Sex Difference in Effects of Low-Dose Aspirin on Prevention of Dementia

314 Diabetes Care Volume 43, February 2020

Chisa Matsumoto,1,2 Hisao Ogawa,3 Sex Difference in Effects of Low- Yoshihiko Saito,4 Sadanori Okada,4,5 Hirofumi Soejima,6 Mio Sakuma,1 Dose Aspirin on Prevention of Izuru Masuda,7 Masafumi Nakayama,8 Naofumi Doi,9 Hideaki Jinnouchi,10 Dementia in Patients With Type 2 Masako Waki,11 Takeshi Morimoto,1 and Diabetes: A Long-term Follow-up the JPAD Trial Investigators* Study of a Randomized Clinical Trial Diabetes Care 2020;43:314–320 | https://doi.org/10.2337/dc19-1188 CLIN CARE/EDUCATION/NUTRITION/PSYCHOSOCIAL

1Department of Clinical Epidemiology, Hyogo OBJECTIVE College of Medicine, Hyogo, Japan 2 fi Center for Health Surveillance and Preventive To evaluate and compare the ef cacy of long-term use of low-dose aspirin for the Medicine, Tokyo Medical University, Tokyo, Japan prevention of dementia in men and women. 3National Cerebral and Cardiovascular Center, Osaka, Japan RESEARCH DESIGN AND METHODS 4Department of Cardiovascular Medicine, Nara This study is a follow-up cohort study of the Japanese Primary Prevention of Medical University, Nara, Japan 5Department of Diabetology, Nara Medical Uni- Atherosclerosis With Aspirin for Diabetes (JPAD) trial, which was a randomized, versity, Nara, Japan open-label, standard care–controlled trial examining the effects of low-dose aspirin 6Department of Cardiology, Graduate School of on cardiovascular events. We followed up 2,536 Japanese patients with type 2 Medical Sciences, Kumamoto University, Kuma- moto, Japan diabetes (T2D) enrolled in the JPAD trial from 2002 to 2017. The primary outcome of 7 fi Medical Examination Center, Takeda Hospital, this post hoc analysis was the incidence of dementia, which was de ned by the Kyoto, Japan prescription of antidementia drugs or admission due to dementia. 8Nakayama Cardiovascular Clinic, Kumamoto, Japan RESULTS 9Department of Cardiovascular Medicine, Nara Among the originally enrolled patients, 2,121 (84%) retained their original allo- Prefectural Seiwa Medical Center, Nara, Japan 10Department of Internal Medicine, Diabetes cation. During a median follow-up of 11.4 years, 128 patients developed dementia. Care Center, Jinnouchi Hospital, Kumamoto, Japan The overall effect of low-dose aspirin on the prevention of dementia adjusted for 11Department of Internal Medicine, Shizuoka age, sex, and other established risk factors was not significant (hazard ratio [HR] City Shizuoka Hospital, Shizuoka, Japan 0.82, 95% CI 0.58–1.16). However, a significant reduction was seen in the risk of Corresponding author: Takeshi Morimoto, dementia in women (HR 0.58, 95% CI 0.36–0.95), but not in men (HR 1.27, 95% CI [email protected] 0.75–2.13) (P 5 0.03). Received 16 June 2019 and accepted 24 October interaction 2019 CONCLUSIONS Clinical trial reg. no. NCT00110448, clinicaltrials Long-term use of low-dose aspirin may reduce the risk for dementia in women with .gov T2D. This article contains Supplementary Data online at http://care.diabetesjournals.org/lookup/suppl/ doi:10.2337/dc19-1188/-/DC1. The number of patients with dementia is growing rapidly and is estimated to reach *Alist of theJPAD TrialInvestigatorscan befound 82 million in 2030 and 152 million in 2050. Dementia has significant social and in the Supplementary Data online. economic implications, and the total global societal cost for managing dementia was © 2019 by the American Diabetes Association. estimatedtobe818billionUSDin2015(1).However,prophylaxis fordementia hasnot Readers may use this article as long as the work is properly cited, the use is educational and not for been established. profit, and the work is not altered. More infor- Several factors have been reported to be risk factors for dementia, such as mation is available at http://www.diabetesjournals hypertension, tobacco use, and obesity (2,3). Type 2 diabetes (T2D) is one of the .org/content/license. care.diabetesjournals.org Matsumoto and Associates 315

important risk factors for the develop- With Aspirin for Diabetes), which was a Ascertainment of Dementia ment of both vascular and nonvascular randomized, open-label, standard care– Dementia was ascertained based on 1) dementia (4,5). Patients with T2D are controlled trial that examined the effects prescription of antidementia drugs or 2) considered to be at a high risk of de- of low-dose aspirin on cardiovascular admission to a hospital/nursing home veloping dementia due to multiple risk events in 2,539 Japanese patients with due to dementia. All events were re- factors such as hypertension and obesity. T2D (Supplementary Figs. 1 and 2). A viewed with a case report form by an Since there is a huge worldwide burden detailed description of both the studies independent event adjudication com- of T2D (6), the establishment of strate- has previously been published (16,17). mittee that was blinded to the assigned gies for prevention of dementia in T2D Briefly, patient enrollment in the JPAD intervention. The event adjudication patients is a pressing issue. trial started in December 2002 and was committee requested detailed informa- Since both vascular dementia and Alz- completed in May 2005 at 163 institu- tion from each participating hospital heimer dementia (AD) share several tions throughout Japan (Supplementary when additional information was neces- pathophysiological factors with athero- Data). After the trial was completed in sary to adjudicate the events. When sclerotic disease, aspirin has been at- April 2008, we continued to follow up all there were disagreements on the diag- tracting interest as a preventive agent the patients and constructed the JPAD2 nosis of dementia, all committee mem- for dementia (7). While some studies cohort. Patients were followed until the bers participated in the discussion and have suggested that low-dose aspirin day of any fatal event or July 2017, made final agreements. may protect against AD by improving regardless of the occurrence of any car- platelet and endothelium functions (7), diovascularevent.BoththeJPADtrialand Statistical Analyses the findings have not been consistent. JPAD2 cohort study were carried out We present the baseline characteristics Meta-analysis of randomized controlled according to the Declaration of Helsinki as mean and SD for continuous variables trials (RCTs) with median follow-up of and were approved by the ethics com- and number and percentage for categor- 5 years evaluating the effects of low- mittee of each participating hospital (the ical variables. We used the t test or dose aspirin on cognitive functions has re- Graduate School of Medical Science, Wilcoxon rank sum test for continuous 2 ported no improvement (8). On the other Kumamoto University, ethics committee variables and x tests for categorical hand, some observational studies have and Nara Medical University ethics com- variables to compare the baseline char- reported an association between low- mittee). All the participants provided acteristics between groups. The follow-up dose aspirin and a lower risk of dementia written informed consent. The JPAD trial time was computed from baseline until the or cognitive decline (9,10). However, no was registered at ClinicalTrials.gov. occurrence of dementia, death, or the date studies have evaluated the long-term of last known contact. Cumulative inci- association between low-dose aspirin Patients dence of dementia in each assigned group and the risk of dementia in patients The details of the inclusion and exclusion was estimated using the Kaplan-Meier with T2D using real world data, even criteria for the JPAD trial have previously method, and differences between groups though the pathological change of typical been published (16,17). Briefly, the in- were assessed using the log-rank test. We dementia develops slowly over decades. clusion criteria were 1) diagnosis of T2D, used the Cox proportional hazards models Furthermore, differences have been 2) age 30–85 years, and 3) ability to to estimate the hazard ratio (HR) with the suggested in the risk of developing de- provide informed consent. The exclusion corresponding 95% CI for the efficacy of mentia between the two sexes (11–14). criteria included a history of cardiovas- low-dose aspirin in lowering the incidence For instance, the genotype of apolipo- cular disease (CVD) including cerebral of dementia. The initial model (model 1) protein E (ApoE), which plays a role in the vascular disease and the use of antiplate- was adjusted for age and sex, while the prevention of dementia by nonsteroidal let or antithrombotic therapy. A total of second model was additionally adjusted for anti-inflammatory drugs (NSAIDs) (15), 2,536 patients were enrolled in the JPAD2 BMI, hypertension, dyslipidemia, smoking seemstohave a stronger effect in women cohort study (Supplementary Figs. 1 and status(currentandpast),andHbA1c (model compared with men (13). However, only 2). None of the patients had dementia at 2).Wethenevaluatedtheassociationand a few studies have evaluated the differ- the baseline of the JPAD2 study. interaction between low-dose aspirin and ence in the effects of low-dose aspirin the risk of dementia based on sex. We also in the prevention of dementia between Intervention performed sensitivity analyses to assess men and women. Patients were randomly allocated (1:1) the robustness of our findings by repeating Therefore, in this cohort study, we to receive low-dose aspirin (81 mg or Cox proportional hazards modeling using evaluated the effects of low-dose aspirin 100 mg daily) or no aspirin in the JPAD the per-protocol cohort. on the prevention of dementia among trial. All participants were allowed to All analyses were conducted using JMP patients with T2D. We also compared receive other concurrent treatments. 12.2 and SAS 9.4 (SAS Institute, Cary, NC). the effects of low-dose aspirin between The details of the intervention have pre- Two-tailed P values ,0.05 were consid- men and women. viously been described (16). At the end of ered statistically significant. the JPAD trial, the participants were RESEARCH DESIGN AND METHODS administered low-dose aspirin based RESULTS Study Design on the decision of each physician dur- The mean 6 SD age of patients at baseline TheJPAD2studyisaprospectivefollow-up ing the follow-up period. We checked was 65 6 10 years, and the median cohort study of the JPAD trial (Japanese whether the participants were administered duration of diabetes was 7.0 years (inter- Primary Prevention of Atherosclerosis low-dose aspirin during the follow-up. quartile range 2.9–12.3). The baseline 316 Low-Dose Aspirin and Prevention of Dementia Diabetes Care Volume 43, February 2020

characteristics were similar between pa- 6.5/1,000 person-years vs. men 4.5/ CI 0.25–0.86), but not in men (HR 1.12, tients in the two groups (Table 1). Among 1,000 person-years, P , 0.001). Women 95% CI 0.62–2.02). the patients initially enrolled in JPAD, in the low-dose aspirin group had a lower 2,121 of them (84%) retained their original incidence of dementia compared with CONCLUSIONS allocation until July 2017. During a me- those in the no aspirin group (Fig. 2A). This study suggests that low-dose aspirin dian follow-up of 11.4 years, 128 patients However, no such difference was seen may be effective in the prevention of developed dementia (5.4/1,000 person- between men in the two groups (Fig. 2B). dementia in women with T2D. Our study years). The incidence of dementia was The adjusted HR for the risk of dementia is the first to prospectively evaluate the not significantly different between the among women in the low-dose aspirin long-term association between low-dose low-dose aspirin and no-aspirin groups group was 0.58 (95% CI 0.36–0.95), while aspirin and the risk of dementia in pa- (log rank, P 5 0.73) (Fig. 1). In addition, that in men was 1.27 (95% CI 0.75–2.13) tients with T2D using real-world data. the Cox proportional hazards model ad- (Table 2). The interaction between the A nationwide retrospective study from justed for age, sex, and other established groups and sexes was statistically signif- Taiwan reported that a mean daily dose risk factors for dementia did not show a icant (Pinteraction 5 0.03). of aspirin within 40 mg was associated significant association between the low- Sensitivity analysis using data from the with a lower risk of AD in patients with dose aspirin group and risk of dementia per-protocol cohort consisting of 2,121 T2D (HR 0.5, 95% CI 0.27–0.97) (18). (HR 0.82, 95% CI 0.58–1.16) (Table 2). patients who retained their original al- However, this study used a health in- Among the covariates included in the location showed the robustness of the surance database, and thus the dose of multivariate Cox proportional hazards primary findings. The low-dose aspirin aspirin as well as the patients’ diagnosis model, only age was significantly asso- group did not have decreased risk of and clinical status did not necessarily ciated with an increased risk of dementia, dementia overall in sensitivity analysis conform with reality. In fact, the dose with an HR of 1.16 (95% CI 1.11–1.20, (HR 0.70, 95% CI 0.46–1.06). On the of ,40 mg/day aspirin reported in this P , 0.001; 1-year increase of age). other hand, the risk of dementia among study, which was calculated by dividing The incidence of dementia was greater womeninthelow-doseaspiringroup the cumulative dose by the total obser- in women compared with men (women was statistically significant (HR 0.47, 95% vationaldays, isfarfromthe optimaldose used in general practice. Some prospective observational studies have also Table 1—Baseline characteristics of the JPAD cohort reported a significant association be- No aspirin Low-dose aspirin tween the use of aspirin and a lower risk of AD or cognitive impairment. Yet, N 1,277 1,259 since the participants in these studies Age, years 64 (10) 65 (10) were elderly (age .70 years), the focus Male sex, n (%) 681 (53) 705 (56) was not on patients with T2D (7,9,10). On Smokers (current and past), n (%) 494 (39) 563 (45) the other hand, several observational BMI, kg/m2 24 (4) 24 (4) studies have reported no significant as- SBP, mmHg 134 (15) 136 (15) sociation between the use of aspirin and DBP, mmHg 76 (9) 77 (9) risk of dementia (19,20). However, many Duration of diabetes, years† 6.7 (3.0–12.5), 8.5 (7.2) 7.3 (2.8–12.3), 8.7 (7.5) of these studies did not clarify the def- HbA1c, mmol/mol, % 57 (13), 7.4 (1.2) 58 (16), 7.5 (1.5) inite dose of aspirin used, and there is a FBS, mmol/L 8.1 (2.7) 8.2 (2.8) possibility that the effects of aspirin TCHO, mg/dL 200 (34) 202 (34) on the prevention of dementia could HDL-C, mg/dL 55 (15) 55 (15) be dose dependent (18). Besides the TG, mg/dL 134 (87) 135 (88) dose, the duration of low-dose aspirin Creatinine, mg/dL 0.8 (0.2) 0.8 (0.3) use is also important. Recently, the As- Hypertension, n (%) 731 (57) 739 (59) pirin in Reducing Events in the Elderly Antihypertensive medications, n (%) (ASPREE) trial, which evaluated the ef- Calcium channel blocker 440 (34) 433 (34) fects of low-dose aspirin on a compos- ACE inhibitor 195 (15) 178 (14) ite of death and dementia prevention, Angiotensin II receptor blocker 266 (21) 266 (21) reported no significant effects of aspirin b-Blocker 87 (7) 75 (6) a-Blocker 38 (52) 53 (4) on dementia prevention in an aged pop- Dyslipidemia 665 (52) 679 (54) ulation (21). Even though ASPREE is a Statins 328 (26) 322 (26) well-designed large RCT, the median Antihyperglycemic medications, n (%) follow-up period of 4.7 years of this trial Sulfonylurea 710 (56) 735 (58) is much shorter than that of our study. Metformin 186 (15) 167 (13) Since the development and progression of Thiazolidinedione 65 (5) 62 (5) dementia usually span over a long period of Insulin 160 (13) 166 (13) time, long-term use of low-dose aspirin, Data are mean (SD) unless otherwise indicated. DBP, diastolic blood pressure; FBS, fasting glucose; rather than short- or intermediate-term HDL-C, HDL cholesterol; SBP, systolic blood pressure; TCHO, total cholesterol; TG, triglyceride. use,isneededto seethepreventiveeffects. †Data are median (interquartile range), mean (SD). In fact, to the best of our knowledge, care.diabetesjournals.org Matsumoto and Associates 317

evaluating the efficacy of aspirin for the primary prevention of CVD in patients with diabetes revealed no sex difference in the effects of aspirin (26). The reason forinconsistentresults isuncertain.How- ever, other than the condition diabetes, age, obesity, and kidney function may influence the effects of aspirin on CVD. Several studies have reported a favor- able association between the use of aspirin and better cognitive function in women (10,23), but the underlying mechanism of the difference between sexes was uncertain. The ApoE genotype could to be a potential factor for this difference. Carriers of the E4 allele of ApoE are more likely to develop AD compared with noncarriers (13). Some studies have suggested effect modifica- tion by the ApoE genotype in the association between NSAIDs and AD (15,27). Users of NSAIDs carrying the E4 allele of ApoE are known to have 50–65% lower risk of developing AD compared with nonusers, and this effect is more pro- nounced in women compared with men, Figure 1—Effect of low-dose aspirin on the incidence of dementia. even though this genotype is equally prevalent in women and men (13). None- among the observational studies that have Dementia and CVD share several path- theless, in this study, we did not obtain evaluated the association between aspirin ophysiological factors, and some previ- any genetic information of the partici- and risk of dementia, our study with a ous studies suggested potential sex pants, which makes it impossible to median follow-up of 11.4 years has been difference in the effects of aspirin on evaluate the influence of the ApoE ge- the longest, while most of the previous CVD prevention (24,25). A meta-analysis notype. In addition, anti-inflammatory studies followed up participants for ,8 of six trials evaluating the effects of effects of aspirin should play an impor- years. Interestingly, in the current study, aspirin in CVD prevention in patients tant role in the prevention of dementia in the cumulative incidence of dementia with diabetes reported that aspirin re- addition to CVD (28), and such effects dramatically increased 8 years after the duced the risk of myocardial infarction might be different between sexes. Thus, initial enrollment. In addition, it is sug- (MI) only in men and not in women (24). further studies evaluating the sex differ- gested that the preventive effects of Also, a meta-analysis of 23 trials that ences in the effects of low-dose aspirin aspirin on dementia may be enhanced evaluated whether sex might play a role on inflammation cytokines in conjunction in subjects with cardiovascular risk in explaining the variation of aspirin with development of dementia should (18,22,23). Since the current study con- efficacy in MI prevention trials suggested be conducted. sisted of patients with a high cardiovas- that sex accounted for a substantial pro- We also need to consider gender cular risk profile, the long-term use of portion of the variability in the efficacy of difference in sociocultural factors that low-dose aspirin could partly explain our aspirin in reducing MI rates (25). On the may play some role in the association of findings. contrary, recent meta-analysis of 12 RCTs low-dose aspirin and risk of dementia by

Table 2—Association between low-dose aspirin and risk of dementia All Women Men Intervention No aspirin Low-dose aspirin P No aspirin Low-dose aspirin P No aspirin Low-dose aspirin P Number of participants 1,277 1,259 596 554 681 705 Case subjects, n (%) 68 (5.3) 60 (4.8) 43 (7.2) 26 (4.7) 25 (3.7) 34 (4.8) Incidence rate (per 1,000 PY) 5.6 5.1 7.6 5.1 3.8 5.2 Model 1*‡ Ref. 0.82 (0.58–1.16) 0.26 Ref. 0.56 (0.43–0.91) 0.02 Ref. 1.28 (0.76–2.15) 0.35 Model 2†§ Ref. 0.82 (0.58–1.16) 0.26 Ref. 0.58 (0.36–0.95) 0.03 Ref. 1.27 (0.75–2.13) 0.37 Data are HR (95% CI) unless otherwise indicated. PY, person-years; Ref., reference. *Model 1: multivariate Cox proportional hazards model 1 (all) adjusted for age and sex (women and men) adjusted for age. †Model 2: multivariate Cox proportional hazards model 2 adjusted for covariates in model 1 and hypertension, dyslipidemia, smoking status, BMI, and HbA1c. ‡P for interaction by sex 5 0.02 (model 1). §P for interaction by sex 5 0.03 (model 2). 318 Low-Dose Aspirin and Prevention of Dementia Diabetes Care Volume 43, February 2020

of dementia in women compared with men in our study was influenced by this sociocultural aspect. For the possible difference in the prescription rate of antidementia drugs by sex in Japan, we could not find any previous report. However, one study from Spain reported that there was no sex difference in the prescription rate of the central nervous system drugs in dementia patients (31). Further studies that include genetic and sociocultural information are needed to assess the sex-based difference in the effects of low-dose aspirin on the prevention of dementia. Our study has several strengths, including its large sample size and long duration of follow-up. However, it also has potential limitations. First, the diagnosis of dementia was not based on a cognitive function test and diagnostic imaging, but the ascertainment of dementia was based on admission due to dementia or prescription of antidementia drugs, and thus, the cases of dementia in our study could tend to be advanced dementia and some cases of mild dementia may not be accounted for in our study. And, thus, there can be concern that the “undiagnosed mild dementia” group primarily consists of subjects who received low-dose aspirin. However, the disproportion of undiagnosed dementia in each intervention group may not the- oretically occur in this study, since the JPAD trial was designed as an RCT originally. Second, we could not differentiate the subtypes of dementia. Because the pathophysiological features of each subtype of dementia were different and the effects of low-dose aspirin might be different by each subtype of dementia, combining all the types could offset the effects of low-dose aspirin. On the other hand, AD and vascular dementia, the major subtypes of dementia, share several pathophysiological factors with atherosclerotic disease. In addition, the differentiation of subtype of dementia is sometimes very difficult in clinical settings. Third, the JPAD trial was designed as an RCT to evaluate the efficacy Figure2—Effectoflow-doseaspirinonthe incidenceof dementiabasedonsex.A: Women.B:Men. of low-dose aspirin for the prevention of CVD but not for dementia. Thus, the sex in our study. For instance, low ed- homes more often than men, as men sample size was insufficient to evaluate ucation level and low occupation history tend to be cared for by their spouse at the latter. Fourth, the residual confounding are important risk factors for the de- home in Japan (30). Because we ascer- risk factors (i.e., physical activity, educa- velopment of dementia (29), which can tained dementia as admission due to de- tion) and genetic variations may have be different by sex. Also, women are mentia or prescription of antidementia impacted our findings, though we have reported to admit to hospital/nursing drugs, it is possible that higher incidence comprehensively controlled for other care.diabetesjournals.org Matsumoto and Associates 319

risk factors for dementia. In addition, and Zeria; lecturer’s fees from Asahi Kasei, 3. Patterson C, Feightner JW, Garcia A, Hsiung since the low-dose aspirin was randomly Astellas, Bayer, Daiichi Sankyo, Sumitomo Dai- GY, MacKnight C, Sadovnick AD. Diagnosis and assigned in the original RCT, and the nippon, Fuji Yakuhin, Kowa, Kyowa Hakko Kirin, treatment of dementia: 1. Risk assessment and Mitsubishi Tanabe, MSD, Boehringer Ingelheim, primary prevention of Alzheimer disease. CMAJ allocation of treatment was not changed Novartis, Ono, Otsuka, Pfizer, Sanofi, Taisho 2008;178:548–556 for the majority of the patients, the effect Toyama, Takeda, and Toa Eiyo; a manuscript 4. Biessels GJ, Staekenborg S, Brunner E, Brayne C, of the residual confounders on the find- fee from Pfizer; service on advisory boards of Scheltens P. Risk of dementia in diabetes mellitus: ings should be small if any. Novartis, Pfizer, Mitsubishi Tanabe, Ono, and a systematic review. Lancet Neurol 2006;5:64–74 Boehringer Ingelheim; and a sponsored office 5. Cukierman T, Gerstein HC, Williamson JD. Nevertheless, no large-scale RCT to from MSD. S.O. reports lecturer’s fees from Novo – fi Cognitive decline and dementia in diabetes date has evaluated the ef cacy of the Nordisc, Mitsubishi Tanabe, Sumitomo Dainip- systematic overview of prospective observa- long-term use of low-dose aspirin for the pon, MSD, Bayer, Eli Lilly, Boehringer Ingelheim, tional studies. Diabetologia 2005;48:2460–2469 prevention of dementia. Additionally, Ono, AstraZeneca, Sanofi, Takeda, and Arkray. 6. World Health Organization. Fact Sheets, Diabe- none of the previous observational studies H.S. reports a research grant from Boehringer tes, 30 October 2018 [Internet]. Available from Ingelheim and lecturer’s fees from Boehringer have evaluated the association of low-dose http://www.who.int/news-room/fact-sheets/detail/ Ingelheim, Sumitomo Dainippon, and MSD. M.N. diabetes. Accessed 10 November 2019 aspirin with the risk of dementia, especially reports lecturer’s fees from Bayer, Shionogi, 7. Broe GA, Grayson DA, Creasey HM, et al. Anti- in a population at high risk, using real-world Takeda, Daiichi Sankyo, Sanofi, Boehringer In- inflammatory drugs protect against Alzheimer dis- data. Our study, therefore, could provide gelheim, Sumitomo Dainippon, Fujifilm Medical, ease at low doses. Arch Neurol 2000;57:1586–1591 fi ’ some important leads in the prevention of Kowa, and P zer. N.D. reports lecturer s fees 8. VeroneseN,StubbsB, MaggiS,etal.Low-dose from Daiichi Sankyo, Mitsubishi Tanabe, Takeda, dementia. aspirin use and cognitive function in older age: Otsuka, Astellas, Boehringer Ingelheim, Abbott, a systematic review and meta-analysis. J Am In conclusion, low-dose aspirin might Bayer, Medtronic, and Pfizer. H.J. reports re- Geriatr Soc 2017;65:1763–1768 reduce the risk for dementia in women search grants from MSD, Boehringer Ingelheim, 9. Nilsson SE, Johansson B, Takkinen S, et al. with T2D but not in men. These findings Novo Nordisk, Daiichi Sankyo, Takeda, Taisho Does aspirin protect against Alzheimer’s demen- fi should be further validated by studies Toyama, Astellas, Chugai, Bayer, Sano , Glaxo- tia? A study in a Swedish population-based SmithKline, Sanwa Kagaku Kenkyusho, Ono, Eli $ with larger sample sizes and longer sample aged 80 years. Eur J Clin Pharmacol Lilly, AstraZeneca, Pfizer, and Shionogi; lecturer’s 2003;59:313–319 follow-up periods including genetic fees from MSD, AstraZeneca, Astellas, Abbott, 10. Kern S, Skoog I, Ostling S, Kern J, Borjesson-¨ fi and sociocultural evaluation of the Sano , Terumo, Novo Nordisk, Bayer, Sanwa Hanson A. Does low-dose acetylsalicylic acid participants. Kagaku Kenkyusho, Kyowa Hakko Kirin, Taisho prevent cognitive decline in women with high Toyama, Daiichi Sankyo, Teijin, Mitsubishi Ta- cardiovascular risk? A 5-year follow-up of a non- nabe, Eli Lilly, Boehringer Ingelheim, and Takeda; demented population-based cohort of Swedish and manuscript fees from Novo Nordisk and elderly women. BMJ Open 2012;2:e001288 Taisho Toyama. M.W. reports a research grant Acknowledgments. The authors are indebted 11. Carter CL, Resnick EM, Mallampalli M, from Sanofi and lecturer’s fees from MSD, As- tothe participants of the JPADtrial andthe JPAD2 Kalbarczyk A. Sex and gender differences in Alzheimer’s tellas, Amgen Astellas BioPharma, AstraZeneca, cohort study for their outstanding commitments disease: recommendations for future research. J Otsuka, Ono, Kowa, Kyowa Hakko Kirin, Novartis, and cooperation. The authors thank M. Ohtorii Womens Health (Larchmt) 2012;21:1018–1023 Sanofi, Sanwa Kagaku Kenkyusho, Johnson & (Institute for Clinical Effectiveness, Kyoto, Japan) 12. De Deyn PP, Goeman J, Vervaet A, Dourcy- Johnson, Daiichi Sankyo, Taisho Toyama, Sumi- for her roles in data management and statistical Belle-RoseB, VanDamD,GeertsE.Prevalenceand tomo Dainippon, Takeda, Mitsubishi Tanabe, analyses. The authors also thank M. Nagahiro, incidence of dementia among 75-80-year-old Teijin, Eli Lilly, Novo Nordisk, Bayer, Pfizer, M. Okamoto, and M. Aoyama (Kumamoto Univer- community-dwelling elderly in different districts and Boehringer Ingelheim. T.M. reports a re- sity) and Y. Wada, Y. Kamada, and M. Miyagawa of Antwerp, Belgium: the Antwerp Cognition search grant from Nexis; lecturer’s fees from (Nara Medical University) for secretarial work. (ANCOG) Study. Clin Neurol Neurosurg 2011; AbbVie, AstraZeneca, Daiichi Sankyo, Kyorin, Funding. JPAD was supported by the Ministry of 113:736–745 Mitsubishi Tanabe, and Pfizer; a manuscript Health, Labour and Welfare of Japan (H16- 13. Rocca WA, Mielke MM, Vemuri P, Miller VM. fee from Pfizer; and service on advisory boards Junkanki-004, H26-Iryo-Ippan-012, H27-Junkanki- Sex and gender differences in the causes of of Asahi Kasei, Bristol-Myers Squibb, and Boston Ippan-001, and H28-ICT-Ippan-004). The JPAD2 dementia: a narrative review. Maturitas 2014; Scientific. No other potential conflicts of interest cohort study was supported by the Japan Heart 79:196–201 relevant to this article were reported. Foundation and Japan Society for the Promotion 14. Li R, Singh M. Sex differences in cognitive Author Contributions. C.M., H.O., Y.S., and of Science KAKENHI grants 26293159, 16H05297, impairment and Alzheimer’s disease. Front Neu- T.M.contributedtostudydesignandconception. 17K18278, and 18H03032. roendocrinol 2014;35:385–403 C.M. and T.M. contributed to data access, re- DualityofInterest. C.M.reportsresearchgrants 15. Szekely CA, Breitner JC, Fitzpatrick AL, et al. sponsibility, and analysis. C.M. and T.M. con- from Morinaga. H.O. reports research grants NSAID use and dementia risk in the Cardiovas- tributed to drafting the manuscript. H.O., Y.S., from Shionogi, Daiichi Sankyo, Chugai, Novartis, cular Health Study: role of APOE and NSAID type. S.O., H.S., M.S., I.M., M.N., N.D., H.J., and M.W. and Bayer; nonpurpose research grants from Neurology 2008;70:17–24 contributed to manuscript review for scientific Abbott, Eisai, Ono, Otsuka, Johnson & Johnson, 16. Ogawa H, Nakayama M, Morimoto T, et al.; content. H.O., Y.S., and T.M. contributed to study Daiichi Sankyo, Sumitomo Dainippon, Takeda, Japanese Primary Prevention of Atherosclerosis supervision. T.M. is the guarantor of this work Teijin, Terumo, Nihon Kohden, Bayer, Fukuda With Aspirin for Diabetes (JPAD) Trial Investi- and, as such, had full access to all the data in the Denshi, Boston Scientific, Mochida, Mitsubishi gators. Low-dose aspirin for primary prevention study and takes responsibility for the integrity of Tanabe, Medtronic, Teijin Pharma Home Health- of atherosclerotic events in patients with type 2 the data and the accuracy of the data analysis. care, and Boehringer Ingelheim; and lecturer’s diabetes: a randomized controlled trial. JAMA fees from Merck Sharp & Dohme (MSD), Daiichi 2008;300:2134–2141 Sankyo, Takeda, Bayer, AstraZeneca, Eisai, Ot- References 17. Saito Y, Okada S, Ogawa H, et al.; JPAD Trial suka, and Teijin. Y.S. reports research grants from 1. World Health Organization. Fact Sheets, De- Investigators. Low-dose aspirin for primary pre- Novartis, Ono, Shionogi, Teijin, St. Jude Medical, mentia, 19 September 2019 [Internet]. Available vention of cardiovascular events in patients with and Mitsubishi Tanabe; nonpurpose research from http://www.who.int/en/news-room/ type 2 diabetes mellitus: 10-year follow-up of a grants from Astellas, Boston Scientific, Chugai, fact-sheets/detail/dementia. Accessed 10 randomized controlled trial. Circulation 2017; Daiichi Sankyo, Sumitomo Dainippon, Eisai, Fuji November 2019 135:659–670 Yakuhin, Kyowa Hakko Kirin, Medtronic, Mitsu- 2. Xu W, Tan L, Wang HF, et al. Meta-analysis of 18. Chang CW, Horng JT, Hsu CC, Chen JM. Mean bishi Tanabe, MSD, Nihon Medi-Physics, Ono, modifiable risk factors for Alzheimer’sdisease.J daily dosage of aspirin and the risk of incident Otsuka, Pfizer, Sanofi, Shionogi, Takeda, Teijin, Neurol Neurosurg Psychiatry 2015;86:1299–1306 Alzheimer’s dementia in patients with type 2 320 Low-Dose Aspirin and Prevention of Dementia Diabetes Care Volume 43, February 2020

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