Alzheimer's disease (AD) is characterized by high heterogeneity in disease manifestation, progression and risk factors. High phenotypic variability is currently regarded as one of the largest hurdles in early diagnosis and in the design of clinical trials; there is therefore great interest in identifying factors driving variability that can be used for patient stratification. In addition to genetic and lifestyle factors, the individual's sex and gender are emerging as crucial drivers of phenotypic variability. Evidence exists on sex and gender differences in the rate of cognitive deterioration and brain atrophy, and in the effect of risk factors as well as in the patterns of diagnostic biomarkers. Such evidence might be of high relevance and requires attention in clinical practice and clinical trials. However, sex and gender differences are currently seldom appreciated; importantly, consideration of sex and gender differences is not currently a focus in the design and analysis of clinical trials for AD. The objective of this position paper is (i) to provide an overview of known sex and gender differences that might have implications for clinical practice, (ii) to identify the most important knowledge gaps in the field (with a special regard to clinical trials) and (iii) to provide conclusions for future studies. This scientific statement is endorsed by the European Academy of Neurology.

College of Fundamental Medicine Shanghai University of Medicine and Health Sciences Shanghai China

Department of Geriatric Psychiatry University Hospital of Psychiatry Zurich Zurich Switzerland

Department of Neurobiology Care Sciences and Society Karolinska Institutet Stockholm Sweden

Department of Neurogeriatrics University Clinic of Neurology Medical University Graz Graz Austria

Division of Internal Medicine University Hospital of Basel Basel Switzerland

Global Medical and Scientific Affairs Roche Diagnostics International Ltd Rotkreuz Switzerland

Institute for Regenerative Medicine IREM University of Zurich Zurich Switzerland

International Clinical Research Center St Anne's University Hospital Brno Brno Czech Republic

Italian Medicines Agency Rome Italy

Memory Clinic Department of Neurology 2nd Faculty of Medicine Charles University and Motol University Hospital Prague Czech Republic

Neurology Clinic Medical University Innsbruck Innsbruck Austria

Neurology Private Practice Lucca Italy

Women's Brain Project Guntershausen Switzerland

See more in PubMed

Food and Drug Administration. Alzheimer’s Disease: Developing Drugs for Treatment Guidance for Industry. 2018. https://www.fda.gov/regulatory-information/search-fda-guidance-documents/alzheimers-disease-developing-drugs-treatment-guidance-industy (accessed 05/05/2019)

European Medicines Agency. Guideline on the Clinical Investigation of Medicines for the Treatment of Alzheimer’s Disease. 2018. https://www.ema.europa.eu/en/documents/scientific-guideline/guideline-clinical-investigation-medicines-treatment-alzheimers-disease-revision-2_en.pdf (accessed 05/05/2019)

Dodge HH, Zhu J, Harvey D, et al. Biomarker progressions explain higher variability in stage-specific cognitive decline than baseline values in Alzheimer disease. Alzheimer’s Dementia 2014; 10: 690-703.

Mehta LS, Beckie TM, DeVon HA, et al. Acute myocardial infarction in women: a scientific statement from the American Heart Association. Circulation 2016; 133: 916-947.

Riecher-Rossler A. Sex and gender differences in mental disorders. Lancet Psychiatr 2017; 4: 8-9.

Vetvik KG, MacGregor EA. Sex differences in the epidemiology, clinical features, and pathophysiology of migraine. Lancet Neurol 2017; 16: 76-87.

Szewczyk-Krolikowski K, Tomlinson P, Nithi 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 2014; 20: 99-105.

Gibson CL. Cerebral ischemic stroke: is gender important? J Cereb Blood Flow Metab 2013; 33: 1355-1361.

Legato MJ, Johnson PA, Manson JE. Consideration of sex differences in medicine to improve health care and patient outcomes. JAMA 2016; 316: 1865-1866.

Conforti F, Pala L, Bagnardi V, et al. Cancer immunotherapy efficacy and patients’ sex: a systematic review and meta-analysis. Lancet Oncol 2018; 19: 737-746.

Irvine K, Laws KR, Gale TM, Kondel TK. Greater cognitive deterioration in women than men with Alzheimer’s disease: a meta analysis. J Clin Exp Neuropsychol 2012; 34: 989-998.

Lin KA, Choudhury KR, Rathakrishnan BG, Marks DM, Petrella JR, Doraiswamy PM. Marked gender differences in progression of mild cognitive impairment over 8 years. Alzheimer’s Dementia 2015; 1: 103-110.

Hua X, Hibar DP, Lee S, et al. Sex and age differences in atrophic rates: An ADNI study with n=1368 MRI scans. Neurobiol Aging 2010; 31: 1463-1480.

Altmann A, Tian L, Henderson VW, Greicius MD. Sex modifies the APOE-related risk of developing Alzheimer disease. Ann Neurol 2014; 75: 563-573.

Depypere H, Vierin A, Weyers S, Sieben A. Alzheimer’s disease, apolipoprotein E and hormone replacement therapy. Maturitas 2016; 94: 98-105.

Scacchi R, Gambina G, Broggio E, Corbo RM. Sex and ESR1 genotype may influence the response to treatment with donepezil and rivastigmine in patients with Alzheimer’s disease. Int J Geriatr Psychiatry 2014; 29: 610-615.

Ferretti MT, Iulita MF, Cavedo E, et al. Sex differences in Alzheimer disease - the gateway to precision medicine. Nat Rev Neurol 2018; 14: 457-469.

Norton S, Matthews FE, Barnes DE, Yaffe K, Brayne C. Potential for primary prevention of Alzheimer’s disease: an analysis of population-based data. Lancet Neurol 2014; 13: 788-794.

Chene G, Beiser A, Au R, et al. Gender and incidence of dementia in the Framingham Heart Study from mid-adult life. Alzheimer’s Dementia 2015; 11: 310-320.

Kivipelto M, Ngandu T, Laatikainen T, Winblad B, Soininen H, Tuomilehto J. Risk score for the prediction of dementia risk in 20 years among middle aged people: a longitudinal, population-based study. Lancet Neurol 2006; 5: 735-741.

Roberts RO, Knopman DS, Geda YE, et al. Association of diabetes with amnestic and nonamnestic mild cognitive impairment. Alzheimer’s Dementia 2014; 10: 18-26.

Pankratz VS, Roberts RO, Mielke MM, et al. Predicting the risk of mild cognitive impairment in the Mayo Clinic Study of Aging. Neurology 2015; 84: 1433-1442.

Hartley A, Marshall DC, Salciccioli JD, Sikkel MB, Maruthappu M, Shalhoub J. Trends in mortality from ischemic heart disease and cerebrovascular disease in Europe: 1980 to 2009. Circulation 2016; 133: 1916-1926.

Farrer LA, Cupples LA, Haines JL, 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: 1349-1356.

Neu SC, Pa J, Kukull W, et al. Apolipoprotein E genotype and sex risk factors for Alzheimer disease: a meta-analysis. JAMA Neurol 2017; 74: 1178-1189.

Hohman TJ, Dumitrescu L, Barnes LL, et al. Sex-specific association of apolipoprotein E with cerebrospinal fluid levels of tau. JAMA Neurol 2018; 75: 989-998.

Nyarko JNK, Quartey MO, Pennington PR, et al. Profiles of β-amyloid peptides and key secretases in brain autopsy samples differ with sex and APOE ε4 status: impact for risk and progression of Alzheimer disease. Neuroscience 2018; 373: 20-36.

World Health Organization. World Health Statistics Overview. Geneva: World Health Organization, 2019.

Luy M, Flandorfer P, Di Giulio P. Ageing in an aged society: experiences and attitudes of Catholic order members towards population ageing and older people. Age Soc 2015; 35: 1-36.

Goyal MS, Blazey TM, Su Y, et al. Persistent metabolic youth in the aging female brain. Proc Natl Acad Sci USA 2019; 116: 3251-3255.

Biskup E, Quevenco FC, Ferretti MT, Santuccione-Chadha A. Sex differences in brain metabolic activity: beyond the concept of brain age. Proc Natl Acad Sci 2019; 116: 10630-10631.

Pirie K, Peto R, Reeves GK, Green J, Beral V. The 21st century hazards of smoking and benefits of stopping: a prospective study of one million women in the UK. Lancet 2013; 381: 133-141.

McCaul KA, Almeida OP, Hankey GJ, Jamrozik K, Byles JE, Flicker L. Alcohol use and mortality in older men and women. Addiction 2010; 105: 1391-1400.

Ramjee G, Daniels B. Women and HIV in Sub-Saharan Africa. AIDS Res Ther 2013; 10: 30.

Värnik P. Suicide in the world. Int J Env Res Public Health 2012; 9: 760-771.

Santamariña-Rubio E, Pérez K, Olabarria M, Novoa AM. Gender differences in road traffic injury rate using time travelled as a measure of exposure. Accid Anal Prev 2014; 65: 1-7.

Grimm A, Mensah-Nyagan AG, Eckert A. Alzheimer, mitochondria and gender. Neurosci Biobehav Rev 2016; 67: 89-101.

National Institute of Mental Health. Major Depression. 2015. https://www.nimh.nih.gov/health/statistics/major-depression.shtml (accessed 23/05/2019)

Makizako H, Shimada H, Doi T, et al. Comorbid mild cognitive impairment and depressive symptoms predict future dementia in community older adults: a 24-month follow-up longitudinal study. J Alzheimer’s Dis 2016; 54: 1473-1482.

Sundermann EE, Katz MJ, Lipton RB. Sex differences in the relationship between depressive symptoms and risk of amnestic mild cognitive impairment. Am J Geriatr Psychiatr 2017; 25: 13-22.

Polyakova M, Sonnabend N, Sander C, et al. Prevalence of minor depression in elderly persons with and without mild cognitive impairment: a systematic review. J Affect Disord 2014; 152-154: 28-38.

Lopez OL, Jagust WJ, Dulberg C, et al. Risk factors for mild cognitive impairment in the Cardiovascular Health Study Cognition Study: part 2. Arch Neurol 2003; 60: 1394-1399.

Grow A, Van Bavel J. Assortative mating and the reversal of gender inequality in education in Europe: an agent-based model. PLoS ONE 2015; 10: e0127806.

Rocca WA, Mielke MM, Vemuri P, Miller VM. Sex and gender differences in the causes of dementia: a narrative review. Maturitas 2014; 79: 196-201.

Schofer E, Meyer JW. The worldwide expansion of higher education in the twentieth century. Am Sociol Rev 2005; 70: 898-920.

Jang H, Bin Bae J, Dardiotis E, et al. Differential effects of completed and incomplete pregnancies on the risk of Alzheimer disease. Neurology 2018; 91: e643-e651.

Fox M, Berzuini C, Knapp LA, Glynn LM. Women’s pregnancy life history and Alzheimer’s risk: can immunoregulation explain the link? Am J Alzheimer’s Dis Other Dementias 2018; 33: 516-526.

Gilsanz P, Lee C, Corrada MM, Kawas CH, Quesenberry CP, Whitmer RA. Reproductive period and risk of dementia in a diverse cohort of health care members. Neurology 2019; 92: e2005-e2014.

Abheiden CNH, van Doornik R, Aukes AM, van der Flier WM, Scheltens P, de Groot CJM. Hypertensive disorders of pregnancy appear not to be associated with Alzheimer’s disease later in life. Dement Geriatr Cogni Dis Extra 2015; 5: 375-385.

Fields JA, Garovic VD, Mielke MM, et al. Preeclampsia and cognitive impairment later in life. Am J Obstet Gynecol 2017; 217: 74.e1-74.e11.

Wallis AB, Saftlas AF, Hsia J, Atrash HK. Secular trends in the rates of preeclampsia, eclampsia, and gestational hypertension, United States, 1987-2004. Am J Hypertens 2008; 21: 521-526.

Rocca WA, Bower JH, Maraganore DM, et al. Increased risk of cognitive impairment or dementia in women who underwent oophorectomy before menopause. Neurology 2007; 69: 1074-1083.

Rocca WA, Grossardt BR, Shuster LT, Stewart EA. Hysterectomy, oophorectomy, estrogen, and the risk of dementia. Neuro-degenerat Dis 2012; 10: 175-178.

Underwood EA, Jerzak KJ, Lebovic G, et al. Cognitive effects of adjuvant endocrine therapy in older women treated for early-stage breast cancer: a 1-year longitudinal study. Support Care Cancer 2019; 27: 3035-3043.

World Health Organization. Breast cancer. https://www.who.int/cancer/prevention/diagnosis-screening/breast-cancer/en/ (accessed 05/04/2019)

Kawas C, Resnick S, Morrison A, et al. A prospective study of estrogen replacement therapy and the risk of developing Alzheimer’s disease: the Baltimore Longitudinal Study of Aging. Neurology 1997; 48: 1517-1521.

Espeland MA, Rapp SR, Shumaker SA, et al. Conjugated equine estrogens and global cognitive function in postmenopausal women: Women’s Health Initiative Memory Study. JAMA 2004; 291: 2959-2968.

Shumaker SA, Legault C, Kuller L, et al. Conjugated equine estrogens and incidence of probable dementia and mild cognitive impairment in postmenopausal women: Women’s Health Initiative Memory Study. JAMA 2004; 291: 2947-2958.

Li R, Cui J, Shen Y. Brain sex matters: estrogen in cognition and Alzheimer’s disease. Mol Cell Endocrinol 2014; 389: 13-21.

Mosconi L, Berti V, Guyara-Quinn C, et al. Perimenopause and emergence of an Alzheimer’s bioenergetic phenotype in brain and periphery. PLoS ONE 2017; 12: e0185926.

Moffat SD, Zonderman AB, Metter EJ, et al. Free testosterone and risk for Alzheimer disease in older men. Neurology 2004; 62: 188-193.

Hogervorst E, Bandelow S, Combrinck M, Smith AD. Low free testosterone is an independent risk factor for Alzheimer’s disease. Exp Gerontol 2004; 39: 1633-1639.

Lv W, Du N, Liu Y, et al. Low testosterone level and risk of Alzheimer’s disease in the elderly men: a systematic review and meta-analysis. Mol Neurobiol 2016; 53: 2679-2684.

Gouras GK, Xu H, Gross RS, et al. Testosterone reduces neuronal secretion of Alzheimer’s β-amyloid peptides. Proc Natl Acad Sci USA 2000; 97: 1202-1205.

Pike CJ. Testosterone attenuates β-amyloid toxicity in cultured hippocampal neurons. Brain Res 2001; 919: 160-165.

Hogervorst E, Lehmann DJ, Warden DR, McBroom J, Smith AD. Apolipoprotein E ε4 and testosterone interact in the risk of Alzheimer’s disease in men. Int J Geriatr Psychiatry 2002; 17: 938-940.

Nead KT, Gaskin G, Chester C, et al. Androgen deprivation therapy and future Alzheimer’s disease risk. J Clin Oncol 2016; 34: 566-571.

Jayadevappa R, Chhatre S, Malkowicz SB, Parikh RB, Guzzo T, Wein AJ. Association between androgen deprivation therapy use and diagnosis of dementia in men with prostate cancer. JAMA Network Open 2019; 2: e196562.

Cherrier MM, Anderson K, Shofer J, Millard S, Matsumoto AM. Testosterone treatment of men with mild cognitive impairment and low testosterone levels. Am J Alzheimer’s Dis Other Demen 2015; 30: 421-430.

Lu PH, Masterman DA, Mulnard R, et al. Effects of testosterone on cognition and mood in male patients with mild Alzheimer disease and healthy elderly men. Arch Neurol 2006; 63: 177.

Buskbjerg CR, Gravholt CH, Dalby HR, Amidi A, Zachariae R. Testosterone supplementation and cognitive functioning in men-a systematic review and meta-analysis. J Endocr Soc 2019; 3: 1465-1484.

Budoff MJ, Ellenberg SS, Lewis CE, et al. Testosterone treatment and coronary artery plaque volume in older men with low testosterone. JAMA 2017; 317: 708-716.

Corona G, Rastrelli G, Di Pasquale G, Sforza A, Mannucci E, Maggi M. Testosterone and cardiovascular risk: meta-analysis of interventional studies. J Sex Med 2018; 15: 820-838.

Klein SL, Flanagan KL. Sex differences in immune responses. Nat Rev Immunol 2016; 16: 626-638.

Guneykaya D, Ivanov A, Hernandez DP, et al. Transcriptional and translational differences of microglia from male and female brains. Cell Rep 2018; 24: 2773-2783.e6.

Thion MS, Low D, Silvin A, et al. Microbiome influences prenatal and adult microglia in a sex-specific manner. Cell 2018; 172: 500-516.e16.

Schwarz JM, Sholar PW, Bilbo SD. Sex differences in microglial colonization of the developing rat brain. J Neurochem 2012; 120: 948-963.

Lenz KM, Nelson LH. Microglia and beyond: Innate immune cells as regulators of brain development and behavioral function. Front Immunol 2018; 9: 698.

Lenz KM, McCarthy MM. A starring role for microglia in brain sex differences. Neuroscientist 2015; 21: 306-321.

Kodama L, Do Gan L. Microglial sex differences contribute to sex differences in neurodegenerative diseases? Trends Mol Med 2019; 25: 741-749.

Swerdlow RH, Khan SM. A “mitochondrial cascade hypothesis” for sporadic Alzheimer’s disease. Med Hypotheses 2004; 63: 8-20.

Swerdlow RH, Burns JM, Khan SM. The Alzheimer’s disease mitochondrial cascade hypothesis. J Alzheimer’s Dis 2010; 20: S265-279.

Moreira PI, Carvalho C, Zhu X, Smith MA, Perry G. Mitochondrial dysfunction is a trigger of Alzheimer's disease pathophysiology. Biochimica et Biophysica Acta (BBA) - Mol Basis Dis 2010; 1802: 2-10.

Wang X, Su B, Siedlak SL, et al. Amyloid-β overproduction causes abnormal mitochondrial dynamics via differential modulation of mitochondrial fission/fusion proteins. Proc Natl Acad Sci USA 2008; 105: 19318-19323.

Eckert A, Nisbet R, Grimm A, Götz J, March separate, strike together - Role of phosphorylated TAU in mitochondrial dysfunction in Alzheimer's disease. Biochimica et Biophysica Acta (BBA) - Mol Basis Dis 1842; 2014: 1258-1266.

Mandal PK, Tripathi M, Sugunan S. Brain oxidative stress: Detection and mapping of anti-oxidant marker “Glutathione” in different brain regions of healthy male/female, MCI and Alzheimer patients using non-invasive magnetic resonance spectroscopy. Biochem Biophys Res Comm 2012; 417: 43-48.

Wang Y, Brinton RD. Triad of risk for late onset Alzheimer’s: Mitochondrial haplotype, APOE genotype and chromosomal sex. Front Aging Neurosci 2016; 8: 232.

Grimm A, Mensah-Nyagan AG, Eckert A. Alzheimer, mitochondria and gender. Neurosci Biobehav Rev 2016; 67: 89-101.

Silaidos C, Pilatus U, Grewal R, et al. Sex-associated differences in mitochondrial function in human peripheral blood mononuclear cells (PBMCs) and brain. Biol Sex Differences 2018; 9: 34.

Viña J, Lloret A. Why women have more Alzheimer's disease than men: gender and mitochondrial toxicity of amyloid-β peptide. J Alzheimer's Dis 2010; 20: S527-S533.

Bellanti F, Matteo M, Rollo T, et al. Sex hormones modulate circulating antioxidant enzymes: Impact of estrogen therapy. Redox Biol 2013; 1: 340-346.

Livingston G, Sommerlad A, Orgeta V, et al. Dementia prevention, intervention, and care. Lancet (London, England) 2017; 390: 2673-2734.

Ngandu T, Lehtisalo J, Solomon A, 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 (London, England) 2015; 385: 2255-2263.

Williamson JD, Pajewski NM, Auchus AP, et al. Effect of intensive vs standard blood pressure control on probable dementia: a randomized clinical trial. JAMA 2019; 321: 553-561.

Towfighi A, Saver JL, Engelhardt R, Ovbiagele B. A midlife stroke surge among women in the United States. Neurology 2007; 69: 1898-1904.

Towfighi A, Zheng L, Ovbiagele B. Sex-specific trends in midlife coronary heart disease risk and prevalence. Arch Intern Med 2009; 169: 1762-1766.

Lutfiyya MN, Ng L, Asner N, Lipsky MS. Disparities in stroke symptomology knowledge among US midlife women: an analysis of population survey data. J Stroke Cerebrovasc Dis 2009; 18: 150-157.

Gorelick PB, Scuteri A, Black SE, et al. Vascular contributions to cognitive impairment and dementia: a statement for healthcare professionals from the American heart association/American stroke association. Stroke 2011; 42: 2672-2713.

Iadecola C. Vascular and metabolic factors in Alzheimer’s disease and related dementias: introduction. Cell Mol Neurobiol 2016; 36: 151-154.

Chibnik LB, Wolters FJ, Backman K, et al. Trends in the incidence of dementia: design and methods in the Alzheimer Cohorts Consortium. Eur J Epidemiol 2017; 32: 931-938.

McKhann G, Drachman D, Folstein M, Katzman R, Price D, Stadlan EM. Clinical diagnosis of Alzheimer’s disease: report of the NINCDS-ADRDA Work Group under the auspices of Department of Health and Human Services Task Force on Alzheimer’s Disease. Neurology 1984; 34: 939-944.

Jack CR Jr, Bennett DA, Blennow K, et al. NIA-AA Research Framework: Toward a biological definition of Alzheimer’s disease. Alzheimer’s Dementia 2018; 1: 535-562.

The University of Tokyo Hospital. Issues to Consider in the Clinical Evaluation and Development of Drugs for Alzheimer’s Disease. 2017. http://www.pmda.go.jp/files/000221585.pdf (accessed 23/05/2019)

Hampel H, Vergallo A, Giorgi FS, et al. Precision medicine and drug development in Alzheimer’s disease: the importance of sexual dimorphism and patient stratification. Front Neuroendocrinol 2018; 50: 31-51.

Li R, Singh M. Sex differences in cognitive impairment and Alzheimer’s disease. Front Neuroendocrinol 2014; 35: 385-403.

Lewin C, Wolgers G, Herlitz A. Sex differences favoring women in verbal but not in visuospatial episodic memory. Neuropsychology 2001; 15: 165-173.

Herlitz A, Nilsson LG, Bäckman L. Gender differences in episodic memory. Mem Cognit 1997; 25: 801-811.

Lindberg SM, Hyde JS, Petersen JL, Linn MC. New trends in gender and mathematics performance: a meta-analysis. Psychol Bull 2010; 136: 1123-1135.

Wallentin M. Putative sex differences in verbal abilities and language cortex: a critical review. Brain Lang 2009; 108: 175-183.

Beinhoff U, Tumani H, Brettschneider J, Bittner D, Riepe MW. Gender-specificities in Alzheimer’s disease and mild cognitive impairment. J Neurol 2008; 255: 117-122.

Proust-Lima C, Amieva H, Letenneur L, Orgogozo J-M, Jacqmin-Gadda H, Dartigues J-F. Gender and education impact on brain aging: a general cognitive factor approach. Psychol Aging 2008; 23: 608-620.

Van Exel E, Gussekloo J, De Craen AJM, et al. Cognitive function in the oldest old: women perform better than men. J Neurol Neurosurg Psychiatry 2001; 71: 29-32.

Sundermann EE, Maki PM, Rubin LH, et al. Female advantage in verbal memory: evidence of sex-specific cognitive reserve. Neurology 2016; 87: 1916-1924.

McPherson S, Back C, Buckwalter JG, Cummings JL. Gender-related cognitive deficits in Alzheimer’s disease. Int Psychogeriatr 1999; 11: 117-122.

Benke T, Delazer M, Sanin G, et al. Cognition, gender, and functional abilities in Alzheimer’s disease: how are they related? J Alzheimer's Dis 2015; 35: 247-252.

Chapman RM, Mapstone M, Gardner MN, et al. Women have farther to fall: gender differences between normal elderly and Alzheimer’s disease in verbal memory engender better detection of Alzheimer’s disease in women. J Int Neuropsychol Soc 2011; 17: 654-662.

Henderson VW, Buckwalter JG. Cognitive deficits of men and women with Alzheimer’s disease. Neurology 1994; 44: 90-96.

Hebert LE, Wilson RS, Gilley DW, et al. Decline of language among women and men with Alzheimer’s Disease. J Gerontol Series B: Psychol Sci Soc Sci 2011; 55: P354-P361.

Koran MEI, Wagener M, Hohman TJ. Sex differences in the association between AD biomarkers and cognitive decline. Brain Imag Behav 2017; 11: 205-213.

Mattsson N, Lönneborg A, Boccardi M, Blennow K, Hansson O. Clinical validity of cerebrospinal fluid Aβ42, tau, and phospho-tau as biomarkers for Alzheimer’s disease in the context of a structured 5-phase development framework. Neurobiol Aging 2017; 52: 196-213.

Cavedo E, Chiesa PA, Houot M, et al. Sex differences in functional and molecular neuroimaging biomarkers of Alzheimer’s disease in cognitively normal older adults with subjective memory complaints. Alzheimer’s Dementia 2018; 14: 1204-1215.

Nabers A, Perna L, Lange J, et al. Amyloid blood biomarker detects Alzheimer’s disease. EMBO Mol Med 2018; 10: e8763.

Nakamura A, Kaneko N, Villemagne VL, et al. High performance plasma amyloid-β biomarkers for Alzheimer’s disease. Nature 2018; 554: 249.

Buckley RF, Mormino EC, Rabin JS, et al. Sex differences in the association of global amyloid and regional tau deposition measured by positron emission tomography in clinically normal older adults. JAMA Neurol 2019; 76: 542.

Jack CR, Wiste HJ, Schwarz CG, et al. Longitudinal tau PET in ageing and Alzheimer’s disease. Brain 2018; 141: 1517-1528.

Jack CR, Wiste HJ, Weigand SD, et al. Age-specific and sex-specific prevalence of cerebral β-amyloidosis, tauopathy, and neurodegeneration in cognitively unimpaired individuals aged 50-95 years: a cross-sectional study. Lancet Neurol 2017; 16: 435-444.

Ardekani BA, Convit A, Bachman AH. Analysis of the MIRIAD data shows sex differences in hippocampal atrophy progression. J Alzheimer’s Dis 2016; 50: 847-857.

Buckley RF, Mormino EC, Amariglio RE, et al. Sex, amyloid, and APOE ε4 and risk of cognitive decline in preclinical Alzheimer’s disease: findings from three well-characterized cohorts. Alzheimer’s Dementia 2018; 14: 1193-1203.

Pradier C, Sakarovitch C, Le Duff F, 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 2014; 9: e103630.

Sundermann EE, Maki P, Biegon A, et al. Sex-specific norms for verbal memory tests may improve diagnostic accuracy of amnestic MCI. Neurology 2019; 93: e1881-e1889.

Luck T, Pabst A, Rodriguez FS, et al. Age-, sex-, and education-specific norms for an extended CERAD Neuropsychological Assessment Battery-Results from the population-based LIFE-Adult-Study. Neuropsychology 2018; 32: 461-475.

Hansson O, Seibyl J, Stomrud E, et al. CSF biomarkers of Alzheimer’s disease concord with amyloid-β PET and predict clinical progression: a study of fully automated immunoassays in BioFINDER and ADNI cohorts. Alzheimer’s Dementia 2018; 14: 1470-1481.

van Maurik IS, Zwan MD, Tijms BM, et al. Interpreting biomarker results in individual patients with mild cognitive impairment in the Alzheimer’s Biomarkers in Daily Practice (ABIDE) Project. JAMA Neurol 2017; 74: 1481.

Waxman DJ, Holloway MG. Sex differences in the expression of hepatic drug metabolizing enzymes. Mol Pharmacol 2009; 76: 215-228.

Marazziti D, Baroni S, Picchetti M, et al. Pharmacokinetics and pharmacodinamics of psychotropic drugs: effect of sex. CNS Spectr 2013; 18: 118-127.

Tamargo J, Rosano G, Walther T, et al. Gender differences in the effects of cardiovascular drugs. Eur Heart J - Cardiovasc Pharmacother 2017; 3: 163-182.

Ofotokun I, Pomeroy C. Sex differences in adverse reactions to antiretroviral drugs. Top HIV Med 2003; 11: 55-59.

Haack S, Seeringer A, Thürmann PA, Becker T, Kirchheiner J. Sex-specific differences in side effects of psychotropic drugs: genes or gender? Pharmacogenomics 2009; 10: 1511-1526.

United States Food and Drug Administration. Center for Drug Evaluation and Research. Drug safety and availability: Questions and answers: Risk of next-morning impairment after use of insomnia drugs; FDA requires lower recommended doses for certain drugs containing zolpidem (Ambien, Ambien CR, Edluar, and Zolpimist). 2013. https://www.fda.gov/drugs/drug-safety-and-availability/questions-andanswers-risk-next-morning-impairment-after-use-insomnia-drugs-fda-requires-lower (accessed 05/05/2019)

Feghali M, Venkataramanan R, Caritis S. Pharmacokinetics of drugs in pregnancy. Semin Perinatol 2015; 39: 512-519.

Kashuba ADM, Nafziger AN. Physiological changes during the menstrual cycle and their effects on the pharmacokinetics and pharmacodynamics of drugs. Clin Pharmacokinet 1998; 34: 203-218.

Giacobini E, Pepeu G. Sex and gender differences in the brain cholinergic system and in the response to therapy of Alzheimer disease with cholinesterase inhibitors. Curr Alzheimer Res 2018; 15: 1077-1084.

Macgowan SH, Wilcock GK, Scott M. Effect of gender and apolipoprotein E genotype on response to anticholinesterase therapy in Alzheimer’s disease. Int J Geriatr Psychiatry 1998; 13: 625-630.

Canevelli M, Quarata F, Remiddi F, et al. Sex and gender differences in the treatment of Alzheimer’s disease: a systematic review of randomized controlled trials. Pharmacol Res 2017; 115: 218-223.

Claxton A, Baker LD, Wilkinson CW, 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 Alzheimer’s Dis 2013; 35: 789-797.

Khramtsova EA, Davis LK, Stranger BE. The role of sex in the genomics of human complex traits. Nat Rev Genet 2019; 20: 173-190.

Cacabelos R. Pharmacogenomics of polypharmacy in Alzheimer’s disease. 2017. https://www.openaccessgovernment.org/pharmacogenomics-polypharmacy-alzheimersdisease/34494/ (accessed 05/05/2019)

Vandenberghe R, Rinne JO, Boada M, et al. Bapineuzumab for mild to moderate Alzheimer’s disease in two global, randomized, phase 3 trials. Alzheimer’s Res Ther 2016; 8: 18.

Salloway S, Sperling R, Fox NC, et al. Two phase 3 trials of bapineuzumab in mild-to-moderate Alzheimer’s disease. N Engl J Med 2014; 370: 322-333.

Lyketsos CG, Breitner JCS, Green RC, et al. Naproxen and celecoxib do not prevent AD in early results from a randomized controlled trial. Neurology 2007; 68: 1800-1808.

Green RC, Schneider LS, Amato DA, et al. Effect of tarenflurbil on cognitive decline and activities of daily living in patients with mild Alzheimer disease: a randomized controlled trial. JAMA 2009; 302: 2557-2564.

Relkin NR, Thomas RG, Rissman RA, et al. A phase 3 trial of IV immunoglobulin for Alzheimer disease. Neurology 2017; 88: 1768-1775.

Ostrowitzki S, Lasser RA, Dorflinger E, et al. A phase III randomized trial of gantenerumab in prodromal Alzheimer’s disease. Alzheimer’s Res Ther 2017; 9: 95.

Rockwood K, Beattie BL, Eastwood MR, et al. A randomized, controlled trial of linopirdine in the treatment of Alzheimer’s disease. Can J Neurol Sci 1997; 24: 140-145.

Gauthier S, Feldman HH, Schneider LS, et al. Efficacy and safety of tau-aggregation inhibitor therapy in patients with mild or moderate Alzheimer’s disease: a randomised, controlled, double-blind, parallel-arm, phase 3 trial. Lancet (London, England) 2016; 388: 2873-2884.

Lawlor B, Segurado R, Kennelly S, et al. Nilvadipine in mild to moderate Alzheimer disease: a randomised controlled trial. PLoS Med 2018; 15: e1002660.

Aisen PS, Davis KL, Berg JD, et al. A randomized controlled trial of prednisone in Alzheimer’s disease. Alzheimer’s Disease Cooperative Study. Neurology 2000; 54: 588-593.

Rother M, Erkinjuntti T, Roessner M, Kittner B, Marcusson J, Karlsson I. Propentofylline in the treatment of Alzheimer’s disease and vascular dementia: a review of phase III trials. Dement Geriatr Cogn Disord 1998; 9(Suppl. 1): 36-43.

Reines SA, Block GA, Morris JC, et al. Rofecoxib: no effect on Alzheimer’s disease in a 1-year, randomized, blinded, controlled study. Neurology 2004; 62: 66-71.

Aisen PS, Schafer KA, Grundman M, et al. Effects of rofecoxib or naproxen vs placebo on Alzheimer disease progression: a randomized controlled trial. JAMA 2003; 289: 2819-2826.

Gold M, Alderton C, Zvartau-Hind M, et al. Rosiglitazone monotherapy in mild-to-moderate Alzheimer’s disease: results from a randomized, double-blind, placebo-controlled phase III study. Dement Geriatr Cogn Disord 2010; 30: 131-146.

Harrington C, Sawchak S, Chiang C, et al. Rosiglitazone does not improve cognition or global function when used as adjunctive therapy to AChE inhibitors in mild-to-moderate Alzheimer’s disease: two phase 3 studies. Curr Alzheimer Res 2011; 8: 592-606.

Doody RS, Raman R, Farlow M, et al. A phase 3 trial of semagacestat for treatment of Alzheimer’s disease. N Engl J Med 2013; 369: 341-350.

Doody RS, Thomas RG, Farlow M, et al. Phase 3 trials of solanezumab for mild-to-moderate Alzheimer’s disease. N Engl J Med 2014; 370: 311-321.

Honig LS, Vellas B, Woodward M, et al. Trial of Solanezumab for mild dementia due to Alzheimer’s disease. N Engl J Med 2018; 378: 321-330.

Aisen PS, Gauthier S, Ferris SH, et al. Tramiprosate in mild-to-moderate Alzheimer’s disease - A randomized, double-blind, placebo-controlled, multi-centre study (the alphase study). Arch Med Sci 2011; 7: 102-111.

Abushakra S, Porsteinsson A, Vellas B, et al. Clinical benefits of tramiprosate in Alzheimer’s disease are associated with higher number of APOE4 alleles: The “APOE4 gene-dose effect”. J Prev Alzheimer’s Dis 2016; 33: 219-228.

Egan MF, Kost J, Tariot PN, et al. Randomized trial of Verubecestat for mild-to-moderate Alzheimer’s disease. N Engl J Med 2018; 378: 1691-1703.

Egan MF, Kost J, Voss T, et al. Randomized trial of Verubecestat for prodromal Alzheimer’s disease. N Engl J Med 2019; 380: 1408-1420.

Vellas B, Coley N, Ousset PJ, et al. Long-term use of standardised ginkgo biloba extract for the prevention of Alzheimer’s disease (GuidAge): A randomised placebo-controlled trial. Lancet Neurol 2012; 11: 851-859.

Zissimopoulos JM, Barthold D, Brinton RD, Joyce G. Sex and race differences in the association between statin use and the incidence of Alzheimer disease. JAMA Neurol 2017; 74: 225-232.

Cummings J, Fox N. Defining disease modifying therapy for Alzheimer’s disease. J Prev Alzheimer’s Dis 2017; 4: 109-115.

Alzheimer disease seen through the lens of sex and gender

Impact of gender on the willingness to participate in clinical trials and undergo related procedures in individuals from an Alzheimer's prevention research cohort

X-chromosome-wide association study for Alzheimer's disease

The structural and social determinants of Alzheimer's disease related dementias

Longitudinal progression of choroid plexus enlargement is associated with female sex, cognitive decline and ApoE E4 homozygote status

Digital biomarkers and sex impacts in Alzheimer's disease management - potential utility for innovative 3P medicine approach