1. World Health Organization and Alzheimer’s Disease International. Dementia: a public health priority. WHO http://www.who.int/mental_health/publications/dementia_report_2012/en/ (2012).

2. Prince, M. Wimo, A., Guerchet, M., Ali, G. C., Wu, Y. & Prina, A. M. World Alzheimer Report 2015: the global impact of dementia. An anlaysis of prevalence, incidence, costs and trends. Alzheimer’s Disease International https://www.alz.co.uk/research/WorldAlzheimerReport2015.pdf (2015).

3. Gauthier, S. et al. Why has therapy development for dementia failed in the last two decades? Alzheimers Dement. 12, 60–64 (2016).

4. Husain, M. Alzheimer’s disease: time to focus on the brain, not just molecules. Brain 140, 251–253 (2017).

5. de Bono, J. S. & Ashworth, A. Translating cancer research into targeted therapeutics. Nature 467, 543–549 (2010).

6. Vargas, A. J. & Harris, C. C. Biomarker development in the precision medicine era: lung cancer as a case study. Nat. Rev. Cancer 16, 525–537 (2016).

7. Qian, J., Hyman, B. T. & Betensky, R. A. Neurofibrillary tangle stage and the rate of progression of Alzheimer symptoms: modeling using an autopsy cohort and application to clinical trial design. JAMA Neurol. 74, 540–548 (2017).

8. Gamberger, D., Lavrac, N., Srivatsa, S., Tanzi, R. E. & Doraiswamy, P. M. Identification of clusters of rapid and slow decliners among subjects at risk for Alzheimer’s disease. Sci. Rep. 7, 6763 (2017).

9. Escott-Price, V., Myers, A. J., Huentelman, M. & Hardy, J. Polygenic risk score analysis of pathologically confirmed Alzheimer disease. Ann. Neurol. 82, 311–314 (2017).

10. Ruigrok, A. N. et al. A meta-analysis of sex differences in human brain structure. Neurosci. Biobehav. Rev. 39, 34–50 (2014).

11. Ingalhalikar, M. et al. Sex differences in the structural connectome of the human brain. Proc. Natl Acad. Sci. USA 111, 823–828 (2014).

12. Li, R. & Singh, M. Sex differences in cognitive impairment and Alzheimer’s disease. Front. Neuroendocrinol. 35, 385–403 (2014).

13. Cordonnier, C. et al. Stroke in women — from evidence to inequalities. Nat. Rev. Neurol. 13, 521–532 (2017). This paper provides a clear summary of the role of sex differences in clinical practice in the stroke field.

14. Szewczyk-Krolikowski, K. et al. The influence of age and gender on motor and non-motor features of early Parkinson’s disease: initial findings from the Oxford Parkinson Disease Center (OPDC) discovery cohort. Parkinsonism Relat. Disord. 20, 99–105 (2014).

15. Vetvik, K. G. & MacGregor, E. A. Sex differences in the epidemiology, clinical features, and pathophysiology of migraine. Lancet Neurol. 16, 76–87 (2017).

16. Liu, G. et al. Prediction of cognition in Parkinson’s disease with a clinical-genetic score: a longitudinal analysis of nine cohorts. Lancet Neurol. 16, 620–629 (2017).

17. Hampel, H. et al. Precision pharmacology for Alzheimer’s disease. Pharmacol. Res. 130, 331–365 (2018).

18. Snyder, H. M. et al. Sex biology contributions to vulnerability to Alzheimer’s disease: A think tank convened by the Women’s Alzheimer’s Research Initiative. Alzheimers Dement. 12, 1186–1196 (2016).

19. Pike, C. J. Sex and the development of Alzheimer’s disease. J. Neurosci. Res. 95, 671–680 (2017).

20. Mielke, M. M., Vemuri, P. & Rocca, W. A. Clinical epidemiology of Alzheimer’s disease: assessing sex and gender differences. Clin. Epidemiol. 6, 37–48 (2014).

21. Rocca, W. A. Time, sex, gender, history, and dementia. Alzheimer Dis. Assoc. Disord. 31, 76–79 (2017). This paper highlights the current debate in the field of AD epidemiology and the potential role of secular trends in some controversial results.

22. Gale, S. D., Baxter, L. & Thompson, J. Greater memory impairment in dementing females than males relative to sex-matched healthy controls. J. Clin. Exp. Neuropsychol. 38, 527–533 (2016).

23. Jack, C. R. Jr. et al. Age, sex, and APOE epsilon4 effects on memory, brain structure, and beta-amyloid across the adult life span. JAMA Neurol. 72, 511–519 (2015).

24. McCarrey, A. C., An, Y., Kitner-Triolo, M. H., Ferrucci, L. & Resnick, S. M. Sex differences in cognitive trajectories in clinically normal older adults. Psychol. Aging 31, 166–175 (2016).

25. Laws, K. R., Irvine, K. & Gale, T. M. Sex differences in cognitive impairment in Alzheimer’s disease. World J. Psychiatry 6, 54–65 (2016).

26. Sundermann, E. E. et al. Better verbal memory in women than men in MCI despite similar levels of hippocampal atrophy. Neurology 86, 1368–1376 (2016).

27. Sundermann, E. E. et al. Female advantage in verbal memory: evidence of sex-specific cognitive reserve. Neurology 87, 1916–1924 (2016).

28. Irvine, K., Laws, K. R., Gale, T. M. & Kondel, T. K. Greater cognitive deterioration in women than men with Alzheimer’s disease: a meta analysis. J. Clin. Exp. Neuropsychol 34, 989–998 (2012). This article is a useful meta-analysis that demonstrated the occurrence of sex differences in cognitive decline in AD.

29. Pusswald, G. et al. Gender-specific differences in cognitive profiles of patients with Alzheimer’s disease: results of the Prospective Dementia Registry Austria (PRODEM-Austria). J. Alzheimers Dis. 46, 631–637 (2015).

30. Benke, T. et al. Cognition, gender, and functional abilities in Alzheimer’s disease: how are they related? J. Alzheimers Dis. 35, 247–252 (2013).

31. Holland, D., Desikan, R. S., Dale, A. M. & McEvoy, L. K., Alzheimer’s Disease Neuroimaging Initiative. Higher rates of decline for women and apolipoprotein E epsilon4 carriers. AJNR. Am. J. Neuroradiol. 34, 2287–2293 (2013).

32. Lin, K. A. et al. Marked gender differences in progression of mild cognitive impairment over 8 years. Alzheimers Dement. 1, 103–110 (2015). This article provides strong evidence from the ADNI cohort of faster cognitive decline in women with MCI than in men with MCI.

33. Tifratene, K., Robert, P., Metelkina, A., Pradier, C. & Dartigues, J. F. Progression of mild cognitive impairment to dementia due to AD in clinical settings. Neurology 85, 331–338 (2015).

34. Pradier, C. et al. The mini mental state examination at the time of Alzheimer’s disease and related disorders diagnosis, according to age, education, gender and place of residence: a cross-sectional study among the French National Alzheimer database. PLoS ONE 9, e103630 (2014).

35. Leening, M. J. et al. Sex differences in lifetime risk and first manifestation of cardiovascular disease: prospective population based cohort study. BMJ 349, g5992 (2014).

36. Karoglu, E. T. et al. Aging alters the molecular dynamics of synapses in a sexually dimorphic pattern in zebrafish (Danio rerio). Neurobiol. Aging 54, 10–21 (2017).

37. Counts, S. E. et al. Cerebrospinal fluid proNGF: a putative biomarker for early Alzheimer’s disease. Curr. Alzheimer Res. 13, 800–808 (2016).

38. Walker, K. A. et al. Midlife systemic inflammatory markers are associated with late-life brain volume: the ARIC study. Neurology 89, 2262–2270 (2017).

39. Schwarz, J. M., Sholar, P. W. & Bilbo, S. D. Sex differences in microglial colonization of the developing rat brain. J. Neurochem. 120, 948–963 (2012).

40. Lenz, K. M., Nugent, B. M., Haliyur, R. & McCarthy, M. M. Microglia are essential to masculinization of brain and behavior. J. Neurosci. 33, 2761–2772 (2013).

41. Villa, A. et al. Sex-specific features of microglia from adult mice. Cell Rep. 23, 3501–3511 (2018).

42. Ott, B. R., Tate, C. A., Gordon, N. M. & Heindel, W. C. Gender differences in the behavioral manifestations of Alzheimer’s disease. J. Am. Geriatr. Soc. 44, 583–587 (1996).

43. Mega, M. S., Cummings, J. L., Fiorello, T. & Gornbein, J. The spectrum of behavioral changes in Alzheimer’s disease. Neurology 46, 130–135 (1996).

44. Ott, B. R., Lapane, K. L. & Gambassi, G. Gender differences in the treatment of behavior problems in Alzheimer’s disease. SAGE Study Group. System. Assess. Geriatr. Drug Epidemiol. Neurol. 54, 427–432 (2000).

45. Kitamura, T., Kitamura, M., Hino, S., Tanaka, N. & Kurata, K. Gender differences in clinical manifestations and outcomes among hospitalized patients with behavioral and psychological symptoms of dementia. J. Clin. Psychiatry 73, 1548–1554 (2012).

46. Teri, L., Borson, S., Kiyak, H. A. & Yamagishi, M. Behavioral disturbance, cognitive dysfunction, and functional skill. Prevalence and relationship in Alzheimer’s disease. J. Am. Geriatr. Soc. 37, 109–116 (1989).

47. Karttunen, K. et al. Neuropsychiatric symptoms and quality of life in patients with very mild and mild Alzheimer’s disease. Int. J. Geriatr. Psychiatry 26, 473–482 (2011).

48. Spalletta, G. et al. Neuropsychiatric symptoms and syndromes in a large cohort of newly diagnosed, untreated patients with Alzheimer disease. Am. J. Geriatr. Psychiatry 18, 1026–1035 (2010).

49. Hollingworth, P. et al. Four components describe behavioral symptoms in 1,120 individuals with late-onset Alzheimer’s disease. J. Am. Geriatr. Soc. 54, 1348–1354 (2006). This paper presents the largest study available documenting sex differences in psychiatric symptoms of AD.

50. Sinforiani, E. et al. Impact of gender differences on the outcome of Alzheimer’s disease. Dement. Geriatr. Cogn. Disord. 30, 147–154 (2010).

51. Jack, C. R. Jr. et al. Age-specific and sex-specific prevalence of cerebral beta-amyloidosis, tauopathy, and neurodegeneration in cognitively unimpaired individuals aged 50–95 years: a cross-sectional study. Lancet Neurol. 16, 435–444 (2017). This landmark study documents sex differences in AD biomarkers across the lifespan.

52. Scheinin, N. M. et al. Cortical (1)(1)C-PIB uptake is associated with age, APOE genotype, and gender in “healthy aging”. J. Alzheimers Dis. 41, 193–202 (2014).

53. Cavedo, E. et al. Sex differences in functional and molecular neuroimaging biomarkers of Alzheimer’s disease in a mono-center cohort of cognitively normal older adults with subjective memory complaints. Alzheimers Dement. (in the press).

54. Gottesman, R. F. et al. The ARIC-PET amyloid imaging study: brain amyloid differences by age, race, sex, and APOE. Neurology 87, 473–480 (2016).

55. Vemuri, P. et al. Evaluation of amyloid protective factors and Alzheimer disease neurodegeneration protective factors in elderly individuals. JAMA Neurol. 74, 718–726 (2017).

56. Barnes, L. L. et al. Sex differences in the clinical manifestations of Alzheimer disease pathology. Arch. Gen. Psychiatry 62, 685–691 (2005). This landmark study examines for the first time sex differences in the clinical manifestation resulting from the accumulation of amyloid plaques and tangles in the brain.

57. Shinohara, M. et al. Impact of sex and APOE4 on cerebral amyloid angiopathy in Alzheimer’s disease. Acta Neuropathol. 132, 225–234 (2016).

58. Mattsson, N. et al. Clinical validity of cerebrospinal fluid Abeta42, tau, and phospho-tau as biomarkers for Alzheimer’s disease in the context of a structured 5-phase development framework. Neurobiol. Aging 52, 196–213 (2017).

59. Jansen, W. J. et al. Prevalence of cerebral amyloid pathology in persons without dementia: a meta-nalysis. JAMA 313, 1924–1938 (2015).

60. Salehi, A., Gonzalez Martinez, V. & Swaab, D. F. A sex difference and no effect of ApoE type on the amount of cytoskeletal alterations in the nucleus basalis of Meynert in Alzheimer’s disease. Neurobiol. Aging 19, 505–510 (1998).

61. Johnson, K. A. et al. Tau positron emission tomographic imaging in aging and early Alzheimer disease. Ann. Neurol. 79, 110–119 (2016).

62. Apostolova, L. G. et al. 3D comparison of hippocampal atrophy in amnestic mild cognitive impairment and Alzheimer’s disease. Brain 129, 2867–2873 (2006).

63. Perlaki, G. et al. Are there any gender differences in the hippocampus volume after head-size correction? A volumetric and voxel-based morphometric study. Neurosci. Lett. 570, 119–123 (2014).

64. Skup, M. et al. Sex differences in grey matter atrophy patterns among AD and aMCI patients: results from ADNI. Neuroimage 56, 890–906 (2011).

65. Hua, X. et al. Sex and age differences in atrophic rates: an ADNI study with n = 1368 MRI scans. Neurobiol. Aging 31, 1463–1480 (2010). This landmark paper shows the faster atrophic rate in women enrolled in the ADNI cohort.

66. Ardekani, B. A., Convit, A. & Bachman, A. H. Analysis of the MIRIAD data shows sex differences in hippocampal atrophy progression. J. Alzheimers Dis. 50, 847–857 (2016).

67. Koran, M. E., Wagener, M. & Hohman, T. J., Alzheimer’s Neuroimaging Initiative. Sex differences in the association between AD biomarkers and cognitive decline. Brain Imaging Behav. 11, 205–213 (2016).

68. Karch, A. et al. Stratification by genetic and demographic characteristics improves diagnostic accuracy of cerebrospinal fluid biomarkers in rapidly progressive dementia. J. Alzheimers Dis. 54, 1385–1393 (2016).

69. Madsen, T. E. et al. Sex-specific stroke incidence over time in the Greater Cincinnati/Northern Kentucky Stroke Study. Neurology 89, 990–996 (2017).

70. Gibson, C. L. Cerebral ischemic stroke: is gender important? J. Cereb. Blood Flow Metab. 33, 1355–1361 (2013).

71. Longstreth, W. T. Jr. et al. Associations between microinfarcts and other macroscopic vascular findings on neuropathologic examination in 2 databases. Alzheimer Dis. Assoc. Disord. 23, 291–294 (2009).

72. National Institute of Mental Health. Major depression. NIMH https://www.nimh.nih.gov/health/statistics/major-depression.shtml (2015).

73. Mallampalli, M. P. & Carter, C. L. Exploring sex and gender differences in sleep health: a Society for Women’s Health Research Report. J. Womens Health (Larchmt) 23, 553–562 (2014).

74. 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 278, 1349–1356 (1997).

75. Altmann, A., Tian, L., Henderson, V. W. & Greicius, M. D., Alzheimer’s Disease Neuroimaging Initiative Investigators. Sex modifies the APOE-related risk of developing Alzheimer disease. Ann. Neurol. 75, 563–573 (2014).

76. Kim, S. et al. Gender differences in risk factors for transition from mild cognitive impairment to Alzheimer’s disease: a CREDOS study. Compr. Psychiatry 62, 114–122 (2015).

77. Neu, S. C. et al. Apolipoprotein E genotype and sex risk factors for Alzheimer disease: a meta-analysis. JAMA Neurol. 74, 1178–1189 (2017). This highly powered meta-analysis refines our understanding of sex–APOE interactions in AD risk.

78. Mosconi, L. et al. Perimenopause and emergence of an Alzheimer’s bioenergetic phenotype in brain and periphery. PLoS ONE 12, e0185926 (2017).

79. Ungar, L., Altmann, A. & Greicius, M. D. Apolipoprotein E, gender, and Alzheimer’s disease: an overlooked, but potent and promising interaction. Brain Imaging Behav. 8, 262–273 (2014).

80. 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. 32, 8254–8262 (2012).

81. Heise, V. et al. Apolipoprotein E genotype, gender and age modulate connectivity of the hippocampus in healthy adults. Neuroimage 98, 23–30 (2014).

82. Sampedro, F. et al. APOE-by-sex interactions on brain structure and metabolism in healthy elderly controls. Oncotarget 6, 26663–26674 (2015).

83. Buckley, R. F. et al. Sex, amyloid, and APOE ε4 and risk of cognitive decline in preclinical Alzheimer’s disease: findings from three well-characterized cohorts. Alzheimers Dement. https://doi.org/10.1016/j.jalz.2018.04.010 (2018).

84. Hohman, T. J. et al. Sex-specific association of Apolipoprotein E with cerebrospinal fluid levels of tau. JAMA Neurol. https://doi.org/10.1001/jamaneurol.2018.0821 (2018).

85. Snowdon, D. A. et al. Brain infarction and the clinical expression of Alzheimer disease. The Nun Study. JAMA 277, 813–817 (1997).

86. Vemuri, P. et al. Vascular and amyloid pathologies are independent predictors of cognitive decline in normal elderly. Brain 138, 761–771 (2015).

87. Roberts, R. O. et al. Association of diabetes with amnestic and nonamnestic mild cognitive impairment. Alzheimers Dement. 10, 18–26 (2014).

88. Gilsanz, P. et al. Female sex, early-onset hypertension, and risk of dementia. Neurology 89, 1886–1893 (2017).

89. Lorius, N. et al. Vascular disease and risk factors are associated with cognitive decline in the alzheimer disease spectrum. Alzheimer Dis. Assoc. Disord. 29, 18–25 (2015).

90. Li, J. et al. Vascular risk factors promote conversion from mild cognitive impairment to Alzheimer disease. Neurology 76, 1485–1491 (2011).

91. Sachdev, P. S. et al. Risk profiles for mild cognitive impairment vary by age and sex: the Sydney Memory and Ageing study. Am. J. Geriatr. Psychiatry 20, 854–865 (2012).

92. Sundermann, E. E., Katz, M. J. & Lipton, R. B. Sex differences in the relationship between depressive symptoms and risk of amnestic mild cognitive impairment. Am. J. Geriatr. Psychiatry 25, 13–22 (2017).

93. Pankratz, V. S. et al. Predicting the risk of mild cognitive impairment in the Mayo Clinic Study of Aging. Neurology 84, 1433–1442 (2015). This landmark paper specifically examines sex differences in MCI risk.

94. Artero, S. et al. Risk profiles for mild cognitive impairment and progression to dementia are gender specific. J. Neurol. Neurosurg. Psychiatry 79, 979–984 (2008).

95. Hayden, K. M. et al. Vascular risk factors for incident Alzheimer disease and vascular dementia: the Cache County study. Alzheimer Dis. Assoc. Disord. 20, 93–100 (2006).

96. Chene, G. et al. Gender and incidence of dementia in the Framingham Heart Study from mid-adult life. Alzheimers Dement. 11, 310–320 (2015).

97. Brown, M. C. et al. Cardiovascular disease risk in women with pre-eclampsia: systematic review and meta-analysis. Eur. J. Epidemiol. 28, 1–19 (2013).

98. Fields, J. A. et al. Preeclampsia and cognitive impairment later in life. Am J Obstet. Gynecol 217, 74.e1–74.e11 (2017).

99. Buhimschi, I. A. et al. Protein misfolding, congophilia, oligomerization, and defective amyloid processing in preeclampsia. Sci. Transl Med. 6, 245ra292 (2014).

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

101. Bove, R. et al. Age at surgical menopause influences cognitive decline and Alzheimer pathology in older women. Neurology 82, 222–229 (2014).

102. Norton, S., Matthews, F. E., Barnes, D. E., Yaffe, K. & Brayne, C. Potential for primary prevention of Alzheimer’s disease: an analysis of population-based data. Lancet Neurol. 13, 788–794 (2014).

103. American Association of University Women. The simple truth about the gender pay gap. AAUW https://www.aauw.org/aauw_check/pdf_download/show_pdf.php?file=The-Simple-Truth (2018).

104. Brown, J. E., Rhee, A., Saad-Lessler, J. & Oakley, D. Shortchanged in retirement, the continuing challenges to women’s financial future. National Institute on Retirement Security https://www.nirsonline.org/wp-content/uploads/2017/06/final_shortchanged_retirement_report_2016.pdf (2016).

105. Prince, M. et al. Dementia incidence and mortality in middle-income countries, and associations with indicators of cognitive reserve: a 10/66 Dementia Research Group population-based cohort study. Lancet 380, 50–58 (2012).

106. Swinkels, J., Tilburg, T. V., Verbakel, E. & Broese van Groenou, M. Explaining the gender gap in the caregiving burden of partner caregivers. J. Gerontol. B Psychol. Sci. Soc. Sci. https://doi.org/10.1093/geronb/gbx036 (2017).

107. Alzheimer’s Association. 2014 Alzheimer’s disease facts and figures. Alzheimers Dement. 10, e47–e92 (2014).

108. Sharma, N., Chakrabarti, S. & Grover, S. Gender differences in caregiving among family — caregivers of people with mental illnesses. World J. Psychiatry 6, 7–17 (2016).

109. Stahl, S. T., Beach, S. R., Musa, D. & Schulz, R. Living alone and depression: the modifying role of the perceived neighborhood environment. Aging Ment. Health 21, 1065–1071 (2017).

110. Doody, R. S. et al. A phase 3 trial of semagacestat for treatment of Alzheimer’s disease. N. Engl. J. Med. 369, 341–350 (2013).

111. Egan, M. F. et al. Randomized trial of verubecestat for mild-to-moderate Alzheimer’s disease. N. Engl. J. Med. 378, 1691–1703 (2018).

112. Doody, R. S. et al. Phase 3 trials of solanezumab for mild-to-moderate Alzheimer’s disease. N. Engl. J. Med. 370, 311–321 (2014).

113. Salloway, S. et al. Two phase 3 trials of bapineuzumab in mild-to-moderate Alzheimer’s disease. N. Engl. J. Med. 370, 322–333 (2014).

114. Religa, D. et al. Dementia diagnosis differs in men and women and depends on age and dementia severity: data from SveDem, the Swedish Dementia Quality Registry. Dement. Geriatr. Cogn. Disord. 33, 90–95 (2012).

115. Ferris, S. et al. Effects of gender on response to treatment with rivastigmine in mild cognitive impairment: a post hoc statistical modeling approach. Gend. Med. 6, 345–355 (2009).

116. MacGowan, S. H., Wilcock, G. K. & Scott, M. Effect of gender and apolipoprotein E genotype on response to anticholinesterase therapy in Alzheimer’s disease. Int. J. Geriatr. Psychiatry 13, 625–630 (1998).

117. Canevelli, M. et al. Sex and gender differences in the treatment of Alzheimer’s disease: a systematic review of randomized controlled trials. Pharmacol. Res. 115, 218–223 (2017). This systematic review of randomized, double-blind trials with cholinesterase inhibitors and memantine reveals that only 4% of studies examined sex effects in their data sets.

118. Haywood, W. M. & Mukaetova-Ladinska, E. B. Sex influences on cholinesterase inhibitor treatment in elderly individuals with Alzheimer’s disease. Am. J. Geriatr. Pharmacother. 4, 273–286 (2006).

119. Davis, M. L. & Barrett, A. M. Selective benefit of donepezil on oral naming in Alzheimer’s disease in men compared to women. CNS Spectr. 14, 175–176 (2009).

120. Buccafusco, J. J., Jackson, W. J., Stone, J. D. & Terry, A. V. Sex dimorphisms in the cognitive-enhancing action of the Alzheimer’s drug donepezil in aged Rhesus monkeys. Neuropharmacology 44, 381–389 (2003).

121. Scacchi, R., Gambina, G., Broggio, E. & Corbo, R. M. Sex and ESR1 genotype may influence the response to treatment with donepezil and rivastigmine in patients with Alzheimer’s disease. Int. J. Geriatr. Psychiatry 29, 610–615 (2014).

122. Wattmo, C., Londos, E. & Minthon, L. Risk factors that affect life expectancy in Alzheimer’s disease: a 15-year follow-up. Dement. Geriatr. Cogn. Disord. 38, 286–299 (2014).

123. Rhodes, M. E. & Rubin, R. T. Functional sex differences (‘sexual diergism’) of central nervous system cholinergic systems, vasopressin, and hypothalamic-pituitary-adrenal axis activity in mammals: a selective review. Brain Res. Brain Res. Rev. 30, 135–152 (1999).

124. Counts, S. E., Che, S., Ginsberg, S. D. & Mufson, E. J. Gender differences in neurotrophin and glutamate receptor expression in cholinergic nucleus basalis neurons during the progression of Alzheimer’s disease. J. Chem. Neuroanat. 42, 111–117 (2011).

125. Wang, R. H., Bejar, C. & Weinstock, M. Gender differences in the effect of rivastigmine on brain cholinesterase activity and cognitive function in rats. Neuropharmacology 39, 497–506 (2000).

126. Smith, C. D., Wright, L. K., Garcia, G. E., Lee, R. B. & Lumley, L. A. Hormone-dependence of sarin lethality in rats: sex differences and stage of the estrous cycle. Toxicol. Appl. Pharmacol. 287, 253–257 (2015).

127. Venerosi, A., Ricceri, L., Tait, S. & Calamandrei, G. Sex dimorphic behaviors as markers of neuroendocrine disruption by environmental chemicals: the case of chlorpyrifos. Neurotoxicology 33, 1420–1426 (2012).

128. Alves-Amaral, G., Pires-Oliveira, M., Andrade-Lopes, A. L., Chiavegatti, T. & Godinho, R. O. Gender-related differences in circadian rhythm of rat plasma acetyl- and butyrylcholinesterase: effects of sex hormone withdrawal. Chem. Biol. Interact. 186, 9–15 (2010).

129. Mehta, N. et al. Systematic review of sex-specific reporting of data: cholinesterase inhibitor example. J. Am. Geriatr. Soc. 65, 2213–2219 (2017).

130. Hampel, H. et al. The cholinergic system in the pathophysiology and treatment of Alzheimer’s disease. Brain 141, 1917–1933 (2018).

131. Ezio, G. & Giancarlo P. Sex and gender differences in the brain cholinergic system and in the response to therapy of Alzheimer disease with cholinesterase inhibitors. Curr. Alzheimer Res. https://doi.org/10.2174/1567205015666180613111504 (2018).

132. Moga, D. C. et al. A comparison of sex differences in psychotropic medication use in older people with Alzheimer’s disease in the US and Finland. Drugs Aging 34, 55–65 (2017).

133. Cooper, C. et al. Inequalities in receipt of mental and physical healthcare in people with dementia in the UK. Age Ageing 46, 393–400 (2017).

134. Cojutti, P., Arnoldo, L., Cattani, G., Brusaferro, S. & Pea, F. Polytherapy and the risk of potentially inappropriate prescriptions (PIPs) among elderly and very elderly patients in three different settings (hospital, community, long-term care facilities) of the Friuli Venezia Giulia region, Italy: are the very elderly at higher risk of PIPs? Pharmacoepidemiol. Drug Saf. 25, (1070–1078 (2016).

135. Henley, D. B., May, P. C., Dean, R. A. & Siemers, E. R. Development of semagacestat (LY450139), a functional gamma-secretase inhibitor, for the treatment of Alzheimer’s disease. Expert Opin. Pharmacother. 10, 1657–16642 (2009).

136. Farlow, M. et al. Safety and biomarker effects of solanezumab in patients with Alzheimer’s disease. Alzheimers Dement. 8, 261–271 (2012).

137. Legato, M. J., Johnson, P. A. & Manson, J. E. Consideration of sex differences in medicine to improve health care and patient outcomes. JAMA 316, 1865–1866 (2016).

138. Berger, J. S. et al. Aspirin for the primary prevention of cardiovascular events in women and men: a sex-specific meta-analysis of randomized controlled trials. JAMA 295, 306–313 (2006).

139. Claxton, A. et al. Sex and ApoE genotype differences in treatment response to two doses of intranasal insulin in adults with mild cognitive impairment or Alzheimer’s disease. J. Alzheimers Dis. 35, 789–797 (2013).

140. Ngandu, T. et al. A 2 year multidomain intervention of diet, exercise, cognitive training, and vascular risk monitoring versus control to prevent cognitive decline in at-risk elderly people (FINGER): a randomised controlled trial. Lancet 385, 2255–2263 (2015).

141. Andrieu, S. et al. Effect of long-term omega 3 polyunsaturated fatty acid supplementation with or without multidomain intervention on cognitive function in elderly adults with memory complaints (MAPT): a randomised, placebo-controlled trial. Lancet Neurol. 16, 377–389 (2017).

142. Farlow, M. R. et al. Treatment outcome of tacrine therapy depends on apolipoprotein genotype and gender of the subjects with Alzheimer’s disease. Neurology 50, 669–677 (1998). This landmark paper suggested for the first time a sex–genotype interaction in the effect of tacrine.

143. Depypere, H., Vierin, A., Weyers, S. & Sieben, A. Alzheimer’s disease, apolipoprotein E and hormone replacement therapy. Maturitas 94, 98–105 (2016). This comprehensive review summarizes the current understanding of HRT and the future challenges.

144. Burkhardt, M. S. et al. Oestrogen replacement therapy may improve memory functioning in the absence of APOE epsilon4. J. Alzheimers Dis. 6, 221–228 (2004).

145. Yaffe, K., Haan, M., Byers, A., Tangen, C. & Kuller, L. Estrogen use, APOE, and cognitive decline: evidence of gene-environment interaction. Neurology 54, 1949–1954 (2000).

146. Ryan, J. et al. Characteristics of hormone therapy, cognitive function, and dementia: the prospective 3C Study. Neurology 73, 1729–1737 (2009).

147. Kang, J. H. & Grodstein, F. Postmenopausal hormone therapy, timing of initiation, APOE and cognitive decline. Neurobiol. Aging 33, 1129–1137 (2012).

148. Zandi, P. P. et al. Hormone replacement therapy and incidence of Alzheimer disease in older women: the Cache County Study. JAMA 288, 2123–2129 (2002).

149. Gleason, C. E. et al. Effects of hormone therapy on cognition and mood in recently postmenopausal women: findings from the randomized, controlled KEEPS-Cognitive and Affective Study. PLoS Med. 12, e1001833 (2015).

150. Lista, S. et al. Application of systems theory in longitudinal studies on the origin and progression of Alzheimer’s disease. Methods Mol. Biol. 1303, 49–67 (2016).

151. Kosik, K. S. Personalized medicine for effective Alzheimer disease treatment. JAMA Neurol. 72, 497–498 (2015).

152. Hampel, H. et al. A precision medicine initiative for Alzheimer’s disease: the road ahead to biomarker-guided integrative disease modeling. Climacteric 20, 107–118 (2017). This landmark paper describes the inception of the APMI.

153. Hampel, H. et al. PRECISION MEDICINE — the golden gate for detection, treatment and prevention of Alzheimer’s disease. J. Prev. Alzheimers Dis. 3, 243–259 (2016).

154. Hebert, L. E., Weuve, J., Scherr, P. A. & Evans, D. A. Alzheimer disease in the United States (2010–2050) estimated using the 2010 census. Neurology 80, 1778–1783 (2013).

155. Katz, M. J. et al. Age-specific and sex-specific prevalence and incidence of mild cognitive impairment, dementia, and Alzheimer dementia in blacks and whites: a report from the Einstein Aging Study. Alzheimer Dis. Assoc. Disord. 26, 335–343 (2012).

156. Roberts, R. O. et al. The incidence of MCI differs by subtype and is higher in men: the Mayo Clinic Study of Aging. Neurology 78, 342–351 (2012).

157. Lin, K. A. & Doraiswamy, P. M. When Mars versus Venus is not a cliche: gender differences in the neurobiology of Alzheimer’s disease. Front. Neurol. 5, 288 (2014).

158. Dubois, B. et al. Advancing research diagnostic criteria for Alzheimer’s disease: the IWG-2 criteria. Lancet Neurol. 13, 614–629 (2014).

159. Lyketsos, C. G. et al. Prevalence of neuropsychiatric symptoms in dementia and mild cognitive impairment: results from the cardiovascular health study. JAMA 288, 1475–1483 (2002).

160. Steinberg, M. et al. Vascular risk factors and neuropsychiatric symptoms in Alzheimer’s disease: the Cache County Study. Int. J. Geriatr. Psychiatry 29, 153–159 (2014).

161. Petersen, R. C. Mild cognitive impairment as a diagnostic entity. J. Intern. Med. 256, 183–194 (2004).

162. Wang, L. et al. Evaluation of tau imaging in staging Alzheimer disease and revealing interactions between beta-amyloid and tauopathy. JAMA Neurol. 73, 1070–1077 (2016).

163. US Department of Health and Human Services, Food and Drug Administration, Center for Drug Evaluation and Research & Center for Biologics Evaluation and Research. Early Alzheimer’s disease: developing drugs for treatment. Guidance for industry. Draft guidance. FDA https://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/UCM596728.pdf (2018).

164. European Medicines Agency. Guideline on the clinical investigation of medicines for the treatment of Alzheimer’s disease. EMA http://www.ema.europa.eu/docs/en_GB/document_library/Scientific_guideline/2018/02/WC500244609.pdf (2018).

165. Standford University. Gendered innovations terminology. Gendered Innovations http://genderedinnovations.stanford.edu/terms.html (2018).

166. Jary, D. & Jary, A. Collins Dictionary of Sociology 3rd edn. (Collins, Glasgow, 2005).

167. World Health Organization. Gender. WHO http://www.who.int/en/news-room/fact-sheets/detail/gender (2015).

168. Dubal, D. B., Broestl, L. & Worden, K. Sex and gonadal hormones in mouse models of Alzheimer’s disease: what is relevant to the human condition? Biol. Sex. Differ. 3, 24 (2012). This paper is a comprehensive overview of sex differences in the most widely used transgenic models of AD-like amyloidosis.

169. Middeldorp, J. et al. Preclinical assessment of young blood plasma for Alzheimer disease. JAMA Neurol. 73, 1325–1333 (2016).

170. LaClair, K. D. et al. Treatment with bexarotene, a compound that increases apolipoprotein-E, provides no cognitive benefit in mutant APP/PS1 mice. Mol. Neurodegener. 8, 18 (2013).

171. Melnikova, T. et al. Sex-related dimorphism in dentate gyrus atrophy and behavioral phenotypes in an inducible tTa:APPsi transgenic model of Alzheimer’s disease. Neurobiol. Dis. 96, 171–185 (2016).

172. Granger, M. W. et al. A TgCRND8 mouse model of Alzheimer’s disease exhibits sexual dimorphisms in behavioral indices of cognitive reserve. J. Alzheimers Dis. 51, 757–773 (2016).

173. Lewis, J. et al. Enhanced neurofibrillary degeneration in transgenic mice expressing mutant tau and APP. Science 293, 1487–1491 (2001).

174. Oikawa, N., Ogino, K., Masumoto, T., Yamaguchi, H. & Yanagisawa, K. Gender effect on the accumulation of hyperphosphorylated tau in the brain of locus-ceruleus-injured APP-transgenic mouse. Neurosci. Lett. 468, 243–247 (2010).

175. Dumont, M. et al. Behavioral deficit, oxidative stress, and mitochondrial dysfunction precede tau pathology in P301S transgenic mice. FASEB J. 25, 4063–4072 (2011).

176. Yue, M., Hanna, A., Wilson, J., Roder, H. & Janus, C. Sex difference in pathology and memory decline in rTg4510 mouse model of tauopathy. Neurobiol. Aging 32, 590–603 (2011).

177. Bour, A. et al. Middle-aged human apoE4 targeted-replacement mice show retention deficits on a wide range of spatial memory tasks. Behav. Brain Res. 193, 174–182 (2008).

178. Reverte, I., Klein, A. B., Ratner, C., Domingo, J. L. & Colomina, M. T. Behavioral phenotype and BDNF differences related to apoE isoforms and sex in young transgenic mice. Exp. Neurol. 237, 116–125 (2012).

179. Rijpma, A. et al. Sex differences in presynaptic density and neurogenesis in middle-aged ApoE4 and ApoE knockout mice. J. Neurodegener Dis. 2013, 531326 (2013).

180. Cacciottolo, M. et al. The APOE4 allele shows opposite sex bias in microbleeds and Alzheimer’s disease of humans and mice. Neurobiol. Aging 37, 47–57 (2016).

181. Hampel, H. et al. Revolution of Alzheimer precision neurology. Passageway of systems biology and neurophysiology. J. Alzheimers Dis. 64, S47–S105 (2018).