IMPORTANCE: Women represent two-thirds of patients with Alzheimer disease (AD), and sex differences might affect results of randomized clinical trials (RCTs). However, little information exists on differences in sex as reported in RCTs for AD. OBJECTIVE: To assess the ratio of females to males and the reporting of sex-stratified data in large pharmaceutical RCTs for AD. DATA SOURCES: A search for pharmaceutical RCTs for AD was conducted on September 4, 2019, using ClinicalTrials.gov with the key word Alzheimer disease, and articles related to those trials were identified using the PubMed, Scopus, and Google Scholar databases. Searches were conducted between September 4 and October 31, 2019, and between April 15 and May 31, 2020. STUDY SELECTION: Controlled RCTs that had more than 100 participants and tested the efficacy of drugs or herbal extracts were included. Of 1047 RCTs identified, 409 were published and therefore screened. A total of 77 articles were included in the final analysis, including 56 primary articles on AD, 13 secondary articles on AD, and 8 articles on mild cognitive impairment. DATA EXTRACTION AND SYNTHESIS: The location and date of publication; number, sex, and age of patients enrolled; disease severity; experimental or approved status of the drug; and whether the study included a sex-stratified analysis in the protocol, methods, or results were extracted by 1 reviewer for each article, and the meta-analysis followed the Preferred Reporting Items for Systematic Reviews and Meta-analyses (PRISMA) reporting guideline. Data were analyzed using a mixed-effects model. MAIN OUTCOMES AND MEASURES: The mean proportion of women enrolled in the trials and the associations between prespecified variables were analyzed. The proportion of articles that included sex-stratified results and the temporal trends in the reporting of these results were also studied. RESULTS: In this review of 56 RCTs for AD involving 39 575 participants, 23 348 women (59.0%) were included. The mean (SD) proportion of women in RCTs of approved drugs was 67.3% (6.9%), and in RCTs of experimental drugs was 57.9% (5.9%). The proportion of women in RCTs of experimental drugs was significantly lower than the proportion of women in the general population with AD in the US (62.1%; difference, -4.56% [95% CI, -6.29% to -2.87%]; P < .001) and Europe (68.2%; difference, -10.67% [95% CI, -12.39% to -8.97%]; P < .001). Trials of approved drugs had a higher probability of including women than trials of experimental drugs (odds ratio [OR], 1.26; 95% CI, 1.05-1.52; P = .02). Both the severity of AD at baseline and the trial location were associated with the probability of women being enrolled in trials (severity: OR, 0.98; 95% CI, 0.97-1.00; P = .02; location in Europe: OR, 1.26; 95% CI, 1.05-1.52; P = .01; location in North America: OR, 0.81; 95% CI, 0.71-0.93; P = .002). Only 7 articles (12.5%) reported sex-stratified results, with an increasing temporal trend (R, 0.30; 95% CI, 0.05-0.59; P = .03). CONCLUSIONS AND RELEVANCE: In this systematic review and meta-analysis, the proportion of women in RCTs for AD, although higher than the proportion of men, was significantly lower than that in the general population. Only a small proportion of trials reported sex-stratified results. These findings support strategies to improve diversity in enrollment and data reporting in RCTs for AD.

Biogen International GMBH Baar Switzerland

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

Faculty of Medicine Dentistry and Health Sciences University of Melbourne Melbourne Australia

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

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

Novartis Pharma AG Basel Switzerland

Roche Diagnostics International Ltd Rotkreuz Switzerland

Stroke Unit Department of Neurology University of Oslo Oslo Norway

Women's Brain Project Guntershausen Switzerland

Komentář v

JAMA Netw Open. 2021 Sep 1;4(9):e2124386. doi: 10.1001/jamanetworkopen.2021.24386. PubMed

Zobrazit více v PubMed

Prince M, Wimo A, Guerchet M, Ali GC, Wu YT, Prina M. World Alzheimer Report 2015: the global impact of dementia—an analysis of prevalence, incidence, cost and trends. Alzheimer’s Disease International. 2015. Accessed June 15, 2020. https://www.alzint.org/resource/world-alzheimer-report-2015/

Gauthier S, Albert M, Fox N, et al. Why has therapy development for dementia failed in the last two decades? Alzheimers Dement. 2016;12(1):60-64. doi: 10.1016/j.jalz.2015.12.003 PubMed DOI

Husain M. Alzheimer’s disease: time to focus on the brain, not just molecules. Brain. 2017;140(2):251-253. doi: 10.1093/brain/aww353 PubMed DOI

Alzheimer Europe.

Alzheimer’s Association. 2020 Alzheimer’s disease facts and figures. Alzheimers Dement. 2020;16(3):391–460. doi:10.1002/alz.12068 doi: 10.1002/alz.12068 DOI

Ferretti MT, Iulita MF, Cavedo E, et al. ; Women’s Brain Project and the Alzheimer Precision Medicine Initiative . Sex differences in Alzheimer disease—the gateway to precision medicine. Nat Rev Neurol. 2018;14(8):457-469. doi: 10.1038/s41582-018-0032-9 PubMed DOI

Ferretti MT, Martinkova J, Biskup E, et al. Sex and gender differences in Alzheimer’s disease: current challenges and implications for clinical practice: position paper of the Dementia and Cognitive Disorders Panel of the European Academy of Neurology. Eur J Neurol. 2020;27(6):928-943. doi: 10.1111/ene.14174 PubMed DOI

Sundermann EE, Biegon A, Rubin LH, et al. ; Alzheimer’s Disease Neuroimaging Initiative . Better verbal memory in women than men in MCI despite similar levels of hippocampal atrophy. Neurology. 2016;86(15):1368-1376. doi: 10.1212/WNL.0000000000002570 PubMed DOI PMC

Sundermann EE, Maki P, Biegon A, et al. ; Alzheimer’s Disease Neuroimaging Initiative . Sex-specific norms for verbal memory tests may improve diagnostic accuracy of amnestic MCI. Neurology. 2019;93(20):e1881-e1889. doi: 10.1212/WNL.0000000000008467 PubMed DOI PMC

Lin KA, Choudhury KR, Rathakrishnan BG, Marks DM, Petrella JR, Doraiswamy PM; Alzheimer’s Disease Neuroimaging Initiative . Marked gender differences in progression of mild cognitive impairment over 8 years. Alzheimers Dement (N Y). 2015;1(2):103-110. doi: 10.1016/j.trci.2015.07.001 PubMed DOI PMC

Sohn D, Shpanskaya K, Lucas JE, et al. Sex differences in cognitive decline in subjects with high likelihood of mild cognitive impairment due to Alzheimer’s disease. Sci Rep. 2018;8(1):7490. doi: 10.1038/s41598-018-25377-w PubMed DOI PMC

Buckley RF, Mormino EC, Amariglio RE, et al. ; Alzheimer’s Disease Neuroimaging Initiative; Australian Imaging, Biomarker and Lifestyle study of ageing; Harvard Aging Brain Study . Sex, amyloid, and APOE ε4 and risk of cognitive decline in preclinical Alzheimer’s disease: findings from three well-characterized cohorts. Alzheimers Dement. 2018;14(9):1193-1203. doi: 10.1016/j.jalz.2018.04.010 PubMed DOI PMC

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(5):542-551. doi: 10.1001/jamaneurol.2018.4693 PubMed DOI PMC

Buckley RF, Scott MR, Jacobs HIL, et al. Sex mediates relationships between regional tau pathology and cognitive decline. Ann Neurol. 2020;88(5):921-932. doi: 10.1002/ana.25878 PubMed DOI PMC

Babapour Mofrad R, Tijms BM, Scheltens P, et al. Sex differences in CSF biomarkers vary by Alzheimer disease stage and PubMed DOI

Hohman TJ, Dumitrescu L, Barnes LL, et al. ; Alzheimer’s Disease Genetics Consortium and the Alzheimer’s Disease Neuroimaging Initiative . Sex-specific association of apolipoprotein E with cerebrospinal fluid levels of tau. JAMA Neurol. 2018;75(8):989-998. doi: 10.1001/jamaneurol.2018.0821 PubMed DOI PMC

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. doi: 10.1016/j.phrs.2016.11.035 PubMed DOI

Chen R, Desai NR, Ross JS, et al. Publication and reporting of clinical trial results: cross sectional analysis across academic medical centers. BMJ. 2016;352:i637. doi: 10.1136/bmj.i637 PubMed DOI PMC

Sreekrishnan A, Mampre D, Ormseth C, et al. Publication and dissemination of results in clinical trials of neurology. JAMA Neurol. 2018;75(7):890-891. doi: 10.1001/jamaneurol.2018.0674 PubMed DOI PMC

Carcel C, Woodward M, Balicki G, et al. Trends in recruitment of women and reporting of sex differences in large-scale published randomized controlled trials in stroke. Int J Stroke. 2019;14(9):931-938. doi: 10.1177/1747493019851292 PubMed DOI

Sterne JAC, Savović J, Page MJ, et al. RoB 2: a revised tool for assessing risk of bias in randomised trials. BMJ. 2019;366:14898. doi: 10.1136/bmj.l4898 PubMed DOI

Ferrari A, Comelli M. A comparison of methods for the analysis of binomial clustered outcomes in behavioral research. J Neurosci Methods. 2016;274:131-140. doi: 10.1016/j.jneumeth.2016.10.005 PubMed DOI

Tu Y-K. Use of generalized linear mixed models for network meta-analysis. Med Decis Making. 2014;34(7):911-918. doi: 10.1177/0272989X14545789 PubMed DOI

R Core Team .

Doody RS, Gavrilova SI, Sano M, et al. ; dimebon investigators . Effect of dimebon on cognition, activities of daily living, behaviour, and global function in patients with mild-to-moderate Alzheimer’s disease: a randomised, double-blind, placebo-controlled study. Lancet. 2008;372(9634):207-215. doi: 10.1016/S0140-6736(08)61074-0 PubMed DOI

Sevigny JJ, Ryan JM, van Dyck CH, Peng Y, Lines CR, Nessly ML; MK-677 Protocol 30 Study Group . Growth hormone secretagogue MK-677: no clinical effect on AD progression in a randomized trial. Neurology. 2008;71(21):1702-1708. doi: 10.1212/01.wnl.0000335163.88054.e7 PubMed DOI

Green RC, Schneider LS, Amato DA, et al. ; Tarenflurbil Phase 3 Study Group . Effect of tarenflurbil on cognitive decline and activities of daily living in patients with mild Alzheimer disease: a randomized controlled trial. JAMA. 2009;302(23):2557-2564. doi: 10.1001/jama.2009.1866 PubMed DOI PMC

Maher-Edwards G, Dixon R, Hunter J, et al. SB-742457 and donepezil in Alzheimer disease: a randomized, placebo-controlled study. Int J Geriatr Psychiatry. 2011;26(5):536-544. doi: 10.1002/gps.2562 PubMed DOI

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(2):131-146. doi: 10.1159/000318845 PubMed DOI PMC

Feldman HH, Doody RS, Kivipelto M, et al. ; LEADe Investigators . Randomized controlled trial of atorvastatin in mild to moderate Alzheimer disease: LEADe. Neurology. 2010;74(12):956-964. doi: 10.1212/WNL.0b013e3181d6476a PubMed DOI

Maher-Edwards G, Zvartau-Hind M, Hunter AJ, et al. Double-blind, controlled phase II study of a 5-HT6 receptor antagonist, SB-742457, in Alzheimer’s disease. Curr Alzheimer Res. 2010;7(5):374-385. doi: 10.2174/156720510791383831 PubMed DOI

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(1):102-111. doi: 10.5114/aoms.2011.20612 PubMed DOI PMC

Alvarez XA, Cacabelos R, Sampedro C, et al. Combination treatment in Alzheimer’s disease: results of a randomized, controlled trial with cerebrolysin and donepezil. Curr Alzheimer Res. 2011;8(5):583-591. doi: 10.2174/156720511796391863 PubMed DOI

Salloway S, Sperling R, Keren R, et al. ; ELND005-AD201 Investigators . A phase 2 randomized trial of ELND005, scyllo-inositol, in mild to moderate Alzheimer disease. Neurology. 2011;77(13):1253-1262. doi: 10.1212/WNL.0b013e3182309fa5 PubMed DOI PMC

Rafii MS, Walsh S, Little JT, et al. ; Alzheimer’s Disease Cooperative Study . A phase II trial of huperzine A in mild to moderate Alzheimer disease. Neurology. 2011;76(16):1389-1394. doi: 10.1212/WNL.0b013e318216eb7b PubMed DOI PMC

Vellas B, Sol O, Snyder PJ, et al. ; EHT0202/002 study group . EHT0202 in Alzheimer’s disease: a 3-month, randomized, placebo-controlled, double-blind study. Curr Alzheimer Res. 2011;8(2):203-212. doi: 10.2174/156720511795256053 PubMed DOI

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(5):592-606. doi: 10.2174/156720511796391935 PubMed DOI

Coric V, van Dyck CH, Salloway S, et al. Safety and tolerability of the γ-secretase inhibitor avagacestat in a phase 2 study of mild to moderate Alzheimer disease. Arch Neurol. 2012;69(11):1430-1440. doi: 10.1001/archneurol.2012.2194 PubMed DOI

Egan M, Yaari R, Liu L, et al. Pilot randomized controlled study of a histamine receptor inverse agonist in the symptomatic treatment of AD. Curr Alzheimer Res. 2012;9(4):481-490. doi: 10.2174/156720512800492530 PubMed DOI

Doody RS, Raman R, Farlow M, et al. ; Alzheimer’s Disease Cooperative Study Steering Committee; Semagacestat Study Group . A phase 3 trial of semagacestat for treatment of Alzheimer’s disease. N Engl J Med. 2013;369(4):341-350. doi: 10.1056/NEJMoa1210951 PubMed DOI

Doody RS, Thomas RG, Farlow M, et al. ; Alzheimer’s Disease Cooperative Study Steering Committee; Solanezumab Study Group . Phase 3 trials of solanezumab for mild-to-moderate Alzheimer’s disease. N Engl J Med. 2014;370(4):311-321. doi: 10.1056/NEJMoa1312889 PubMed DOI

Marek GJ, Katz DA, Meier A, et al. Efficacy and safety evaluation of HSD-1 inhibitor ABT-384 in Alzheimer’s disease. Alzheimers Dement. 2014;10(5)(suppl):S364-S373. doi: 10.1016/j.jalz.2013.09.010 PubMed DOI

Wilkinson D, Windfeld K, Colding-Jørgensen E. Safety and efficacy of idalopirdine, a 5-HT6 receptor antagonist, in patients with moderate Alzheimer’s disease (LADDER): a randomised, double-blind, placebo-controlled phase 2 trial. Lancet Neurol. 2014;13(11):1092-1099. doi: 10.1016/S1474-4422(14)70198-X PubMed DOI

Salloway S, Sperling R, Fox NC, et al. ; Bapineuzumab 301 and 302 Clinical Trial Investigators . Two phase 3 trials of bapineuzumab in mild-to-moderate Alzheimer’s disease. N Engl J Med. 2014;370(4):322-333. doi: 10.1056/NEJMoa1304839 PubMed DOI PMC

Grove RA, Harrington CM, Mahler A, et al. A randomized, double-blind, placebo-controlled, 16-week study of the H3 receptor antagonist, GSK239512 as a monotherapy in subjects with mild-to-moderate Alzheimer’s disease. Curr Alzheimer Res. 2014;11(1):47-58. doi: 10.2174/1567205010666131212110148 PubMed DOI

Galasko D, Bell J, Mancuso JY, et al. ; Alzheimer’s Disease Cooperative Study . Clinical trial of an inhibitor of RAGE-Aβ interactions in Alzheimer disease. Neurology. 2014;82(17):1536-1542. doi: 10.1212/WNL.0000000000000364 PubMed DOI PMC

Maher-Edwards G, Watson C, Ascher J, et al. Two randomized controlled trials of SB742457 in mild-to-moderate Alzheimer’s disease. Alzheimers Dement (N Y). 2015;1(1):23-36. doi: 10.1016/j.trci.2015.04.001 PubMed DOI PMC

Lenz RA, Pritchett YL, Berry SM, et al. Adaptive, dose-finding phase 2 trial evaluating the safety and efficacy of ABT-089 in mild to moderate Alzheimer disease. Alzheimer Dis Assoc Disord. 2015;29(3):192-199. doi: 10.1097/WAD.0000000000000093 PubMed DOI

Gault LM, Ritchie CW, Robieson WZ, Pritchett Y, Othman AA, Lenz RA. A phase 2 randomized, controlled trial of the α7 agonist ABT-126 in mild-to-moderate Alzheimer’s dementia. Alzheimers Dement (N Y). 2015;1(1):81-90. doi: 10.1016/j.trci.2015.06.001 PubMed DOI PMC

Wischik CM, Staff RT, Wischik DJ, et al. Tau aggregation inhibitor therapy: an exploratory phase 2 study in mild or moderate Alzheimer’s disease. J Alzheimers Dis. 2015;44(2):705-720. doi: 10.3233/JAD-142874 PubMed DOI

Gauthier S, Rountree S, Finn B, LaPlante B, Weber E, Oltersdorf T. Effects of the acetylcholine release agent ST101 with donepezil in Alzheimer’s disease: a randomized phase 2 study. J Alzheimers Dis. 2015;48(2):473-481. doi: 10.3233/JAD-150414 PubMed DOI

Maher-Edwards G, De’Ath J, Barnett C, Lavrov A, Lockhart A. A 24-week study to evaluate the effect of rilapladib on cognition and cerebrospinal fluid biomarkers of Alzheimer’s disease. Alzheimers Dement (N Y). 2015;1(2):131-140. doi: 10.1016/j.trci.2015.06.003 PubMed DOI PMC

Pasquier F, Sadowsky C, Holstein A, et al. ; ACC-001 (QS-21) Study Team . Two phase 2 multiple ascending-dose studies of vanutide cridificar (ACC-001) and QS-21 adjuvant in mild-to-moderate Alzheimer’s disease. J Alzheimers Dis. 2016;51(4):1131-1143. doi: 10.3233/JAD-150376 PubMed DOI

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. 2016;388(10062):2873-2884. doi: 10.1016/S0140-6736(16)31275-2 PubMed DOI PMC

Gault LM, Lenz RA, Ritchie CW, et al. ABT-126 monotherapy in mild-to-moderate Alzheimer’s dementia: randomized double-blind, placebo and active controlled adaptive trial and open-label extension. Alzheimers Res Ther. 2016;8(1):44. doi: 10.1186/s13195-016-0210-1 PubMed DOI PMC

Florian H, Meier A, Gauthier S, et al. Efficacy and safety of ABT-126 in subjects with mild-to-moderate Alzheimer’s disease on stable doses of acetylcholinesterase inhibitors: a randomized, double-blind, placebo-controlled study. J Alzheimers Dis. 2016;51(4):1237-1247. doi: 10.3233/JAD-150978 PubMed DOI

Vandenberghe R, Rinne JO, Boada M, et al. ; Bapineuzumab 3000 and 3001 Clinical Study Investigators . Bapineuzumab for mild to moderate Alzheimer’s disease in two global, randomized, phase 3 trials. Alzheimers Res Ther. 2016;8(1):18. doi: 10.1186/s13195-016-0189-7 PubMed DOI PMC

Brody M, Liu E, Di J, et al. A phase II, randomized, double-blind, placebo-controlled study of safety, pharmacokinetics, and biomarker results of subcutaneous bapineuzumab in patients with mild to moderate Alzheimer’s disease. J Alzheimers Dis. 2016;54(4):1509-1519. doi: 10.3233/JAD-160369 PubMed DOI

Nave S, Doody RS, Boada M, et al. Sembragiline in moderate Alzheimer’s disease: results of a randomized, double-blind, placebo-controlled phase II trial (MAyflOwer RoAD). J Alzheimers Dis. 2017;58(4):1217-1228. doi: 10.3233/JAD-161309 PubMed DOI PMC

Relkin NR, Thomas RG, Rissman RA, et al. ; Alzheimer’s Disease Cooperative Study . A phase 3 trial of IV immunoglobulin for Alzheimer disease. Neurology. 2017;88(18):1768-1775. doi: 10.1212/WNL.0000000000003904 PubMed DOI PMC

Xiao S, Wang T, Ma X, et al. Efficacy and safety of a novel acetylcholinesterase inhibitor octohydroaminoacridine in mild-to-moderate Alzheimer’s disease: a phase II multicenter randomised controlled trial. Age Ageing. 2017;46(5):767-773. doi: 10.1093/ageing/afx045 PubMed DOI

Rinne JO, Wesnes K, Cummings JL, et al. Tolerability of ORM-12741 and effects on episodic memory in patients with Alzheimer’s disease. Alzheimers Dement (N Y). 2016;3(1):1-9. PubMed PMC

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(18):1691-1703. doi: 10.1056/NEJMoa1706441 PubMed DOI PMC

Lawlor B, Segurado R, Kennelly S, et al. ; NILVAD Study Group . Nilvadipine in mild to moderate Alzheimer disease: a randomised controlled trial. PLoS Med. 2018;15(9):e1002660. doi: 10.1371/journal.pmed.1002660 PubMed DOI PMC

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(4):321-330. doi: 10.1056/NEJMoa1705971 PubMed DOI

Atri A, Frölich L, Ballard C, et al. Effect of idalopirdine as adjunct to cholinesterase inhibitors on change in cognition in patients with Alzheimer disease: three randomized clinical trials. JAMA. 2018;319(2):130-142. doi: 10.1001/jama.2017.20373 PubMed DOI PMC

Fullerton T, Binneman B, David W, et al. A phase 2 clinical trial of PF-05212377 (SAM-760) in subjects with mild to moderate Alzheimer’s disease with existing neuropsychiatric symptoms on a stable daily dose of donepezil. Alzheimers Res Ther. 2018;10(1):38. doi: 10.1186/s13195-018-0368-9 PubMed DOI PMC

Voss T, Li J, Cummings J, et al. Randomized, controlled, proof-of-concept trial of MK-7622 in Alzheimer’s disease. Alzheimers Dement (N Y). 2018;4:173-181. doi: 10.1016/j.trci.2018.03.004 PubMed DOI PMC

Cummings JL, Cohen S, van Dyck CH, et al. ABBY: a phase 2 randomized trial of crenezumab in mild to moderate Alzheimer disease. Neurology. 2018;90(21):e1889-e1897. doi: 10.1212/WNL.0000000000005550 PubMed DOI PMC

Schneider LS, Thomas RG, Hendrix S, et al. ; Alzheimer’s Disease Cooperative Study TCAD Study Group . Safety and efficacy of edonerpic maleate for patients with mild to moderate Alzheimer disease: a phase 2 randomized clinical trial. JAMA Neurol. 2019;76(11):1330-1339. doi: 10.1001/jamaneurol.2019.1868 PubMed DOI PMC

van Dyck CH, Nygaard HB, Chen K, et al. Effect of AZD0530 on cerebral metabolic decline in Alzheimer disease: a randomized clinical trial. JAMA Neurol. 2019;76(10):1219-1229. doi: 10.1001/jamaneurol.2019.2050 PubMed DOI PMC

Burns A, Bernabei R, Bullock R, et al. Safety and efficacy of galantamine (Reminyl) in severe Alzheimer’s disease (the SERAD study): a randomised, placebo-controlled, double-blind trial. Lancet Neurol. 2009;8(1):39-47. doi: 10.1016/S1474-4422(08)70261-8 PubMed DOI

Farlow MR, Salloway S, Tariot PN, et al. Effectiveness and tolerability of high-dose (23 mg/d) versus standard-dose (10 mg/d) donepezil in moderate to severe Alzheimer’s disease: a 24-week, randomized, double-blind study. Clin Ther. 2010;32(7):1234-1251. doi: 10.1016/j.clinthera.2010.06.019 PubMed DOI PMC

Nakamura Y, Imai Y, Shigeta M, et al. A 24-week, randomized, double-blind, placebo-controlled study to evaluate the efficacy, safety and tolerability of the rivastigmine patch in Japanese patients with Alzheimer’s disease. Dement Geriatr Cogn Dis Extra. 2011;1(1):163-179. doi: 10.1159/000328929 PubMed DOI PMC

Cummings J, Froelich L, Black SE, et al. Randomized, double-blind, parallel-group, 48-week study for efficacy and safety of a higher-dose rivastigmine patch (15 vs. 10 cm PubMed DOI

Grossberg GT, Manes F, Allegri RF, et al. The safety, tolerability, and efficacy of once-daily memantine (28 mg): a multinational, randomized, double-blind, placebo-controlled trial in patients with moderate-to-severe Alzheimer’s disease taking cholinesterase inhibitors. CNS Drugs. 2013;27(6):469-478. doi: 10.1007/s40263-013-0077-7 PubMed DOI PMC

Hager K, Baseman AS, Nye JS, et al. Effects of galantamine in a 2-year, randomized, placebo-controlled study in Alzheimer’s disease. Neuropsychiatr Dis Treat. 2014;10:391-401. PubMed PMC

Nakamura Y, Strohmaier C, Tamura K, et al. A 24-week, randomized, controlled study to evaluate the tolerability, safety and efficacy of 2 different titration schemes of the rivastigmine patch in Japanese patients with mild to moderate Alzheimer’s disease. Dement Geriatr Cogn Dis Extra. 2015;5(3):361-374. doi: 10.1159/000439269 PubMed DOI PMC

Zhang ZX, Hong Z, Wang YP, et al. Rivastigmine patch in Chinese patients with probable Alzheimer’s disease: a 24-week, randomized, double-blind parallel-group study comparing rivastigmine patch (9.5 mg/24 h) with capsule (6 mg twice daily). CNS Neurosci Ther. 2016;22(6):488-496. doi: 10.1111/cns.12521 PubMed DOI PMC

Homma A, Atarashi H, Kubota N, Nakai K, Takase T. Efficacy and safety of sustained release donepezil high dose versus immediate release donepezil standard dose in Japanese patients with severe Alzheimer’s disease: a randomized, double-blind trial. J Alzheimers Dis. 2016;52(1):345-357. doi: 10.3233/JAD-151149 PubMed DOI

Frölich L, Wunderlich G, Thamer C, Roehrle M, Garcia M Jr, Dubois B. Evaluation of the efficacy, safety and tolerability of orally administered BI 409306, a novel phosphodiesterase type 9 inhibitor, in two randomised controlled phase II studies in patients with prodromal and mild Alzheimer’s disease. Alzheimers Res Ther. 2019;11(1):18. doi: 10.1186/s13195-019-0467-2 PubMed DOI PMC

Scheltens P, Hallikainen M, Grimmer T, et al. Safety, tolerability and efficacy of the glutaminyl cyclase inhibitor PQ912 in Alzheimer’s disease: results of a randomized, double-blind, placebo-controlled phase 2a study. Alzheimers Res Ther. 2018;10(1):107. doi: 10.1186/s13195-018-0431-6 PubMed DOI PMC

Sevigny J, Chiao P, Bussière T, et al. The antibody aducanumab reduces Aβ plaques in Alzheimer’s disease. Nature. 2016;537(7618):50-56. doi: 10.1038/nature19323 PubMed DOI

Ostrowitzki S, Lasser RA, Dorflinger E, et al. ; SCarlet RoAD Investigators . A phase III randomized trial of gantenerumab in prodromal Alzheimer’s disease. Alzheimers Res Ther. 2017;9(1):95. doi: 10.1186/s13195-017-0318-y PubMed DOI PMC

Coric V, Salloway S, van Dyck CH, et al. Targeting prodromal Alzheimer disease with avagacestat: a randomized clinical trial. JAMA Neurol. 2015;72(11):1324-1333. doi: 10.1001/jamaneurol.2015.0607 PubMed DOI

Egan MF, Kost J, Voss T, et al. Randomized trial of verubecestat for prodromal Alzheimer’s disease. N Engl J Med. 2019;380(15):1408-1420. doi: 10.1056/NEJMoa1812840 PubMed DOI PMC

Schneeberger A, Hendrix S, Ellison N, Bürger V, Dubois B. Additional results from a phase II study to assess the clinical and immunological activity, safety, and tolerability of AFFITOPE® AD02 in patients with early Alzheimer’s disease (AD). Alzheimers Dement. 2015;11(7):276. doi: 10.1016/j.jalz.2015.07.365 PubMed DOI

Craft S, Baker LD, Montine TJ, et al. Intranasal insulin therapy for Alzheimer disease and amnestic mild cognitive impairment: a pilot clinical trial. Arch Neurol. 2012;69(1):29-38. doi: 10.1001/archneurol.2011.233 PubMed DOI PMC

Ferris SH, Schmitt FA, Saxton J, et al. Analyzing the impact of 23 mg/day donepezil on language dysfunction in moderate to severe Alzheimer’s disease. Alzheimers Res Ther. 2011;3(3):22. doi: 10.1186/alzrt84 PubMed DOI PMC

Doody RS, Geldmacher DS, Farlow MR, Sun Y, Moline M, Mackell J. Efficacy and safety of donepezil 23 mg versus donepezil 10 mg for moderate-to-severe Alzheimer’s disease: a subgroup analysis in patients already taking or not taking concomitant memantine. Dement Geriatr Cogn Disord. 2012;33(2-3):164-173. doi: 10.1159/000338236 PubMed DOI

Ohnishi T, Sakiyama Y, Okuri Y, et al. The prediction of response to galantamine treatment in patients with mild to moderate Alzheimer’s disease. Curr Alzheimer Res. 2014;11(2):110-118. doi: 10.2174/15672050113106660167 PubMed DOI PMC

Yoshida K, Moein A, Bittner T, et al. Pharmacokinetics and pharmacodynamic effect of crenezumab on plasma and cerebrospinal fluid beta-amyloid in patients with mild-to-moderate Alzheimer’s disease. Alzheimers Res Ther. 2020;12(1):16. doi: 10.1186/s13195-020-0580-2 PubMed DOI PMC

Abushakra S, Porsteinsson A, Scheltens P, et al. Clinical effects of tramiprosate in APOE4/4 homozygous patients with mild Alzheimer’s disease suggest disease modification potential. J Prev Alzheimers Dis. 2017;4(3):149-156. doi: 10.14283/jpad.2017.26 PubMed DOI

Salloway S, Mintzer J, Cummings JL, et al. Subgroup analysis of US and non-US patients in a global study of high-dose donepezil (23 mg) in moderate and severe Alzheimer’s disease. Am J Alzheimers Dis Other Demen. 2012;27(6):421-432. doi: 10.1177/1533317512454708 PubMed DOI PMC

Schmitt FA, Saxton J, Ferris SH, Mackell J, Sun Y. Evaluation of an 8-item Severe Impairment Battery (SIB-8) vs. the full SIB in moderate to severe Alzheimer’s disease patients participating in a donepezil study. Int J Clin Pract. 2013;67(10):1050-1056. doi: 10.1111/ijcp.12188 PubMed DOI PMC

Hager K, Baseman AS, Nye JS, et al. Effect of concomitant use of memantine on mortality and efficacy outcomes of galantamine-treated patients with Alzheimer’s disease: post-hoc analysis of a randomized placebo-controlled study. Alzheimers Res Ther. 2016;8(1):47. doi: 10.1186/s13195-016-0214-x PubMed DOI PMC

Doody RS, Raman R, Sperling RA, et al. ; Alzheimer’s Disease Cooperative Study . Peripheral and central effects of γ-secretase inhibition by semagacestat in Alzheimer’s disease. Alzheimers Res Ther. 2015;7(1):36. doi: 10.1186/s13195-015-0121-6 PubMed DOI PMC

Liu E, Schmidt ME, Margolin R, et al. ; Bapineuzumab 301 and 302 Clinical Trial Investigators . Amyloid-β 11C-PiB-PET imaging results from 2 randomized bapineuzumab phase 3 AD trials. Neurology. 2015;85(8):692-700. doi: 10.1212/WNL.0000000000001877 PubMed DOI PMC

Samtani MN, Xu SX, Russu A, et al. Alzheimer’s disease assessment scale-cognitive 11-item progression model in mild-to-moderate Alzheimer’s disease trials of bapineuzumab. Alzheimers Dement (N Y). 2015;1(3):157-169. doi: 10.1016/j.trci.2015.09.001 PubMed DOI PMC

Molinuevo JL, Frölich L, Grossberg GT, et al. Responder analysis of a randomized comparison of the 13.3 mg/24 h and 9.5 mg/24 h rivastigmine patch. Alzheimers Res Ther. 2015;7(1):9. doi: 10.1186/s13195-014-0088-8 PubMed DOI PMC

Grossberg GT, Alva G, Hendrix S, Ellison N, Kane MC, Edwards J. Memantine ER maintains patient response in moderate to severe Alzheimer’s disease: post hoc analyses from a randomized, controlled, clinical trial of patients treated with cholinesterase inhibitors. Alzheimer Dis Assoc Disord. 2018;32(3):173-178. doi: 10.1097/WAD.0000000000000261 PubMed DOI PMC

Bartlett VL, Dhruva SS, Shah ND, Ryan P, Ross JS. Feasibility of using real-world data to replicate clinical trial evidence. JAMA Netw Open. 2019;2(10):e1912869-e1912869. doi: 10.1001/jamanetworkopen.2019.12869 PubMed DOI PMC

Stauffer VL, Dodick DW, Zhang Q, Carter JN, Ailani J, Conley RR. Evaluation of galcanezumab for the prevention of episodic migraine: the EVOLVE-1 randomized clinical trial. JAMA Neurol. 2018;75(9):1080-1088. doi: 10.1001/jamaneurol.2018.1212 PubMed DOI PMC

Boada M. Gender and sex bias in clinical trials, recruitment in Alzheimer’s disease: findings from Fundacio ACE. Presented at: Clinical Trials on Alzheimer’s Disease (CTAD) 2019; December 4-7, 2019; San Diego, CA; and Alzheimer’s Association International Conference (AAIC) 2020; July 27-31, 2020.

Marshall DL, Hazlet TK, Gardner JS, Blough DK. Neuroleptic drug exposure and incidence of tardive dyskinesia: a records-based case-control study. J Manag Care Pharm. 2002;8(4):259-265. doi: 10.18553/jmcp.2002.8.4.259 PubMed DOI

EXELON (rivastigmine tartrate). Draft package insert. Food and Drug Administration; 2000. Accessed July 24, 2020. https://www.accessdata.fda.gov/drugsatfda_docs/label/2000/20823lbl.pdf

Namenda (Memantine HCI) tablets medical review, Part 4. Food and Drug Administration; 2003. Accessed July 24, 2020. https://www.accessdata.fda.gov/drugsatfda_docs/nda/2003/21-487_Namenda_Medr_P4.pdf

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

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