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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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.
Alzheimer’s, A., 2016 Alzheimer’s disease facts and figures. Alzheimers Dement, 2016. 12(4): p. 459–509.
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.
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.
Brinton, R.D., et al., Perimenopause as a neurological transition state. Nat Rev Endocrinol, 2015. 11(7): p. 393–405.
Sperling, R.A., J. Karlawish, and K.A. Johnson, Preclinical Alzheimer diseasethe challenges ahead. Nat Rev Neurol, 2013. 9(1): p. 54–8.
Nelson, H.D., Menopause. Lancet, 2008. 371(9614): p. 760–70.
Mosconi, L., et al., Perimenopause and emergence of an Alzheimer’s bioenergetic phenotype in brain and periphery PLoS One, 2017. in press: p. e0193314.
Mosconi, L., et al., Sex differences in Alzheimer risk Brain imaging of endocrine vs chronologic aging. Neurology, 2017. 89(13): p. 1382–1390.
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.
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.
Brinton, R.D., Estrogen-induced plasticity from cells to circuits: predictions for cognitive function. Trends Pharmacol Sci, 2009. 30(4): p. 212–22.
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.
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.
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.
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.
Liu, F., et al., Activation of estrogen receptor-beta regulates hippocampal synaptic plasticity and improves memory. Nat Neurosci, 2008. 11(3): p. 334–43.
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.
Yao, J., et al., Ovarian hormone loss induces bioenergetic deficits and mitochondrial beta-amyloid. Neurobiol Aging, 2012. 33(8): p. 1507–21.
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.
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.
Mattson, M.P. and T. Magnus, Ageing and neuronal vulnerability. Nat Rev Neurosci, 2006. 7(4): p. 278–94.
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.
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.
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.
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.
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.
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.
Bove, R., et al., Age at surgical menopause influences cognitive decline and Alzheimer pathology in older women. Neurology, 2014. 82(3): p. 222–9.
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.
Menopause & Hormones, FDA, Editor. 2014.
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.
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.
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.
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.
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.
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.
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.
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.
Shao, H., et al., Hormone therapy and Alzheimer disease dementia New findings from the Cache County Study. Neurology, 2012. 79(18): p. 1846–1852.
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.
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.
Espeland, M.A., et al., Postmenopausal hormone therapy, type 2 diabetes mellitus, and brain volumes. Neurology, 2015. 85(13): p. 1131–8.
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.
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.
Brinton, R.D., The healthy cell bias of estrogen action: mitochondrial bioenergetics and neurological implications. Trends in neurosciences, 2008. 31(10): p. 529–537.
FDA approves first nonhormonal hot flash treatment. 2013, The North American Menopause Society.
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.
Alexandersen, P., et al., Ipriflavone in the treatment of postmenopausal osteoporosis: a randomized controlled trial. Jama, 2001. 285(11): p. 1482–1488.
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.
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.
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.
Nagel, G., et al., Reproductive and dietary determinants of the age at menopause in EPIC-Heidelberg. Maturitas, 2005. 52(3): p. 337–347.
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.
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.
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.
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.
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.
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.
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.
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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
- Alzheimer’s disease
- early detection
- brain imaging