ABSTRACT Alzheimer disease (AD) is characterized by wide heterogeneity in cognitive and behavioural syndromes, risk factors and pathophysiological mechanisms. Addressing this phenotypic

variation will be crucial for the development of precise and effective therapeutics in AD. Sex-related differences in neural anatomy and function are starting to emerge, and sex might

constitute an important factor for AD patient stratification and personalized treatment. Although the effects of sex on AD epidemiology are currently the subject of intense investigation,

the notion of sex-specific clinicopathological AD phenotypes is largely unexplored. In this Review, we critically discuss the evidence for sex-related differences in AD symptomatology,

Elucidating sex differences in disease phenotypes will be instrumental in the development of a ‘precision medicine’ approach in AD, encompassing individual, multimodal, biomarker-driven and

sex-sensitive strategies for prevention, detection, drug development and treatment. KEY POINTS * Men and women with Alzheimer disease (AD) exhibit different cognitive and psychiatric

symptoms, and women show faster cognitive decline after diagnosis of mild cognitive impairment (MCI) or AD dementia. * Levels of amyloid-β measured with PET-based brain imaging and with

biochemical analysis of cerebrospinal fluid do not differ between the sexes. * Brain atrophy rates and patterns differ along the AD continuum between the sexes; in MCI, brain atrophy is

faster in women than in men. * The prevalence and effects of cerebrovascular, metabolic and socio-economic risk factors for AD are different between men and women. * No data are available on

sex differences in the efficacy and safety of drugs used in recently completed phase III clinical trials for mild to moderate AD. * Systematic studying and reporting of sex differences in

disease symptomatology, biomarkers, progression, risk factors and treatment responses will be crucial for the development and implementation of precision medicine in AD. Access through your

institution Buy or subscribe This is a preview of subscription content, access via your institution ACCESS OPTIONS Access through your institution Access Nature and 54 other Nature Portfolio

journals Get Nature+, our best-value online-access subscription $29.99 / 30 days cancel any time Learn more Subscribe to this journal Receive 12 print issues and online access $209.00 per

year only $17.42 per issue Learn more Buy this article * Purchase on SpringerLink * Instant access to full article PDF Buy now Prices may be subject to local taxes which are calculated

during checkout ADDITIONAL ACCESS OPTIONS: * Log in * Learn about institutional subscriptions * Read our FAQs * Contact customer support SIMILAR CONTENT BEING VIEWED BY OTHERS ALZHEIMER

DISEASE SEEN THROUGH THE LENS OF SEX AND GENDER Article 14 April 2025 ALZHEIMER’S DISEASE AS A WOMEN’S HEALTH CHALLENGE: A CALL FOR ACTION ON INTEGRATIVE PRECISION MEDICINE APPROACHES

Article Open access 20 May 2024 LEVERAGING RESEARCH INTO SEX DIFFERENCES AND STEROID HORMONES TO IMPROVE BRAIN HEALTH Article 25 November 2024 REFERENCES * 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). * 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). * Gauthier, S. et al. Why has therapy development for dementia failed in the last two decades? _Alzheimers

Dement._ 12, 60–64 (2016). Article  PubMed  Google Scholar  * Husain, M. Alzheimer’s disease: time to focus on the brain, not just molecules. _Brain_ 140, 251–253 (2017). Article  PubMed 

Google Scholar  * de Bono, J. S. & Ashworth, A. Translating cancer research into targeted therapeutics. _Nature_ 467, 543–549 (2010). Article  PubMed  CAS  Google Scholar  * 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). Article  PubMed  CAS  Google Scholar  * 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). Article  PubMed  PubMed Central  Google Scholar  * 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). Article  PubMed  PubMed Central  CAS  Google Scholar  * 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). Article  PubMed  PubMed Central 

Google Scholar  * Ruigrok, A. N. et al. A meta-analysis of sex differences in human brain structure. _Neurosci. Biobehav. Rev._ 39, 34–50 (2014). Article  PubMed  PubMed Central  Google

Scholar  * Ingalhalikar, M. et al. Sex differences in the structural connectome of the human brain. _Proc. Natl Acad. Sci. USA_ 111, 823–828 (2014). Article  PubMed  CAS  Google Scholar  *

Li, R. & Singh, M. Sex differences in cognitive impairment and Alzheimer’s disease. _Front. Neuroendocrinol._ 35, 385–403 (2014). Article  PubMed  PubMed Central  CAS  Google Scholar  *

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. Article  PubMed  Google Scholar  * 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). Article  PubMed  Google Scholar  * Vetvik, K. G. &

MacGregor, E. A. Sex differences in the epidemiology, clinical features, and pathophysiology of migraine. _Lancet Neurol._ 16, 76–87 (2017). Article  PubMed  CAS  Google Scholar  * 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). Article  PubMed  PubMed

Central  Google Scholar  * Hampel, H. et al. Precision pharmacology for Alzheimer’s disease. _Pharmacol. Res._ 130, 331–365 (2018). Article  PubMed  CAS  Google Scholar  * 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).

Article  PubMed  Google Scholar  * Pike, C. J. Sex and the development of Alzheimer’s disease. _J. Neurosci. Res._ 95, 671–680 (2017). Article  PubMed  PubMed Central  CAS  Google Scholar  *

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). Article  PubMed  PubMed

Central  Google Scholar  * 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. Article  PubMed  PubMed Central  Google Scholar  * 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). Article  PubMed  PubMed Central  Google Scholar

  * 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). Article  PubMed 

PubMed Central  Google Scholar  * 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). Article  PubMed  PubMed Central  Google Scholar  * Laws, K. R., Irvine, K. & Gale, T. M. Sex differences in cognitive impairment in

Alzheimer’s disease. _World J. Psychiatry_ 6, 54–65 (2016). Article  PubMed  PubMed Central  Google Scholar  * 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). Article  PubMed  PubMed Central  Google Scholar  * Sundermann, E. E. et al. Female advantage in verbal memory:

evidence of sex-specific cognitive reserve. _Neurology_ 87, 1916–1924 (2016). Article  PubMed  PubMed Central  Google Scholar  * 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. Article  PubMed  Google Scholar  * 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). Article  PubMed  Google Scholar  * Benke,

T. et al. Cognition, gender, and functional abilities in Alzheimer’s disease: how are they related? _J. Alzheimers Dis._ 35, 247–252 (2013). Article  PubMed  Google Scholar  * 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). Article  PubMed  PubMed Central  CAS  Google Scholar  * 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. Google Scholar 

* 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). Article  PubMed  Google Scholar  * 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). Article  PubMed  PubMed Central  Google Scholar

  * 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). Article 

PubMed  PubMed Central  Google Scholar  * 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). Article  PubMed  CAS  Google Scholar  * Counts, S. E. et al. Cerebrospinal fluid proNGF: a putative biomarker for early Alzheimer’s disease. _Curr. Alzheimer Res._ 13,

800–808 (2016). Article  PubMed  PubMed Central  CAS  Google Scholar  * Walker, K. A. et al. Midlife systemic inflammatory markers are associated with late-life brain volume: the ARIC study.

_Neurology_ 89, 2262–2270 (2017). Article  PubMed  Google Scholar  * 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). PubMed  PubMed Central  CAS  Google Scholar  * 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). Article  PubMed  PubMed Central  CAS  Google Scholar  * Villa, A. et al. Sex-specific features of microglia from adult mice. _Cell

Rep._ 23, 3501–3511 (2018). * 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). Article  PubMed  CAS  Google Scholar  * Mega, M. S., Cummings, J. L., Fiorello, T. & Gornbein, J. The spectrum of behavioral changes in Alzheimer’s disease.

_Neurology_ 46, 130–135 (1996). Article  PubMed  CAS  Google Scholar  * 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). CAS  Google Scholar  * 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).

Article  PubMed  Google Scholar  * 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). Article  PubMed  CAS  Google Scholar  * 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). Article  PubMed  Google Scholar  * 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). Article  PubMed  Google Scholar  * 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. Article  PubMed  Google Scholar  * Sinforiani, E. et al. Impact of gender differences on the outcome of Alzheimer’s

disease. _Dement. Geriatr. Cogn. Disord._ 30, 147–154 (2010). Article  PubMed  CAS  Google Scholar  * 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. Article  PubMed  PubMed Central  CAS  Google Scholar  * 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). Article  PubMed  CAS  Google Scholar  * 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). *

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). Article  PubMed  PubMed Central  Google

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

Article  PubMed  PubMed Central  Google Scholar  * 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. Article 

PubMed  Google Scholar  * Shinohara, M. et al. Impact of sex and APOE4 on cerebral amyloid angiopathy in Alzheimer’s disease. _Acta Neuropathol._ 132, 225–234 (2016). Article  PubMed  PubMed

Central  CAS  Google Scholar  * 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). Article  PubMed  CAS  Google Scholar  * Jansen, W. J. et al. Prevalence of cerebral amyloid pathology in

persons without dementia: a meta-nalysis. _JAMA_ 313, 1924–1938 (2015). Article  PubMed  PubMed Central  Google Scholar  * 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). Article 

PubMed  CAS  Google Scholar  * Johnson, K. A. et al. Tau positron emission tomographic imaging in aging and early Alzheimer disease. _Ann. Neurol._ 79, 110–119 (2016). Article  PubMed 

Google Scholar  * Apostolova, L. G. et al. 3D comparison of hippocampal atrophy in amnestic mild cognitive impairment and Alzheimer’s disease. _Brain_ 129, 2867–2873 (2006). Article  PubMed

  Google Scholar  * 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). Article  PubMed  CAS  Google Scholar  * Skup, M. et al. Sex differences in grey matter atrophy patterns among AD and aMCI patients: results from ADNI.

_Neuroimage_ 56, 890–906 (2011). Article  PubMed  PubMed Central  Google Scholar  * 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. Article  PubMed  PubMed Central  Google Scholar  * 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). Article  PubMed  Google

Scholar  * 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). Article  Google Scholar  * 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). Article  PubMed  CAS  Google Scholar  * Madsen, T. E. et al. Sex-specific stroke incidence over time in

the Greater Cincinnati/Northern Kentucky Stroke Study. _Neurology_ 89, 990–996 (2017). Article  PubMed  PubMed Central  Google Scholar  * Gibson, C. L. Cerebral ischemic stroke: is gender

important? _J. Cereb. Blood Flow Metab._ 33, 1355–1361 (2013). Article  PubMed  PubMed Central  Google Scholar  * 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). Article  PubMed  PubMed Central  Google Scholar  * National

Institute of Mental Health. Major depression. _NIMH_ https://www.nimh.nih.gov/health/statistics/major-depression.shtml (2015). * 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). Article  Google Scholar  * 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). Article  PubMed  CAS  Google Scholar  * 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). Article  PubMed  PubMed Central  CAS  Google Scholar  * 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). Article  PubMed  Google Scholar  * 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. Article  PubMed  PubMed Central  Google Scholar  * Mosconi, L. et al. Perimenopause and emergence of an Alzheimer’s bioenergetic phenotype in brain and

periphery. _PLoS ONE_ 12, e0185926 (2017). Article  PubMed  PubMed Central  CAS  Google Scholar  * 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). Article  PubMed  PubMed Central  Google Scholar  * 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). Article 

PubMed  PubMed Central  CAS  Google Scholar  * Heise, V. et al. Apolipoprotein E genotype, gender and age modulate connectivity of the hippocampus in healthy adults. _Neuroimage_ 98, 23–30

(2014). Article  PubMed  CAS  Google Scholar  * Sampedro, F. et al. APOE-by-sex interactions on brain structure and metabolism in healthy elderly controls. _Oncotarget_ 6, 26663–26674

(2015). Article  PubMed  PubMed Central  Google Scholar  * 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). * 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). * Snowdon, D. A. et al. Brain infarction and the clinical expression of Alzheimer

disease. The Nun Study. _JAMA_ 277, 813–817 (1997). Article  PubMed  CAS  Google Scholar  * Vemuri, P. et al. Vascular and amyloid pathologies are independent predictors of cognitive decline

in normal elderly. _Brain_ 138, 761–771 (2015). Article  PubMed  PubMed Central  Google Scholar  * Roberts, R. O. et al. Association of diabetes with amnestic and nonamnestic mild cognitive

impairment. _Alzheimers Dement._ 10, 18–26 (2014). Article  PubMed  Google Scholar  * Gilsanz, P. et al. Female sex, early-onset hypertension, and risk of dementia. _Neurology_ 89,

1886–1893 (2017). Article  PubMed  Google Scholar  * 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). Article  PubMed  PubMed Central  Google Scholar  * Li, J. et al. Vascular risk factors promote conversion from mild cognitive impairment to Alzheimer

disease. _Neurology_ 76, 1485–1491 (2011). Article  PubMed  CAS  Google Scholar  * 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). Article  PubMed  Google Scholar  * 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). Article  PubMed  Google Scholar  * 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.

Article  PubMed  PubMed Central  Google Scholar  * 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). Article  PubMed  CAS  Google Scholar  * 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). Article  PubMed  Google Scholar  * Chene, G. et al. Gender and incidence of dementia in the Framingham Heart Study from mid-adult

life. _Alzheimers Dement._ 11, 310–320 (2015). Article  PubMed  Google Scholar  * 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). Article  PubMed  Google Scholar  * Fields, J. A. et al. Preeclampsia and cognitive impairment later in life. _Am J Obstet. Gynecol_ 217,

74.e1–74.e11 (2017). Article  Google Scholar  * Buhimschi, I. A. et al. Protein misfolding, congophilia, oligomerization, and defective amyloid processing in preeclampsia. _Sci. Transl Med._

6, 245ra292 (2014). Article  CAS  Google Scholar  * Rocca, W. A. et al. Increased risk of cognitive impairment or dementia in women who underwent oophorectomy before menopause. _Neurology_

69, 1074–1083 (2007). Article  PubMed  CAS  Google Scholar  * Bove, R. et al. Age at surgical menopause influences cognitive decline and Alzheimer pathology in older women. _Neurology_ 82,

222–229 (2014). Article  PubMed  PubMed Central  Google Scholar  * 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). Article  PubMed  Google Scholar  * 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). * 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). * 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). Article  PubMed  PubMed Central  Google

Scholar  * 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). * Alzheimer’s Association. 2014 Alzheimer’s disease facts and figures. _Alzheimers Dement._ 10, e47–e92 (2014). Article  Google

Scholar  * 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).

Article  PubMed  PubMed Central  Google Scholar  * 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). Article  PubMed  Google Scholar  * 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). Article  PubMed  CAS  Google Scholar  * Egan, M. F. et al. Randomized trial of verubecestat for mild-to-moderate Alzheimer’s disease. _N. Engl. J. Med._ 378,

1691–1703 (2018). Article  PubMed  CAS  Google Scholar  * 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).

Article  PubMed  CAS  Google Scholar  * 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). Article 

PubMed  PubMed Central  CAS  Google Scholar  * 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). Article  PubMed  Google Scholar  * 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). Article  PubMed  Google Scholar  * 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). Article  PubMed  CAS  Google Scholar

  * 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. Article  PubMed 

CAS  Google Scholar  * 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). Article  PubMed  CAS  Google Scholar  * 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). Article  PubMed  PubMed Central  Google Scholar  * 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). Article  PubMed  CAS  Google Scholar  * 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). Article  PubMed  Google Scholar  * 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). Article  PubMed  Google Scholar  * 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). Article 

PubMed  CAS  Google Scholar  * 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). Article  PubMed  PubMed Central  CAS  Google Scholar  * 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). Article  PubMed  CAS 

Google Scholar  * 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). Article  PubMed  PubMed Central  CAS  Google Scholar  * 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). Article  PubMed  CAS  Google Scholar  * 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). Article  PubMed  CAS  Google Scholar  * Mehta, N. et al. Systematic review of sex-specific reporting of data: cholinesterase

inhibitor example. _J. Am. Geriatr. Soc._ 65, 2213–2219 (2017). Article  PubMed  Google Scholar  * Hampel, H. et al. The cholinergic system in the pathophysiology and treatment of

Alzheimer’s disease. _Brain_ 141, 1917–1933 (2018). Article  PubMed  Google Scholar  * 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). Article  PubMed  Google Scholar  *

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). Article 

PubMed  PubMed Central  CAS  Google Scholar  * 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).

Article  PubMed  Google Scholar  * 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). Google Scholar  * 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). Article  PubMed  CAS  Google Scholar  * Farlow, M. et al.

Safety and biomarker effects of solanezumab in patients with Alzheimer’s disease. _Alzheimers Dement._ 8, 261–271 (2012). Article  PubMed  CAS  Google Scholar  * 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). Article  PubMed  Google Scholar  * 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). Article 

PubMed  CAS  Google Scholar  * 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). Article  PubMed  PubMed Central  CAS  Google Scholar  * 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). Article  PubMed  Google Scholar  * 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). Article  PubMed  CAS  Google Scholar  * 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. Article  PubMed  CAS  Google Scholar  * 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.

Article  PubMed  CAS  Google Scholar  * 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). Article  PubMed  CAS  Google Scholar  * 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). Article  PubMed  CAS  Google Scholar  * Ryan, J. et al. Characteristics of hormone therapy, cognitive function, and dementia: the prospective

3C Study. _Neurology_ 73, 1729–1737 (2009). Article  PubMed  PubMed Central  CAS  Google Scholar  * Kang, J. H. & Grodstein, F. Postmenopausal hormone therapy, timing of initiation, APOE

and cognitive decline. _Neurobiol. Aging_ 33, 1129–1137 (2012). Article  PubMed  CAS  Google Scholar  * 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). Article  PubMed  CAS  Google Scholar  * 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). Article  PubMed  PubMed Central  CAS  Google Scholar  *

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). Article  PubMed  Google

Scholar  * Kosik, K. S. Personalized medicine for effective Alzheimer disease treatment. _JAMA Neurol._ 72, 497–498 (2015). Article  PubMed  Google Scholar  * 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. Article  PubMed  CAS  Google Scholar  * 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). PubMed  PubMed Central  CAS  Google Scholar  * 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). Article  PubMed  PubMed Central  Google Scholar  * 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).

Article  PubMed  PubMed Central  Google Scholar  * 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). Article  PubMed  PubMed Central  CAS  Google Scholar  * 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). Article  PubMed  Google Scholar  * Dubois, B. et al. Advancing research diagnostic criteria for Alzheimer’s disease: the IWG-2 criteria.

_Lancet Neurol._ 13, 614–629 (2014). Article  PubMed  Google Scholar  * 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). Article  PubMed  Google Scholar  * 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). Article  PubMed  Google Scholar  * Petersen, R. C. Mild cognitive impairment as a diagnostic entity. _J.

Intern. Med._ 256, 183–194 (2004). Article  PubMed  CAS  Google Scholar  * 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). Article  PubMed  PubMed Central  Google Scholar  * 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). * 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). * Standford University.

Gendered innovations terminology. _Gendered Innovations_ http://genderedinnovations.stanford.edu/terms.html (2018). * Jary, D. & Jary, A. Collins Dictionary of Sociology 3rd edn.

(Collins, Glasgow, 2005). * World Health Organization. Gender. _WHO_ http://www.who.int/en/news-room/fact-sheets/detail/gender (2015). * 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. Article  PubMed  PubMed Central  Google Scholar  * Middeldorp, J. et al. Preclinical assessment of young blood plasma for

Alzheimer disease. _JAMA Neurol._ 73, 1325–1333 (2016). Article  PubMed  PubMed Central  Google Scholar  * 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). Article  PubMed  PubMed Central  CAS  Google Scholar  * 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). Article 

PubMed  CAS  Google Scholar  * 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). Article  PubMed  CAS  Google Scholar  * Lewis, J. et al. Enhanced neurofibrillary degeneration in transgenic mice expressing mutant tau and APP. _Science_ 293, 1487–1491

(2001). Article  PubMed  CAS  Google Scholar  * 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). Article  PubMed  CAS  Google Scholar  * Dumont, M. et al. Behavioral deficit, oxidative stress,

and mitochondrial dysfunction precede tau pathology in P301S transgenic mice. _FASEB J._ 25, 4063–4072 (2011). Article  PubMed  PubMed Central  CAS  Google Scholar  * 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). Article  PubMed  CAS  Google

Scholar  * 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). Article

  PubMed  CAS  Google Scholar  * 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). Article  PubMed  CAS  Google Scholar  * 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). PubMed  PubMed Central  CAS  Google Scholar  * 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). Article  PubMed  CAS  Google Scholar  * Hampel, H. et al. Revolution of Alzheimer precision

neurology. Passageway of systems biology and neurophysiology. _J. Alzheimers Dis._ 64, S47–S105 (2018). * Hampel, H. et al. Precision medicine and drug development in Alzheimer’s disease:

the importance of sexual dimorphism and patient stratification. _Front. Neuroendocrinol._ https://doi.org/10.1016/j.yfrne.2018.06.001 (2018). Download references ACKNOWLEDGEMENTS H.H. was

supported by the AXA Research Fund, the Fondation Partenariale Sorbonne Université, the Fondation pour la Recherche sur Alzheimer, Paris, France and the programme ‘Investissements d’avenir’

(ANR-10-IAIHU-06; Agence Nationale de la Recherche-10-IA, Agence Institut Hospitalo-Universitaire-6; awarded to H.H.). Further support was provided by the Colam Initiatives and the Fondation

pour la Recherche sur Alzheimer, Paris, France (awarded to H.H. and P.A.C.) and the programme ‘PHOENIX’, led by the Sorbonne University Foundation and sponsored by the Fondation pour la

Recherche sur Alzheimer (awarded to H.H. and E.C.). H.G. acknowledges support from the Heart and Stroke Foundation of Canada, the Canadian Institutes of Health Research and the Canadian

Foundation for Innovation. H.G. is also the holder of an investigator award from the Fonds de Recherche du Québec-Santé. M.T.F. is supported by a research fellowship by the Synapsis

Foundation–Alzheimer Research Switzerland (ARS). M.F.I. acknowledges support from the Fonds de Recherche du Québec-Santé and from the Herbert H. Jasper Postdoctoral Research Fellowship from

the Groupe de Recherche sur le Système Nerveux Central (GRSNC), Université de Montréal. The authors thank A. Kato (Department of Basic Neuroscience, University of Geneva, Geneva,

Switzerland) and L. Kulic (Institute for Regenerative Medicine, University of Zurich, Schlieren, Switzerland) for encouragement and help with the first draft of the manuscript and A.

Herrmann (Cambridge Stem Cell Institute, University of Cambridge, Cambridge, UK) for continuous support, insightful discussions and editorial work. The authors thank the contributors to the

Alzheimer Precision Medicine Initiative Working Group (Supplementary Box 1). The initial idea and draft of this Review was conceived by the Women’s Brain Project (a non-profit organization

advocating for women’s brain and mental health; www.womensbrainproject.com) as part of its advocacy and scientific activity. REVIEW CRITERIA We searched PubMed and Google Scholar for

articles published in English without time limitations with the search terms “Alzheimer AND gender (or sex or women or female)”, “Amyloid AND gender (or sex or women or female)”, “plaques

AND gender (or sex or women or female)”, “tau AND gender (or sex or women or female)”, “atrophy AND Alzheimer AND gender (or sex or women or female)”, “cognitive decline AND gender (or sex

or women or female)”, “risk AND Alzheimer AND gender (or sex or women or female)”, “stroke AND Alzheimer AND gender (or sex or women or female)”, “cardiovascular AND Alzheimer AND gender (or

sex or women or female)”, “cerebrovascular AND gender (or sex or women or female)”, “diabetes AND Alzheimer AND gender (or sex or women or female)”, “depression AND Alzheimer AND gender (or

sex or women or female)” and “APOE AND Alzheimer AND gender (or sex or women or female)”. We also searched in the reference lists of identified articles for additional relevant

publications. The final reference list was generated by choosing only papers published since 2012. Papers preceding 2012 were included only if considered by the authors to be landmark

studies. Papers were selected on the basis of their perceived relevance to the topics covered in this Review. AUTHOR INFORMATION AUTHORS AND AFFILIATIONS * Institute for Regenerative

Medicine, University of Zurich, Schlieren, Switzerland Maria Teresa Ferretti * Neuroscience Center Zurich, University of Zurich, Zurich, Switzerland Maria Teresa Ferretti * Département de

Neurosciences, Université de Montréal, Montreal, Quebec, Canada Maria Florencia Iulita * Groupe de Recherche sur le Système Nerveux Central (GRSNC), Université de Montréal, Montreal, Quebec,

Canada Maria Florencia Iulita & Hélène Girouard * AXA Research Fund and Sorbonne University, Paris, France Enrica Cavedo, Patrizia Andrea Chiesa & Harald Hampel * Sorbonne

University, GRC n° 21, Alzheimer Precision Medicine, Pitié-Salpêtrière Hospital, Paris, France Enrica Cavedo, Patrizia Andrea Chiesa & Harald Hampel * Brain and Spine Institute, INSERM

U, 1127, Paris, France Enrica Cavedo, Patrizia Andrea Chiesa & Harald Hampel * Institute of Memory and Alzheimer’s Disease, Department of Neurology, Pitié-Salpêtrière Hospital, Paris,

France Enrica Cavedo, Patrizia Andrea Chiesa & Harald Hampel * IRCCS Centro San Giovanni di Dio Fatebenefratelli, Brescia, Italy Enrica Cavedo * Interdisciplinary Competence Centre for

Ageing IKOA-FHS, University of Applied Sciences, St. Gallen, Switzerland Annemarie Schumacher Dimech & Sabina Misoch * Swiss Agency for Therapeutic Products, Bern, Switzerland Antonella

Santuccione Chadha * Pulmonary Clinic, Division of Pulmonology, University Hospital Zurich, Zurich, Switzerland Francesca Baracchi * Départment de Pharmacologie et Physiologie, Université de

Montréal, Montreal, Quebec, Canada Hélène Girouard * Institut Universitaire de Gériatrie de Montréal, Montreal, Quebec, Canada Hélène Girouard * Department of Internal Medicine,

Rehabilitation and Geriatrics, University of Geneva Hospitals, Geneva, Switzerland Ezio Giacobini * Department of Obstetrics and Gynaecology, Ghent University Hospital, Ghent, Belgium Herman

Depypere Authors * Maria Teresa Ferretti View author publications You can also search for this author inPubMed Google Scholar * Maria Florencia Iulita View author publications You can also

search for this author inPubMed Google Scholar * Enrica Cavedo View author publications You can also search for this author inPubMed Google Scholar * Patrizia Andrea Chiesa View author

publications You can also search for this author inPubMed Google Scholar * Annemarie Schumacher Dimech View author publications You can also search for this author inPubMed Google Scholar *

Antonella Santuccione Chadha View author publications You can also search for this author inPubMed Google Scholar * Francesca Baracchi View author publications You can also search for this

author inPubMed Google Scholar * Hélène Girouard View author publications You can also search for this author inPubMed Google Scholar * Sabina Misoch View author publications You can also

search for this author inPubMed Google Scholar * Ezio Giacobini View author publications You can also search for this author inPubMed Google Scholar * Herman Depypere View author

publications You can also search for this author inPubMed Google Scholar * Harald Hampel View author publications You can also search for this author inPubMed Google Scholar CONSORTIA FOR

THE WOMEN’S BRAIN PROJECT AND THE ALZHEIMER PRECISION MEDICINE INITIATIVE CONTRIBUTIONS M.T.F., E.G. and H.H. conceived the paper. All authors contributed to the literature search and to the

writing. M.T.F., E.C. and P.A.C. designed the figures. E.G., H.H., H.D., H.G. and S.M. provided guidance for specific areas of competence and overall paper design. A.C.S. contributed to the

paper with her own expertise and points of view; the views and opinions expressed herein are those of the author and do not reflect the view of the Swiss Agency for Therapeutic Products

(Swissmedic). CORRESPONDING AUTHOR Correspondence to Maria Teresa Ferretti. ETHICS DECLARATIONS COMPETING INTERESTS H.H. is a Senior Associate Editor for the journal _Alzheimer’s &

Dementia_. He has received fees for lecturing from Biogen and Roche; research grants from Pfizer, Avid, and MSD Avenir (all three paid to his institution); travel funding from Axovant, Eli

Lilly, Functional Neuromodulation, GE Healthcare, Oryzon Genomics and Takeda and Zinfandel; and consultancy fees from Anavex, Axovant, Cytox, Functiona Neuromoduation, GE Healthcare, Jung

Diagnostics, Oryzon Genomics and Takeda and Zinfandel. He participated in scientific advisory boards of Axovant, Cytox, Eli Lilly, Functional Neuromodulation, GE Healthcare, Oryzon Genomics,

Roche Diagnostics and Takeda and Zinfandel. He is a co-inventor on several patents related to markers and the diagnosis of neurodegenerative disease (numbers 8916388, 8298784, 20120196300,

20100062463, 20100035286, 20090263822, 7547553, 20080206797, 20080199966 and 20080131921) but has received no royalties. All other authors declare no conflicts of interest. ADDITIONAL

INFORMATION PUBLISHER’S NOTE Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations. RELATED LINKS THE WOMEN’S BRAIN PROJECT:

www.womensbrainproject.com ELECTRONIC SUPPLEMENTARY MATERIAL SUPPLEMENTARY BOX 1 RIGHTS AND PERMISSIONS Reprints and permissions ABOUT THIS ARTICLE CITE THIS ARTICLE Ferretti, M., Iulita,

M.F., Cavedo, E. _et al._ Sex differences in Alzheimer disease — the gateway to precision medicine. _Nat Rev Neurol_ 14, 457–469 (2018). https://doi.org/10.1038/s41582-018-0032-9 Download

citation * Published: 09 July 2018 * Issue Date: August 2018 * DOI: https://doi.org/10.1038/s41582-018-0032-9 SHARE THIS ARTICLE Anyone you share the following link with will be able to read

this content: Get shareable link Sorry, a shareable link is not currently available for this article. Copy to clipboard Provided by the Springer Nature SharedIt content-sharing initiative