology, 2012. 79(18): p. 1846–1852.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  41. Whitmer, R.A., et al., Timing of hormone therapy and dementia: the critical window theory revisited. Annals of neurology, 2011. 69(1): p. 163–169.

    Article  PubMed  Google Scholar 

  42. Hodis, H.N., et al., Methods and baseline cardiovascular data from the Early versus Late Intervention Trial with Estradiol testing the menopausal hormone timing hypothesis. Menopause, 2015. 22(4): p. 391–401.

    Article  PubMed  PubMed Central  Google Scholar 

  43. Espeland, M.A., et al., Postmenopausal hormone therapy, type 2 diabetes mellitus, and brain volumes. Neurology, 2015. 85(13): p. 1131–8.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  44. Rasgon, N.L., et al., Insulin resistance and hippocampal volume in women at risk for Alzheimer’s disease. Neurobiol Aging, 2011. 32(11): p. 1942–8.

    Article  PubMed  CAS  Google Scholar 

  45. Zhang, Q.-g., et al., C terminus of Hsc70-interacting protein (CHIP)-mediated degradation of hippocampal estrogen receptor-a and the critical period hypothesis of estrogen neuroprotection. Proceedings of the National Academy of Sciences, 2011. 108(35): p. E617–E624.

    Article  Google Scholar 

  46. Brinton, R.D., The healthy cell bias of estrogen action: mitochondrial bioenergetics and neurological implications. Trends in neurosciences, 2008. 31(10): p. 529–537.

    Article  PubMed  CAS  Google Scholar 

  47. FDA approves first nonhormonal hot flash treatment. 2013, The North American Menopause Society.

  48. Freeman, E.W., et al., Efficacy of escitalopram for hot flashes in healthy menopausal women: a randomized controlled trial. Jama, 2011. 305(3): p. 267–274.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  49. Alexandersen, P., et al., Ipriflavone in the treatment of postmenopausal osteoporosis: a randomized controlled trial. Jama, 2001. 285(11): p. 1482–1488.

    Article  PubMed  CAS  Google Scholar 

  50. Liu, Z., et al., A mild favorable effect of soy protein with isoflavones on body composition—a 6-month double-blind randomized placebo-controlled trial among Chinese postmenopausal women. International journal of obesity, 2010. 34(2): p.309.

    Article  PubMed  CAS  Google Scholar 

  51. Levis, S., et al., Soy isoflavones in the prevention of menopausal bone loss and menopausal symptoms: a randomized, double-blind trial. Archives of internal medicine, 2011. 171(15): p. 1363–1369.

    Article  PubMed  CAS  Google Scholar 

  52. Nedrow, A., et al., Complementary and alternative therapies for the management of menopause-related symptoms: a systematic evidence review. Archives of internal medicine, 2006. 166(14): p. 1453–1465.

    Article  PubMed  Google Scholar 

  53. Nagel, G., et al., Reproductive and dietary determinants of the age at menopause in EPIC-Heidelberg. Maturitas, 2005. 52(3): p. 337–347.

    Article  PubMed  Google Scholar 

  54. Dorjgochoo, T., et al., Dietary and lifestyle predictors of age at natural menopause and reproductive span in the Shanghai Women’s Health Study. Menopause (New York, NY), 2008. 15(5): p.924.

    Article  Google Scholar 

  55. Dunneram, Y., et al., Dietary intake and age at natural menopause: results from the UK Women’s Cohort Study. J Epidemiol Community Health, 2018: p. jech-2017-209887.

    Google Scholar 

  56. Hamer, M. and Y. Chida, Physical activity and risk of neurodegenerative disease: a systematic review of prospective evidence. Psychological medicine, 2009. 39(1): p. 3–11.

    Article  PubMed  CAS  Google Scholar 

  57. Hogervorst, E., et al., Exercise to prevent cognitive decline and Alzheimer’s disease: for whom, when, what, and (most importantly) how much. J Alzheimers Dis Parkinsonism, 2012. 2: p. e117.

    Article  Google Scholar 

  58. Fallah, N., et al., Modeling the impact of sex on how exercise is associated with cognitive changes and death in older Canadians. Neuroepidemiology, 2009. 33(1): p. 47–54.

    Article  PubMed  Google Scholar 

  59. Middleton, L.E., et al., Physical activity over the life course and its association with cognitive performance and impairment in old age. Journal of the American Geriatrics Society, 2010. 58(7): p. 1322–1326.

    Article  PubMed  PubMed Central  Google Scholar 

  60. Norton, S., et al., Potential for primary prevention of Alzheimer’s disease: an analysis of population-based data. The Lancet Neurology, 2014. 13(8): p. 788–794.

    Article  PubMed  Google Scholar 

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Correspondence to Lisa Mosconi.

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Scheyer, O., Rahman, A., Hristov, H. et al. Female Sex and Alzheimer’s Risk: The Menopause Connection. J Prev Alzheimers Dis 5, 225–230 (2018). https://doi.org/10.14283/jpad.2018.34

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