Prevention of sporadic Alzheimer's disease: lessons learned from clinical trials and future directions

Review

Prevention of sporadic Alzheimer’s disease: lessons learned from clinical trials and future directions Sandrine Andrieu*, Nicola Coley*, Simon Lovestone, Paul S Aisen, Bruno Vellas

Interventions that have even quite modest effects at the individual level could drastically reduce the future burden of dementia associated with Alzheimer’s disease at the population level. In the past three decades, both pharmacological and lifestyle interventions have been studied for the prevention of cognitive decline or dementia in randomised controlled trials of individuals mostly aged older than 50–55 years with or without risk factors for Alzheimer’s disease. Several trials testing the effects of physical activity, cognitive training, or antihypertensive interventions showed some evidence of efficacy on a primary cognitive endpoint. However, most of these trials had short follow-up periods, and further evidence is needed to confirm effectiveness and establish the optimum design or dose of interventions and ideal target populations. Important innovations in ongoing trials include the development of multidomain interventions, and the use of biomarker or genetic inclusion criteria. Challenges include the use of adaptive trial designs, the development of standardised, sensitive outcome measures, and the need for interventions that can be implemented in resource-poor settings.

Introduction Dementia, of which Alzheimer’s disease is the most common cause, affects an estimated 36 million people worldwide.1 Although the prevalence of dementia might be decreasing, especially in Europe and North America,2 we face a huge increase in the absolute number of individuals affected by age-related diseases such as Alzheimer’s disease, because of demographic ageing.3,4 Evidence-based interventions are needed to prevent the onset of Alzheimer’s disease, or to slow or stop the progression of the disease, to tackle the growing burden of cognitive decline and dementia. The ability of such interventions to prevent a substantial number of cases of Alzheimer’s disease dementia will depend on careful testing in well-designed studies and successful implementation at the levels of individuals and populations. The projected effects of preventive interventions with even quite modest effects at the individual level are impressive, dramatically reducing the future burden of dementia. For example, an intervention that delays disease onset and progression by 1 year, or a reduction in the prevalence of several modifiable lifestyle risk factors of 10% per decade, could potentially reduce the number of Alzheimer’s disease dementia cases worldwide in 2050 by around 9 million.5,6 However, this projection6 is based on findings from observational studies and assumes that a causal association exists between lifestyle risk factors and Alzheimer’s disease dementia onset. Moreover, the overall effect of lifestyle changes that encompass behaviours such as dietary habits or physical exercise would depend on such changes being acceptable to many individuals throughout their lifespan. A large gap exists between the fairly consistent findings of observational studies of preventive interventions and the generally inconclusive or negative results of clinical trials,7 which is troublesome both for decision makers, in terms of promoting public health messages at the collective level, and for physicians, in terms of delivering

clear messages at the individual level. This situation has led to controversy within the scientific community. Some researchers conclude that no reliable evidence exists for any kind of recommendations,8 whereas others assess in quantitative terms the expected effect on the future number of Alzheimer’s disease cases of the removal of one or more risk factors.6,9,10 The aim of this Review is to summarise the findings of and lessons learned from completed randomised prevention trials that have tested either pharmacological interventions, lifestyle interventions, or a combination of these in Alzheimer’s disease, to draw attention to innovative ongoing trials, and to underline research priorities for the future. Our definition of prevention trials is given in panel 1.

Lancet Neurol 2015 Published Online July 24, 2015 http://dx.doi.org/10.1016/ S1474-4422(15)00153-2 *Authors contributed equally Inserm UMR1027, F-31073, Toulouse, France (Prof S Andrieu MD, N Coley PhD, Prof B Vellas MD); University Toulouse III, Toulouse, France (Prof S Andrieu, N Coley, B Vellas); Department of Epidemiology and Public Health (Prof S Andrieu, N Coley) and Department of Geriatric Medicine (Prof B Vellas), CHU Toulouse, Toulouse, France; Department of Psychiatry, University of Oxford, Oxford, UK (Prof S Lovestone BM); and Alzheimer’s Therapeutic Research Institute, University of Southern California, San Diego, CA, USA (Prof P S Aisen MD) Correspondence to: Prof Sandrine Andrieu, Faculté de Médecine, 37 allées Jules Guesde, 31062 Toulouse, France [email protected]

Prevention studies Initial prevention trials, which were ancillary studies of large trials testing pharmacological interventions for other conditions, began from the early 1990s onwards and measured dementia incidence as their primary cognitive endpoint (figure 1). Then, in the late 1990s and early 2000s, drugs that had recently been approved as symptomatic treatments for patients with Alzheimer’s disease dementia were tested for the prevention of dementia, cognitive decline, or both in the then newly defined entity of mild cognitive impairment. In view of the widespread failure of trials that aimed to prevent dementia, attention in the following decade (the early to mid-2000s) turned to the prevention of cognitive decline, especially in studies testing the effectiveness of lifestyle interventions. In parallel, several phase 3 trials testing specific Alzheimer’s disease treatments were initiated in patients with Alzheimer’s disease dementia with the hope of finding a disease-modifying agent able to slow or stop the disease process,69 but all went on to fail, perhaps because intervention at the dementia stage was too late to stop or slow the disease process.16,70–72 Thus, trials testing pharmacological interventions for the

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Panel 1: What is a prevention trial? For the purpose of this Review, prevention trials were defined as randomised controlled trials testing interventions for the prevention of sporadic Alzheimer’s disease dementia or all-cause dementia (since Alzheimer’s disease is the most common form of dementia)11 or the clinical (cognitive decline or cognitive impairment) or biological (measured by blood, CSF, or imaging biomarkers) manifestations of Alzheimer’s disease in individuals without a previous diagnosis of Alzheimer’s disease or dementia. Our definition encompasses both primary and secondary prevention of Alzheimer’s disease, but the distinction between these two concepts is evolving with the advent of biomarker testing and the changing diagnostic landscape of the disease. Until recently, Alzheimer’s disease was defined only by its clinical features and diagnosed at the dementia stage.12 Thus, primary prevention concerned individuals with no symptoms of cognitive impairment (ie, prevention of the onset of symptoms) and secondary prevention concerned individuals with some form of cognitive impairment, such as mild cognitive impairment, which was not severe enough to merit a diagnosis of dementia (ie, prevention of further cognitive decline or dementia).12 A seemingly widely accepted proposal is that primary prevention should now concern individuals with no evidence of Alzheimer’s disease pathology (ie, prevention of the disease in biomarker-negative individuals) and that secondary prevention should concern individuals who are positive for Alzheimer’s disease biomarkers without any clinical symptoms (ie, prevention of symptoms in people with preclinical Alzheimer’s disease).13–15 In this research framework, individuals with biomarkers of Alzheimer’s disease pathology, with or without evidence of cognitive impairment or dementia, are classed as having the disease.16 However, this classification is based on the hypothesis that brain amyloid deposition is diagnostic of early-stage sporadic Alzheimer’s disease, which has not yet been conclusively proven.16 Indeed, the diagnostic and prognostic value of amyloid status, as defined by existing imaging techniques, is not yet well understood,17,18 and not all individuals with positive biomarkers will go on to develop clinical Alzheimer’s disease.13,19 Furthermore, alternatives (eg, vascular disease, tau, or inflammation) to the amyloid hypothesis could provide other definitions of preclinical disease and prevention phases.20 In view of these evolving hypotheses and classifications, we do not distinguish between primary and secondary prevention in this Review. Further well-designed trials are needed to better elucidate the effectiveness of interventions to prevent the symptoms of Alzheimer’s disease or to slow or stop disease progression using these new primary and secondary prevention paradigms.

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prevention of cognitive decline in cognitively normal individuals with positive Alzheimer’s disease biomarkers have recently begun. There has also been continued interest in lifestyle interventions, with multidomain interventions that target several different lifestyle factors simultaneously attracting much interest. We identified prevention trials for this Review using the definition described in panel 1. 47 published, completed trials were included, along with 72 ongoing trials (figure 2 and appendix p 1), which tested or are testing pharmacological, nutritional, physical exercise, cognitive training, and multidomain interventions (the combination of two or more types of intervention). Full details of the trials included in this Review are available in appendix pp 2–30 and a list of those excluded because of a lack of a-priori sample size for cognitive outcomes or because cognitive outcomes were not measured at baseline is provided in appendix pp 31–46.

The completed and ongoing intervention trials are described below by type of intervention. Panel 2 provides a summary of the interventions tested in completed trials.

Pharmacological interventions Six completed trials and one ongoing trial have tested or are testing the effects of pharmacological treatments that target several known features of the neuropathology of Alzheimer’s disease. Pharmacological agents already approved for other disorders have also been tested in prevention trials for Alzheimer’s disease, mainly on the basis of findings from observational research.

Specific anti-Alzheimer’s disease treatments Cholinesterase inhibitors (donepezil, galantamine, and rivastigmine) are approved as symptomatic treatments for Alzheimer’s disease dementia. They are cognitive enhancers that increase the brain’s cholinergic function by inhibiting the enzyme acetylcholinesterase, which degrades the neurotransmitter acetylcholine.88 None of the six completed trials that tested cholinesterase inhibitors (in one case in conjunction with memantine) as Alzheimer’s disease dementia prevention strategies in populations with mild cognitive impairment showed efficacy on their predefined primary or coprimary endpoints of incident dementia and/or cognitive decline (assessed by the New York University Paragraph Recall test, the Alzheimer’s Disease Assessment Scale– cognitive subscale [ADAS-Cog], and the Clinical Dementia Rating scale–Sum of Boxes [CDR-SB]).28,29,31,37,40,67 The ongoing Anti-Amyloid Treatment in Asymptomatic Alzheimer’s Disease (A4) trial14 is testing the efficacy of the anti-amyloid β monoclonal antibody solanezumab on a composite cognitive measure in 1000 healthy old individuals (65–85 years of age) who are judged to be at highest risk of imminent cognitive decline (based on cognitive screening tests) and have PET evidence of cerebral amyloid accumulation. The added value of the A4 trial is that it is selecting cognitively normal individuals with a positive amyloid signature and treating them with an anti-amyloid drug. Until now, such Figure 1: Timeline, primary endpoints, and main results of completed, published dementia prevention trials In the study timeline section, the bars represent the study period (start of recruitment to end of follow-up for the primary analysis) and the plotted circles represent year of publication of the primary analysis. Types of interventions tested are colour coded as follows: non-specific pharmacological (light blue); specific anti-Alzheimer’s disease pharmacological (dark blue); cognitive training or activity (purple); physical exercise (light green); nutritional (red); and multidomain (dark green). When two different endpoints are shown for the same trial, they are coprimary endpoints. The main result refers to the primary study analysis (ie, result for the primary endpoint). *Study began in 1989. †Study began in 1995. ‡Both nutritional and pharmacological interventions were tested (separately). §Study end date not specified in publication or trial registry (and not deducible from information provided). ¶Both cognitive training and physical exercise interventions were tested (separately). ||Only one of the four interventions tested showed significant positive effects on the primary outcome measure compared with the control group. **Study period not specified in publication or trial registry (and not deducible from information provided).

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D Incident dementia or Alzheimer’s disease Study timeline C Cognitive function or cognitive decline B Biomarker 1996 1997 1998 1999 2000 2001 2002 2003 2004 2005 2006 2007 2008 2009 2010 2011 2012 2013 2014 2015 Forette et al (1998)21* Syst-Eur study n=2418 Tzourio et al (2003)22† PROGRESS n=6105 study Shumaker et al (2004)23 WHIMS study, n=2947 oestrogen group Shumaker et al (2003)24 WHIMS study, n=4532 oestrogen + progesterone group n=150 Viswanathan et al (2009)25 VISP study

Type of primary endpoint and end result Positive

Negative

D C

D D D B

Ball et al (2002)26 ACTIVE study

n=2832

Thal et al (2005)27 Rofecoxib protocol 078

n=1457

Petersen et al (2005)28‡ ADCS Donepezil and Vitamin E trial

C D

n=769

D

Feldman et al (2007)29 InDDEx study

n=1018

D

C

Oken et al (2006)30

n=135

C

B

Salloway et al (2004)31 Donepezil 401 study

n=270

C

Ford et al (2010)32

n=299

C

DeKosky et al (2008)33 GEM study

n=3069

D

Tierney et al (2009)34

n=142

C

Lykestos et al (2007)35 ADAPT study

n=2528

D

Peters et al (2008)36 HYVET-COG study

n=3336

D

Winblad et al (2008)37 GAL-INT-11/18 studies

n=2048

D

Vellas et al (2012)38 GuidAge study

n=2854

D

McMahon et al (2006)39

n=276

C

Doody et al (2009)40

n=821

C

Launer et al (2011)41 ACCORD-MIND study

n=2977

C

Eussen et al (2006)42

n=195

Muscari et al (2010)43§

n=120

C C

Lautenschlager et al (2008)44 FABS study

n=170

Smith et al (2010)45 VITACOG study

n=271

C B

van de Rest et al (2008)46

n=302

Yurko-Mauro et al (2010)47 MIDAS study

n=485

Dangour et al (2010)48 OPAL study

n=867

C C C

Smith et al (2009)49 IMPACT study

n=487

Klusmann et al (2010)50¶ BBF study

n=259

C

Kwok et al (2012)51

n=429

C

Mastroiacovo et al (2015)52 CoCoA study-cognitively healthy

n=90

C

C

Desideri et al (2012)53 CoCoA study-mild cognitive impairment

n=90

C

Lui-Ambrose et al (2010)54 Brain Power study

n=155

C

Ihle-Hanson et al (2014)55

n=195

C

Vidovich et al (2015)56 PACE study

n=160

C

Anderson-Hanley et al (2012)57 Cybercycle study

n=79

C

Hajjar et al (2012)58 AVEC study

n=53

C

Barnes et al (2013)59 MAX study

n=126

Lee et al (2014)60||

n=460

C C

Diamond et al (2015)61

n=90

Ngandu et al (2015)62 FINGER study

n=1200

C C

Wolinsky et al (2013)63 Iowa Healthy and Active Minds study

n=681

C

Kwok et al (2013)64

n=200

C

Suzuki et al (2013)65§

n=100

Gomez-Isla et al (2008)66** TRIMCI study

C

n=257

Peters et al (2012)67** Makizako et al (2012)68**

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B

C n=232 n=50

(D) C C

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A Participants not selected on the basis of specific risk factors C Nutrition (2005)46 C Nutrition (2005)48 C Nutrition (2006)51 C Nutrition (2006)52 C Physical exercise (1999)30 C Physical exercise (2003)43 C Physical exercise (2006)50* C Physical exercise (2007)54 C Physical exercise (2008)57 C Cognitive stimulation (1998)26 C Cognitive stimulation (2006)50* C Cognitive stimulation (2006)49 C Cognitive stimulation (2010)63 C Multidomain (2008)60

4

B C C C C

Nutrition (1996) Nutrition (2000)32 Nutrition (2002)39 Nutrition (2003)42 Physical exercise (2004)44

D Nutrition (1999)28† B Nutrition (2004)45 C Nutrition (2005)47 C Nutrition (2007)53 C B Physical exercise (2010)65 C Physical exercise68

C C

Cognitive stimulation (2010)64 Cognitive stimulation (2009)61

C

25

C Multidomain (2007)55 C Multidomain (2008)59 C Multidomain (2009)62 D Pharmacological (1989)21 D C Pharmacological (1995)22 D Pharmacological (2001)35 D Pharmacological (2001)36 D Pharmacological (2002)38 C Pharmacological (2003)41

D Pharmacological (1996)23,24 D Pharmacological (2000)33 C Pharmacological (2000)34

Figure 2: Types of interventions tested and primary endpoints used to assess efficacy in completed and ongoing dementia prevention trials (A) Completed (published) trials. (B) Ongoing trials. Each shape represents an intervention tested in a randomised controlled trial for the prevention of dementia (or a related outcome, such as cognitive decline or a biomarker outcome). The type of primary endpoint used to assess efficacy is shown in the box on the left-hand side of each trial. When two different endpoints are shown for the same intervention, they are coprimary endpoints. The years in brackets represent the start date of each trial when available. Pharmacological (sp) indicates a pharmacological intervention specifically targeted towards Alzheimer’s disease or targeting disease pathology (eg, cholinesterase inhibitors, memantine, or anti-amyloid treatments). Other pharmacological treatments—eg, non-steroidal anti-inflammatory drugs or hormone replacement therapy—are regarded as non-specific treatments. *†§Interventions sharing the same symbol were tested separately in the same trial.

Cognitively impaired

At risk

Primary endpoints Cognitive function or cognitive decline C Biomarker B D Incident dementia or Alzheimer’s disease M Incident mild cognitive impairment due to Alzheimer’s disease O Composite endpoint (including dementia incidence)

Cognitive stimulation (2007)56

D Pharmacological (1998)27 C B Pharmacological (2008)58 C Pharmacological66

D Pharmacological (sp) (1999)28† C Pharmacological (sp) (1999)31 D C Pharmacological (sp) (1999)29 D Pharmacological (sp) (2001)37 C Pharmacological (sp) (2003)40 D C Pharmacological (sp)67

B D C C C C C C C C C C C C B C C C C B B B C C C C D C C C C C C O B C

Nutrition (2002)73 Nutrition (2007)74 Nutrition (2009) (ACTRN12609001025224) Nutrition (2010) (NCT01669915) Nutrition (2010) (ACTRN12611000094976) Nutrition (2011) (NCT01571193) Nutrition (2012) (NCT01620567) Nutrition (2012) (NCT01621646) Nutrition (2012) (NCT01734213) Nutrition (2012) (NCT01634841) Nutrition (2012) (NCT01625195) Nutrition (2013) (NCT01877967) Nutrition (2014) (NCT02063646) Nutrition (2014) (NCT01953705) Physical exercise (2006) (NCT01475396) Physical exercise (2009)§ (NCT00977418) Physical exercise (2011) (NCT02236416) Physical exercise (2013) (NCT01906957) Physical exercise (2013) (NCT02000583) C Physical exercise (2014) (NCT02057354) C Physical exercise (2014) (NCT02068612) Physical exercise (2014) (NCT02270320) Cognitive stimulation (2009)§ (NCT00977418)

C C C C C

Nutrition (2009) (NCT00996229) Nutrition (2012) (NCT01515098) Nutrition (2012) (NCT01817101) Nutrition (2014) (NCT02185222) Nutrition (2015) (NCT02416193)

C Nutrition (2007) (ACTRN12607000321448) C Nutrition (2012) (NCT01708005)

C C C B C

Physical exercise (2010)79 Physical exercise (2010) (NCT01219231) Physical exercise (2013) (NCT02312843) Physical exercise80 Physical exercise81

C Physical exercise (2010) (NCT01146717) C Physical exercise (2012) (NCT01572311) C Physical exercise (2012) (JPRN-UMIN000007749) Physical exercise (2014) (NCT02286791) B C

(Computer-based) social engagement (2012) (NCT01571427)

Cognitive stimulation (2015) (NCT02228187) Multidomain (2006)75 Multidomain (2010) (NCT01621646) Multidomain (2010) (NCT01094509) Multidomain (2010) (NCT01603784) Multidomain (2012) (NCT01745263) Multidomain (2014) (NCT02290912) Pharmacological (2007)76 Pharmacological (2010)77 Pharmacological (2010) (NCT01142336) Pharmacological (2011)78

C B C C C

Multidomain (2008)82 Multidomain (2009) (NCT01038726) Multidomain (2010)83 Multidomain (2014) (NCT02136368) Multidomain (2015) (NCT02292511)

B C D M C C

Pharmacological (2009) (NCT00939822) Pharmacological (2010)84 Pharmacological (2012)85 Pharmacological (2013)86 Pharmacological (2014) (NCT01994265) Pharmacological (sp) (2014)14

C C C C C C C B C C D

Cognitive stimulation (2011) (NCT01358955) Cognitive stimulation (2015) (NCT02301546) Cognitive stimulation (2015) (NCT02386670) Multidomain (2010)87 Multidomain (2010) (NCT01219244) Multidomain (2011) (ChiCTR-TRC-11001359) Multidomain (2012) (NCT01553929) Multidomain (2013) (NCT01811381) Multidomain (2014) (NCT02237560) Multidomain (2015) (NCT02390453) Pharmacological (2008) (NCT00842920)

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Panel 2: Interventions tested in completed Alzheimer’s disease prevention trials Alzheimer’s disease-specific pharmacological interventions • Donepezil (5 mg/day, 10 mg/day, or 5 mg/day for 42 days followed by forced dose escalation to 10 mg/day)28,31,40 • Rivastigmine (3–12 mg/day)29 • Galantamine (16 mg/day or 16–24 mg/day)37,67 • Galantamine (16 mg/day) + memantine (20 mg/day)67 Non-specific pharmacological interventions Non-steroidal anti-inflammatory drugs • Naproxen (400 mg/day)35 • Celecoxib (440 mg/day)35 • Rofecoxib (25 mg/day)27 • Triflusal (900 mg/day)66 Antihypertensive treatment • Lisinopril (10–40 mg/day)58 • Candesartan (8–32 mg/day)58 • Slow-release indapamide (1·5 mg/day) with optional perindopril (2–4 mg/day)36 • Nitrendipine (10–40 mg/day) with optional enalapril (5–20 mg/day), hydrochlorothiazide (12·5–25 mg/day), or both21 • Perinopril (4 mg/day) with optional indapamide (2·5 mg/day [or 2 mg/day in Japan])22 Hormone replacement therapy • 17β-oestradiol (1 mg/day) and norethindrone (0·35 mg on 3 days per week)34 • Conjugated equine oestrogen (0·625 mg/day)23 • Conjugated equine oestrogen (0·625 mg/day) + medroxyprogesterone acetate (2·5 mg/day)24 Other • Intensive glycaemic control targeting HbA1c to less than 6·0% (42 mmol/mol) using various antidiabetic treatments41 • Ginkgo biloba (240 mg/day)33,38 Nutritional interventions Nutritional supplements Homocysteine-lowering vitamins: • Vitamin B12 (1000 μg/day)42 • Vitamin B12 (1000 μg/day) + folic acid (400 μg/day)42 • Vitamin B12 (400–500 μg/day) + folic acid (2–2·5 mg/day) or folate (800–1000 μg/day) + vitamin B6 (10–25 mg/day)25,32,39,45 Fish oil or omega-3 fatty acids: • Docosahexaenoic acid (DHA; 900 mg/day)47 • DHA (500 mg) + eicosapentaenoic acid (EPA; 200 mg/day)48 • Fish oil (1800 or 400 mg/day EPA–DHA)46 Other: • High-dose (990 mg/day), medium-dose (520 mg/day), or low-dose (45 mg/day) flavanol supplement52,53 • Vitamin E (2000 IU/day)28 Advice or counselling • Regular group dietary counselling and menu changes51

Cognitive activity or training Global (or unspecified) cognitive training • Active Mind cognitive training program (including attention, verbal fluency, and memory training)64 • Healthy Brain Ageing Cognitive Training Program (involving psychoeducation and computer-based cognitive training)61 • Discussion of age-associated changes in cognition and activities employing strategies to enhance attention capacity, memory functions, and executive processes56 • General or unspecified cognitive activity or training programme50 Specific cognitive training • Memory training26 • Reasoning training26 • Speed of processing training26,63 • Auditory information processing-targeted brain plasticitybased training49 • Intensive computer visual and auditory processing training59 Physical exercise Non-specific physical intervention • Physical activity intervention (weekly goal: 150 min exercise)44 Specific exercise • Aerobic exercise or endurance training43,59 • Resistance training54 • Cybercycling57 • Yoga30 • Walking30 Multicomponent exercise programme • Aerobic exercise, muscle strength training, postural balance retraining and dual-task training, and focus on promoting exercise and behaviour change65 • Aerobic endurance, strength, flexibility, balance, and coordination50 • Aerobic exercise, muscle strength training, and postural balance training68 Multidomain interventions • Intensive computer intervention and aerobic intervention59 • Multidomain lifestyle counselling (nutritional guidance, physical activity, cognitive training, increased social activity, and intensive monitoring of vascular and metabolic risk factors)62 • Bimonthly or monthly telephonic care management (targeting physical activity, smoking cessation, social activity, cognitive activity, moderate alcohol consumption, lean body mass, and healthy diet) alone or with educational materials, healthworker-initiated visits and counselling, or rewards for adherence to the programme60 • Intensive multifactorial vascular risk factor management (targeting blood pressure, cholesterol, homocysteine, and body-mass index via diet, medication, smoking cessation, and physical activity)55

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treatments have been tested in heterogeneous populations (individuals with and without amyloid in the brain), essentially at the dementia stage. If the results of this trial (which will be completed in 2020) are positive, it will reopen the door to anti-amyloid drugs in prevention.

Other pharmacological interventions Trials of pharmacological agents already approved for disorders other than Alzheimer’s disease are presented in the following paragraphs by type of intervention, in the order in which the interventions were first tested. Antihypertensive treatments are postulated to protect against Alzheimer’s disease and all-cause dementia through their blood pressure-lowering action (since hypertension is a risk factor for both all-cause dementia and Alzheimer’s disease dementia),89 but some might also act through specific mechanisms, such as inhibition of the activity of the renin–angiotensin system or calcium channel blockade.90,91 Three trials that were designed specifically to assess effects on cognition tested three different types of antihypertensive treatment regimens in patients with either hypertension alone, or hypertension and mild cognitive impairment. Results have been promising, but are not yet conclusive. In the Systolic Hypertension in Europe Trial (Syst-Eur) of 2418 old adults (aged >60 years) with hypertension, nitrendipine treatment (with optional enalapril and/or hydrochlorothiazide) reduced incident dementia by 50% (p=0·05) but only 32 dementia cases were reported (11 in the treatment group and 21 in the placebo group);21 the Antihypertensives and Vascular, Endothelial and Cognitive Function Trial (AVEC) showed significant beneficial effects of angiotensin receptor blockers on cognitive performance in old hypertensive individuals with early cognitive impairment (ie, executive dysfunction assessed by the executive clock-drawing test), but only 53 participants were randomly assigned to three groups (18 received lisinopril, 20 candesartan, and 15 hydrochlorothiazide);58 and the Hypertension in the Very Elderly Trial cognitive function assessment (HYVET-COG) reported a non-significant reduced risk of dementia (hazard ratio [HR] 0·86, 95% CI 0·67–1·09, p=0·21) with indapamide (and optional perindopril) treatment for a mean of 2·2 years versus placebo in a population of 2977 very elderly patients, aged 80 years and older.36 Furthermore, in the Perindopril Protection Against Recurrent Stroke Study (PROGRESS), which enrolled 6105 individuals with previous stroke or transient ischaemic attack, perindopril treatment was associated with a nonsignificant 12% reduced risk of dementia (95% CI –8% to 28%; p=0·2) and a significant 19% decreased risk of cognitive decline (4% to 32%; p=0·01) compared with the placebo group.22 Notably, the beneficial effects were limited to dementia or cognitive decline associated with recurrent stroke, and some participants might already have had dementia at baseline. The ongoing Systolic Blood Pressure Intervention Trial: Memory and Cognition in Decreased Hypertension 6

(SPRINT-MIND) substudy is assessing whether or not intensive systolic blood pressure lowering (to levels lower than current recommendations) using all classes of antihypertensive medication will reduce dementia incidence compared with standard treatment in more than 9000 individuals aged 50 years and older with raised systolic blood pressure who are free of stroke and diabetes, treated for up to 6 years.85 This study will therefore be one of the largest dementia prevention trials so far and will include both middle-aged and elderly adults, which is important because the benefits of blood pressure lowering might be age dependent.89 Hormone replacement therapy has been suggested as a preventive intervention because, after the age of 70 years, women have a greater risk of Alzheimer’s disease dementia than men, perhaps because of decreasing oestrogen levels after the menopause.92 Proposed mechanisms of action of oestrogen against Alzheimer’s disease include protection against neuronal death, regulation of amyloid β accumulation and tau hyperphosphorylation, and interaction with the cholinergic and other neurotransmitter systems.93,94 Some forms of progesterone might also be neuroprotective.93 Two published trials met our inclusion criteria: a 2-year trial in 142 postmenopausal women showed no effect of daily 17β-oestradiol with norethindrone 3 days per week on delayed verbal recall,34 whereas the Women’s Health Initiative Memory Study (WHIMS)23,24 showed that, compared with placebo, the risk of dementia increased significantly after about 4 years of treatment with oestrogen and progestin in 4500 postmenopausal women (HR 2·05, 95% CI 1·21–3·48; p=0·01), and increased non-significantly with oestrogen alone in 2947 postmenopausal women (1·49, 0·83–2·66; p=0·18). Following the WHIMS trial, findings from initial observational studies were widely believed to be biased by the so-called healthy user effect. However, hormone replacement therapy has been suggested to benefit cognition only during the critical period around the time of menopause,95 and oestradiol might be more beneficial than the oestrone-containing form of hormone replacement therapy (conjugated equine oestrogens) used in WHIMS.76 The ongoing Kronos Early Estrogen Prevention Study Cognitive and Affective (KEEPS Cog) substudy76 is addressing these issues by testing the efficacy of 4-year treatment with oral conjugated equine oestrogens or transdermal oestradiol on cognition (assessed with tests of verbal and visual memory, attention, and executive function) in 700 healthy, recently postmenopausal women. Non-steroidal anti-inflammatory drugs, including nonselective COX inhibitors (eg, aspirin, ibuprofen, and naproxen) and COX-2 selective inhibitors (eg, celecoxib and rofecoxib) could protect against Alzheimer’s disease, since inflammatory mechanisms might play a part in Alzheimer’s disease neuropathology.96,97 One placebocontrolled trial showed a small but significant increased risk of Alzheimer’s disease dementia with up to 4 years’ treatment with rofecoxib in 1457 patients with mild

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cognitive impairment.27 A second trial tested 18 months of treatment with the aspirin-like agent triflusal in 257 patients with amnestic mild cognitive impairment (129 of whom were treated and 128 given placebo) but was stopped prematurely because of a slower-thananticipated rate of recruitment.66 The trial showed no significant difference on the primary outcome (ADASCog), and a significantly lower probability of progression to Alzheimer’s disease dementia—a secondary endpoint—in the triflusal group than in the placebo group. The primary analysis of the largest trial so far, comparing naproxen or celecoxib against placebo in 2528 cognitively normal elderly adults (aged ≥70 years) with a family history of Alzheimer’s disease dementia, which was stopped early because of safety concerns, suggested an increased risk of Alzheimer’s disease dementia with either treatment compared with placebo, although the results were not statistically significant (celecoxib HR 1·99, 95% CI 0·80–4·97, p=0·14; naproxen 2·35, 0·95–5·77, p=0·06).35 To draw conclusions about the efficacy of non-steroidal anti-inflammatory drugs for the prevention of Alzheimer’s disease is difficult because all trials so far have been done in elderly populations with short treatment durations, whereas long-term use starting at a younger age and before the onset of substantial Alzheimer’s disease pathology might be needed to achieve preventive effects.97–99 An ongoing trial aiming to recruit 19 000 elderly individuals (aged ≥70 years for non-minorities or aged ≥65 years for US minorities) will test the 5-year efficacy of aspirin on a composite disability-free life endpoint, including dementia, and could provide useful evidence about the preventive effects of non-steroidal antiinflammatory drugs.77 Notably, little evidence seems to support the continued investigation of COX-2 selective inhibitors for Alzheimer’s disease prevention.100 Ginkgo biloba extract is widely used to prevent agerelated memory decline or Alzheimer’s disease dementia. It is classified as a dietary supplement in the USA and is approved for the treatment of dementia and memory complaints in some European countries. Proposed mechanisms of action include antioxidant effects,101,102 and inhibition of caspase-3 activation and amyloid β aggregation.103 Two specifically designed large-scale prevention trials were unable to show any effect of 5–6 years of treatment with standardised ginkgo biloba extract on their primary outcomes of incident all-cause or Alzheimer’s disease dementia in 3069 individuals aged 75 years and older with normal cognition or mild cognitive impairment and 2854 people aged 70 years and older with spontaneously reported memory complaints.33,38 The latter trial lacked statistical power since the incidence of Alzheimer’s disease dementia was lower than expected.38 Type 2 diabetes is a risk factor for vascular dementia and might also increase the risk of Alzheimer’s disease dementia.104 Suggested mechanisms include cerebro-

vascular disease and inflammation, insulin resistance, and mitochondrial dysfunction.105,106 Hypoglycaemia might also adversely affect cerebral metabolism, which is highly glucose dependent. The Action to Control Cardiovascular Risk in Diabetes Memory in Diabetes Study (ACCORDMIND)41 showed no effect of intensive versus standard glycaemic control on cognitive performance in 2977 people with type 2 diabetes aged 55 years and older with high HbA1c concentrations and a high risk of cardiovascular events (in the trial, 1378 participants received intensive treatment and 1416 standard treatment). Therefore, prevention of cognitive decline and dementia in people with diabetes should probably be addressed in the same way as in those without this disorder. The peroxisome proliferator-activated receptor-γ (PPAR-γ) agonist pioglitazone, which is approved as an antidiabetic treatment and might also affect Alzheimer’s disease pathology,107 is being tested for the prevention of mild cognitive impairment caused by Alzheimer’s disease in a population of 5800 cognitively normal individuals.86 Those judged to be at high risk of developing symptomatic Alzheimer’s disease because of the presence of a genetic biomarker (based on APOE and TOMM40 genotypes) will be randomly assigned to pioglitazone or placebo for up to 5 years, whereas those without the genetic biomarker will automatically receive placebo. Statins have also been suggested as a preventive treatment for Alzheimer’s disease. Proposed mechanisms of action include reduction of neurofibrillary tangles through cholesterol-lowering effects, and reduced inflammation and improved endothelial function through noncholesterol-lowering (pleiotropic) effects.108 No completed trials meeting our inclusion criteria were identified, but one quite large ongoing placebo-controlled trial is testing the efficacy of 4 years of treatment with simvastatin on the progression of mild cognitive impairment to Alzheimer’s disease dementia in 640 individuals (ClinicalTrials.gov identifier NCT00842920). Two smaller trials (NCT01142336 and NCT00939822) are also assessing the effects of simvastatin on biomarkers.

Nutritional interventions The nutritional interventions tested in completed or ongoing prevention trials are described in the following paragraphs by general type of intervention (supplement or dietary patterns or counselling), in the order in which they were first tested.

Homocysteine-lowering vitamins Raised plasma homocysteine is both neurotoxic and a vascular risk factor, and has been linked in observational studies to the development of Alzheimer’s disease dementia and cognitive impairment.109 Dietary supplementation with some B vitamins lowers blood homocysteine.110 In the 2-year Homocysteine and B vitamins in Cognitive Impairment (VITACOG) trial45 of 271 individuals with mild cognitive impairment, the mean annual rate of whole brain atrophy

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was significantly lower with homocysteine-lowering treatment than with placebo, but no significant effect was recorded on three of four predefined secondary cognitive outcome measures.111 Three other trials showed no significant cognitive effects of 1–2 years of treatment with homocysteine-lowering vitamins in up to 300 individuals with mild vitamin B deficiency, raised homocysteine, or hypertension.32,39,42 Furthermore, a substudy of the Vitamin Intervention for Stroke Prevention (VISP) trial25 reported no effect of 2 years of treatment with high-dose homocysteinelowering vitamins on plasma amyloid β changes in 300 individuals with raised homocysteine and recent ischaemic stroke at baseline who did not have recurrent stroke during follow-up.

Antioxidants Oxidative stress might have an important role in neurodegeneration and neuronal death in Alzheimer’s disease.112 However, a 3-year trial of 2000 IU per day of vitamin E showed no significant effect on progression from mild cognitive impairment to Alzheimer’s disease dementia in 769 individuals (253 in the donepezil group, 257 in the vitamin E group, and 259 in the placebo group).28 The ongoing Prevention of Alzheimer’s Disease with Vitamin E and Selenium (PREADVISE) trial is testing the efficacy of vitamin E, selenium, or both on the incidence of dementia, including Alzheimer’s disease, in 7547 healthy men aged 62 years and older (or ≥60 years for African Americans). This trial is an ancillary study of the Selenium and Vitamin E Cancer Prevention Trial (SELECT), in which treatment was stopped after an average of 5 years of exposure because of a futility analysis for a cancer outcome, but masked follow-up of cognitive status is ongoing.113 However, lower-than-expected statistical power as a consequence of enrolling a cohort that was too healthy (ie, healthier than the general population), and shortened treatment duration might reduce the usefulness of this large trial.113 At present, no evidence exists for a preventive role of antioxidants, such as vitamin E, in Alzheimer’s disease and ongoing trials are unlikely to provide conclusive evidence about their efficacy.

n-3 long-chain polyunsaturated fatty acids n-3 long-chain polyunsaturated fatty acids (PUFAs), especially docosahexaenoic acid (DHA), are an important component of neural membrane phospholipids and reduced levels, often recorded during ageing, could increase the risk of cognitive decline and Alzheimer’s disease dementia.114 A 24-week trial47 of 900 mg DHA per day in 485 individuals with subjective memory complaints and age-related cognitive decline showed significant beneficial effects on the primary visuospatial learning and episodic memory outcome measure, and on some, but not all, secondary cognitive outcome measures, excluding one—CANTAB Pattern Recognition Memory, a test of visual pattern recognition—which was dropped as a coprimary outcome measure after a negative interim 8

analysis. Two trials testing DHA–eicosapentaenoic acid (EPA) showed no significant cognitive effects after 26 weeks and 2 years of treatment in 302 and 867 elderly individuals (aged 70–79 years in the first trial and ≥65 years in the second) without specific Alzheimer’s disease dementia risk factors.46,48 Eight ongoing trials are testing the efficacy of PUFAs, either alone or in combination with other interventions (multivitamins, vitamin D, physical exercise, and multidomain lifestyle intervention), for up to 5 years, on cognitive function or biomarkers in elderly individuals with or without specific risk factors for Alzheimer’s disease dementia74,82 (ClinicalTrials.gov identifiers NCT01625195, NCT01817101, NCT01669915, NCT01953705, NCT00996229; Australian New Zealand Clinical Trials Registry identifier ACTRN12611000094976).

Flavonoids Flavanols, a type of flavonoid, could protect against agerelated cognitive decline by increasing expression of neuroprotective and neuromodulatory proteins, and connections between neurons through actions on various cellular pathways. Some flavonoids might also inhibit amyloid β generation and aggregation.115 An 8-week trial of flavanol supplementation in 90 people with mild cognitive impairment recorded significant beneficial effects of highdose versus low-dose supplementation on the primary trial outcome (global cognitive Z score) and other cognitive measures.53 The second part of this trial also showed significant (p<0·001) beneficial effects of high-dose versus low-dose supplementation on the global cognitive Z score and measures of executive function and verbal fluency after 8 weeks in 90 individuals aged 60 years and older with no evidence of cognitive dysfunction.52 Larger and longer trials are needed to confirm these initial promising results, but we did not identify any other trials in our search.

Vitamin D Vitamin D has an important role in brain function and is associated with the synthesis of neurotrophic factors and neurotransmitters, and a reduction of amyloid β peptides.116,117 Its potential as a preventive treatment for Alzheimer’s disease remains to be established, since no completed trials have assessed its efficacy. However, five ongoing trials, including one testing 2000 IU vitamin D3 per day, an omega-3 supplement, or both, versus placebo for 5 years in 3000 elderly adults (VITAL-Cog, an ancillary study of the Vitamin D and Omega-3 Trial; ClinicalTrials. gov identifier NCT01669915) and one testing 100 000 IU vitamin D3 per month versus placebo for 2 years in 350 old individuals with a memory complaint (D-COG; NCT02185222) might help to ascertain its efficacy for the prevention of cognitive decline.

Other nutritional interventions Most completed nutritional intervention trials were based on dietary supplements, but whole foods or dietary

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patterns (eg, a Mediterranean-style diet) might be more important than supplements.7 A 33-month trial of dietary counselling and menu changes versus advice on hostel menu only in 429 residents of hostels for elderly people in Hong Kong showed that the intervention had no significant effect on cognitive decline.51 The specific setting of this trial, whose participants were older and less well educated than the general elderly population, limits the generalisability of its results. An ongoing trial is testing caloric restriction in 300 individuals at risk of Alzheimer’s disease dementia for 6 months (ClinicalTrials.gov identifier NCT00996229) and two further ongoing trials are testing dietary counselling, as part of 3-year and 6-year multidomain interventions, for the prevention of cognitive decline or dementia in 1680 pre-frail elderly adults at risk (aged ≥70 years with at least one of the following criteria: spontaneously reported memory complaint, slow gait speed, or difficulty performing instrumental activities of daily living) and 3700 elderly people who were not selected on the basis of specific risk factors,75,82 respectively, but to ascertain the effects of the nutritional part of the intervention alone will not be possible since the efficacy of these multidomain interventions will be assessed as a whole and not by individual component.

Cognitive training interventions Late-life cognitive stimulation could protect against dementia, especially by increasing cognitive reserve and brain plasticity.118 Specific teaching of useful strategies could maintain the abilities targeted by those strategies such as memory or reasoning training. Three of eight completed trials49,63,64 showed significant effects of cognitive training on their predefined primary endpoint (Chinese Mattis Dementia Rating Scale, Useful Field of View test, and the Repeatable Battery for the Assessment of Neuropsychological Status auditory memory and attention composite score) in elderly individuals with or without specific Alzheimer’s disease risk factors. Sample sizes were moderate, but intervention and follow-up periods were very short (5–8 weeks) and two trials’ analyses had some methodological limitations (complete case analysis, baseline imbalances across groups, or cluster randomisation not taken into account).63,64 The larger Advanced Cognitive Training for Independent and Vital Elderly (ACTIVE) trial of 2832 adults aged 65 years and older showed no significant effect of any form of cognitive training (5–6 weeks’ memory [n=711], reasoning [n=705], or speed of processing [n=712] training, with boosters for some participants at 11 months) on its primary outcome of everyday function at 2 years, but reasoning training significantly reduced difficulties in instrumental activities of daily living (IADL) compared with the control group at 5 years (effect size 0·29, 95% CI 0·03–0·55), and all intervention groups showed sustained effects on their targeted cognitive ability up to 5 years.26,119 Two additional trials involving 259 elderly individuals with

no specific risk factors and 90 individuals aged 50 years and older with no depression or mild depressive symptoms, respectively, showed significant beneficial effects of 6-month or 2-month computer courses (in conjunction with psychoeducation in one of these trials) on some cognitive endpoints (especially tests of episodic or verbal memory) but not all.50,61 Cognitive training therefore shows promise, but further large, long-term trials are needed. The largest ongoing trial of cognitive training is testing the effects of transcranial direct current stimulation and computer-based exercises relevant to attention, processing speed, executive function, and verbal and working memory versus a sham control for 2–5 years on cognitive change over time in 375 individuals aged 60 years and older with mild cognitive impairment, late-life depression, or both (ClinicalTrials.gov identifier NCT02386670).

Physical activity interventions High levels of physical activity could maintain cognitive function with ageing and reduce the risk of dementia. Possible mechanisms include increased neurogenesis, angiogenesis and synaptic plasticity, mediated by neurotrophic factors (BDNF and IGF-1),120 cardiovascular and immunological or anti-inflammatory effects.121 Four trials testing cybercycling, home-based physical activity, endurance training, or resistance training showed a significant effect on their predefined primary cognitive endpoint (ADAS-Cog, Mini-Mental State Examination [MMSE], Stroop test, or a battery of tests of executive function) in cohorts of up to 170 old individuals either with or without specific Alzheimer’s disease dementia risk factors (see appendix pp 2–15 for further details).43,44,54,57 However, two trials’ analyses had methodological limitations: baseline imbalances between groups were not fully taken into account in one trial, and the other used a complete case analysis rather than an intention-totreat analysis.54,57 A fifth trial50 showed beneficial effects of endurance and resistance training on some, but not all, primary cognitive endpoints in a 6-month, three-group trial involving 259 individuals. Three further 3–6-month trials testing yoga, walking, or multicomponent exercise programmes in 50–135 individuals showed no beneficial effects on cognitive function.30,65,68 Despite several encouraging trials, conclusive evidence about the preventive effects of exercise on Alzheimer’s disease is scarce, because of the small sample sizes and short intervention periods of these trials. Furthermore, effects have generally been small, and whether aerobic or resistance training, or a combination of both, could be most beneficial remains unclear. Larger and longer trials are therefore needed. However, most ongoing trials testing physical exercise interventions are quite small. One exception is the cognition study of the Lifestyle Interventions and Independence for Elders (LIFE) trial, testing an average of 2·7 years’ intervention with a structured aerobic, strength, flexibility, and balance training programme with a weekly goal of 150 min of

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walking at moderate intensity and at least two sessions a week of strength, flexibility, and balance exercises, versus a health education intervention (1:1 randomisation) for preservation of cognitive function (measured by tests of processing speed and memory) in 1600 sedentary individuals aged 70–89 years and at increased risk for incident motor disability.79 Additionally, the Physical Exercise for Prevention of Dementia (EPD) trial is assessing 4 years of supervised, multimodal physical activity (including aerobic, resistance, and stretching exercises) against a posture education control in 600 individuals aged 50–90 years with or without cognitive impairment for the prevention of cognitive decline (ClinicalTrials.gov identifier NCT02236416). These longer and larger trials should provide more conclusive evidence about the effects of physical activity on cognitive function, although they are unlikely to establish which particular form of exercise is most beneficial because both trials are studying multimodal exercise interventions.

Multidomain interventions In view of the multifactorial causes of Alzheimer’s disease, multidomain interventions might have additive or synergistic effects compared with single-domain interventions alone.7,122 Four completed and 18 ongoing trials testing multidomain interventions—essentially, physical exercise with cognitive training, nutritional intervention, or both—were identified, drawing attention to a major shift in the prevention field towards multidomain interventions. In the Finnish Geriatric Intervention Study to Prevent Cognitive Impairment and Disability (FINGER),62 the largest completed trial so far, 1200 individuals aged 60–77 years with an increased dementia risk score were randomly assigned to receive multidomain lifestyle counselling (nutritional guidance, group and individual physical activity, cognitive training, and intensive monitoring of vascular and metabolic risk factors; n=631) or regular health advice (n=629). Cognitive function, measured by the Neuropsychological Test Battery Z score, improved significantly during the 2 years of intervention in both groups, and the multidomain group improved by significantly more than the control group (between-group difference in annual Neuropsychological Test Battery score change 0·022, 95% CI 0·002–0·042, p=0·030). The second, smaller, five-group, cluster-randomised trial involving 460 individuals aged 60 years and older reported a significant improvement in 18-month MMSE change from baseline compared with the control group (p<0·05) in one intervention group only (bimonthly or monthly telephone consultation or in-person care management targeting a healthy lifestyle, with or without rewards).60 The third trial tested an intensive computer and aerobic exercise intervention, either alone or in combination, in 126 inactive old individuals with cognitive complaints. Global cognitive scores significantly improved during the 3-month follow-up period but did not differ between 10

groups (p=0·26).59 The fourth trial, which enrolled 195 survivors of a first-ever stroke or transient ischaemic attack, reported no significant benefit of 6 months of intensive multifactorial vascular risk factor management on 1-year change in memory and executive function compared with usual care.55 Of note, three of the ongoing multidomain trials (two of which are partly published75,82 and one of which is registered [ClinicalTrials.gov identifier NCT01745263]) involve between 1680 and 3700 participants and have up to 6 years of follow-up, including one75 that has dementia incidence as the primary outcome.

Methodological issues Randomised trials are regarded as the gold standard of clinical research, but they need to be done as efficiently and robustly as possible to be able to draw meaningful conclusions that can be translated quickly into clinical practice or public health policy. For example, testing a suboptimal form of an intervention (eg, incorrect dose or treatment duration) in the wrong target population or the use of unsuitable outcome measures could lead to erroneous conclusions about the efficacy of the intervention. Regulatory authorities have begun to develop guidance for the design of pharmacological trials in predementia stages of Alzheimer’s disease, in particular outlining suitable outcome measures,123 but little standardisation exists for the methods used for nonpharmacological interventions. Variability in trial design can also make it difficult to draw conclusions about the efficacy of a given type of intervention, since evidence is needed from several well-designed and sufficiently long or large trials. The different methodological aspects of the included trials are discussed in the following paragraphs.

Interventions Within each type of intervention, apart from the specific pharmacological interventions, there was much heterogeneity across the trials in terms of the nature of the intervention and intensity or dose (panel 2). The method of intervention delivery also varied, especially for physical exercise and cognitive training interventions (eg, interventions could be individual or group-based activities delivered in study centres or at home, exercise could be supervised or unsupervised, and cognitive training could be done on the computer or using pencil and paper, etc). Furthermore, the type of comparator used in control groups also varied widely for the non-pharmacological interventions, with some trials using inactive comparators (eg, wait-list control), and others using active comparators of varying intensities (eg, health education, and different forms or intensities of physical exercise to those tested in active intervention groups).

Primary endpoints Four types of primary endpoints were used in the completed and ongoing trials: incident dementia or

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Alzheimer’s disease dementia; incident mild cognitive impairment caused by Alzheimer’s disease; cognitive function or decline; and biomarker changes, of which cognitive function or decline was by far the most common type (figure 2). Incident Alzheimer’s disease or all-cause dementia was the primary endpoint in nearly a quarter of the completed studies, but is much less common in ongoing trials, which increasingly use biomarkers, such as MRI80 or PET imaging (ClinicalTrials.gov identifier NCT02000583) and CSF markers (NCT01142336), as primary or coprimary endpoints, with the aim of either intervening at an earlier stage of the disease or showing potential effects of the intervention on disease pathophysiology. Incident mild cognitive impairment due to Alzheimer’s disease is being used as a primary outcome measure for the first time in one ongoing trial.86 In several publications, the primary endpoints and prespecified analysis plan were not clearly delineated and in some cases had to be inferred from the text. This finding poses a significant problem for interpretation; meaningful results must be based on a fully specific and prespecified analysis plan to control type I error. We studied the primary outcome measures from completed trials in more detail and found that the criteria used to measure incident dementia were quite similar (all trials used the internationally validated Diagnostic and Statistical Manual of Mental Disorders, fourth edition [DSM-IV], the National Institute of Neurological and Communicative Disorders and Stroke and the Alzheimer’s Disease and Related Disorders Association [NINCDS-ADRDA] criteria, except for three studies that used newer or older DSM criteria or transition from Clinical Dementia Rating 0·5 to Clinical Dementia Rating 1·0), whereas a wide range of different test batteries and methods of analysis were used to measure cognitive function or cognitive decline (figure 3). Outcome measures are therefore a key aspect of prevention trial methods with room for improvement. Owing to advances in our understanding of the Alzheimer’s disease continuum, the specialty is moving away from the use of dementia diagnosis (with the difficulties of reliably ascertaining the diagnosis and date of occurrence, loss of data from dropouts, and low incidence in prevention trial populations) as a primary endpoint, and instead focusing on the measurement of disease progression, especially in terms of cognitive decline or biomarker outcomes.124 However, whether or not an effect on a biomarker or even on cognitive decline actually translates into a delay in the onset of dementia remains to be shown. The demonstration of simultaneous effects on both cognitive decline and biomarker changes would provide more evidence to support this premise. In a recent draft guidance document, the US Food and Drug Administration has supported a cognitive composite primary outcome measure in preclinical Alzheimer’s disease as a pathway to accelerated approval with a requirement for further post-marketing study.123

Investigators continue to seek sensitive assessment of patient-reported and family-reported outcomes that might establish the clinical meaningfulness of subtle cognitive benefits. So far, no consensus has been established about the optimum instruments to use to measure cognitive decline, and no gold standard primary outcome or minimum dataset exists for Alzheimer’s disease prevention trials. Furthermore, many cognitive tests used so far have suffered from so-called learning or practice effects.125 As we move towards intervening even earlier in the life course, we must develop sensitive measures of cognitive function that are suitable for repeated use over time. Various composite outcome measures are now in development, with the aim of creating instruments or test batteries that are sufficiently sensitive to detect early Alzheimer’s disease-related cognitive changes.126,127 Biomarkers, such as volumetric (total brain or hippocampal volume) or functional MRI and blood or CSF amyloid β or tau levels, have also received much interest as Alzheimer’s disease outcome measures. However, knowledge about the evolution of such biomarkers before dementia onset is still scarce, and their use as outcome measures in prevention trials has been limited so far. Nonetheless, biomarkers could increasingly be used as intermediate outcomes in early-phase prevention trials. The ideal goal is a surrogate marker that could substitute for clinical outcomes. Such a marker is unlikely to be available in the near future for dementia syndromes, but a marker or set of markers that could be used to guide the development of early-phase secondary prevention trials is quite plausible. Indeed, in other disease areas, new trial designs are being considered.128 The European Innovative Medicines Initiative funding programme has proposed the establishment of an adaptive trial process for prevention. Multigroup adaptive trials depend on biomarkers as intermediate outcomes, a development that is now realisable in dementia research and might do much to accelerate the search for a preventive treatment for Alzheimer’s disease.

For more on the European Innovative Medicines Initiative funding programme see http://www.imi.europa.eu/ content/11th-call-2013-8

Target population The studies reviewed here also had very diverse target populations, although all trials excluded individuals with dementia at baseline (except for the PROGRESS trial,22 in which some individuals might have had dementia at baseline). We identified three main types of target populations on the basis of the inclusion criteria of the trials (elderly participants not selected on the basis of specific risk factors, those at risk, and cognitively impaired elderly people), but there was some overlap between the groups and a mutually exclusive classification was not feasible based on the available information. “Elderly participants not selected on the basis of specific risk factors” referred to individuals selected purely on the basis of age, allowing those with either normal cognition or some form of mild cognitive impairment, with or without Alzheimer’s disease risk factors, or participants with

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11 dementia studies*

All-cause dementia incidence 3 DSM-IV criteria† 1 DSM-IIIR criteria 1 conversion on CDR from 0·5 to 1

36 cognition studies*

Alzheimer’s disease incidence 3 DSM-IV and NINCDS-ADRDA criteria 2 NINCDS-ADRDA criteria 1 DSM-IV-TR and NINCDS-ADRDA criteria‡

Global measure(s)

Global test(s)

Rate of change 1 whole brain atrophy

Specific domain measure(s)

Change from baseline 1 cerebral blood flow and central endothelial function¶ 1 medial temporal lobe and whole brain atrophy§ 1 plasma amyloid β

Global and specific domain measures

Change from baseline 1 visual memory (CANTAB PAL) 1 verbal learning and memory (California Verbal Learning Test) 1 verbal learning and memory (RAVLT, WMS-III Logical Memory) 1 memory and executive function (Trail Making Test-A, 10-word list) 1 processing speed (Useful Field of View) 1 domain scores for: everyday problem solving; everyday speed, Activities of Daily Living and Instrumental Activities of Daily Living functioning; and driving habits|| 1 domain Z scores for: construction; sensorimotor speed; memory; attention and executive function** 1 tests of episodic memory, working memory, and executive function†† 1 domain Z scores for: sensorimotor speed; memory and executive function‡‡ 1 tests of memory, attention, and executive function¶ §§ 1 reaction time

Composite measure

Change from baseline 4 ADAS-Cog 2 MMSE 1 ADAS-Cog and CDR Sum of Boxes 1 Mattis Dementia Rating Scale 1 CAMCOG-R

Responder rate 1 CDR 1 MMSE†

4 biomarker studies*

Change from baseline 1 composite score from six RBANS subtests 1 extended neuropsychological test battery 1 global Z score (Cognitive Test Battery A) 1 global Z score (Cognitive Test Battery B)‡ 1 global Z score (Cognitive Test Battery C)

End level of cognitive impairment 1 verbal learning and memory (California Verbal Learning Test) 2 executive function (Stroop test) 1 psychomotor speed (Digit Symbol Substitution Test)

Change from baseline 1 CGIC-MCI and episodic memory (NYU Paragraph Delayed Recall) 1 ADAS-Cog, MMSE, and WMS Logical Memory I and II§

End level of cognitive impairment 1 tests of global cognitive function, memory, learning and executive function, and reasoning¶¶ 2 tests of global cognitive function, executive function and working memory (both individual scores and global Z score calculated)||||

Figure 3: Primary endpoints in published, completed Alzheimer’s disease prevention trials ADAS-Cog=Alzheimer’s Disease Assessment Scale–Cognition. CAMCOG-R=Cambridge Cognitive Examination–Revised. CANTAB PAL=Cambridge Neuropsychological Test Automated Battery Paired Associates Learning. CDR=Clinical Dementia Rating. CGIC-MCI=Clinical Global Impression of Change–Mild Cognitive Impairment. DSM=Diagnostic and Statistical Manual of Mental Disorders. MMSE=MiniMental State Examination. NINCDS-ADRDA=National Institute of Neurological and Communicative Disorders and Stroke and the Alzheimer’s Disease and Related Disorders Association. NYU=New York University. RAVLT=Rey Auditory Verbal Learning Test. RBANS=Repeatable Battery for the Assessment of Neuropsychological Status. WMS=Wechsler Memory Scale. *Four studies had coprimary endpoints (two studies had dementia and cognition coprimary endpoints, and two had biomarker and cognition coprimary endpoints). †‡§¶Endpoints sharing the same symbol are coprimary endpoints from the same study. For a key to the other footnotes in this figure, see appendix p 47.

normal cognition only; “at risk” referred to individuals selected on the basis of having at least one specific Alzheimer’s disease risk factor (other than age), such as family history of Alzheimer’s disease dementia, vitamin B12 deficiency, hypertension, subjective memory complaints, or some form of very mild cognitive impairment (but not meeting specific mild cognitive impairment criteria) or genetic or biomarker risk factors; and “cognitive impairment” referred to individuals 12

specifically selected on the basis of having some degree of cognitive impairment, such as those meeting specific criteria for mild cognitive impairment, Cognitive Impairment No Dementia, or age-related cognitive decline, or with a Clinical Dementia Rating of 0·5. Notably, within the at-risk group are populations of patients who were specifically chosen because they would be more likely to benefit from the intervention being tested, such as those with raised homocysteine levels for

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trials of B vitamins or sedentary individuals for trials of physical exercise. Although to test preventive interventions in different types of target population is of course very useful, such populations should be distinct and well characterised, in terms of both clinical features and biomarkers, to be able to establish specifically in which individuals and at which stage of the disease process the intervention is (or is not) effective. Many trials, including those assessing cholinesterase inhibitors, have targeted individuals with mild cognitive impairment, a heterogeneous entity that includes individuals in the early stages of Alzheimer’s disease in addition to cognitive impairment of various other origins.129 Thus, it is possible that cholinesterase inhibitor trials did not show efficacy on their Alzheimer’s diseaserelated primary outcome measures because not all the participants had underlying Alzheimer’s disease.130 In view of the heterogeneous nature of mild cognitive impairment, the identification of suitable outcome measures capable of detecting the effects of an intervention in such populations might be difficult. Although some trials were done in enriched populations, no completed trials have yet used amyloid-based inclusion criteria and the proportion of amyloid-positive participants in previous trials is generally not known. The ongoing A4 trial is recruiting individuals who are believed to have presymptomatic or preclinical Alzheimer’s disease—ie, those with positive amyloid biomarkers but no clinical symptoms.14 It will therefore address the hypothesis that intervention at the dementia stage of Alzheimer’s disease is too late, and that previous secondary prevention trials have failed because they were done in populations that were too heterogeneous. A second ongoing trial is testing a novel genetic biomarker for sporadic Alzheimer’s disease as an enrichment strategy.86 Both these trials will include observational groups to better understand cognitive decline and dementia risk. Even if an anti-amyloid treatment had beneficial results in presymptomatic individuals, many hurdles would remain in its development for Alzheimer’s disease prevention. Such treatments could be associated with significant side-effects that are tolerated in patients with manifest disease, but might not be acceptable in patients without any clinical symptoms, even those with positive Alzheimer’s disease biomarkers. Furthermore, to recruit asymptomatic individuals with positive Alzheimer’s disease biomarkers might be difficult, in view of costs and ethical issues regarding disclosure of amyloid status, especially since not all individuals with positive biomarkers will go on to develop clinical Alzheimer’s disease.13,19 Careful attention to informed consent, education of participants, and disclosure practices is essential in such trials. Moreover, if an intervention is found to be effective in a clinical trial population that is defined by biomarkers, the same costly or invasive biomarker assessments will need to be used in clinical practice to ascertain which patients should receive the treatment.131 More

straightforward techniques (eg, blood tests), which are less costly and invasive than PET imaging or CSF sampling, need to be developed to measure amyloid load. Beyond amyloid load, we expect the biomarker specialty to evolve rapidly in the coming years to measure other pathological correlates of disease, especially tau PET imaging.132 Imaging of other types, electrophysiological measures, and markers of proteins, metabolites, and gene expression in both the blood and CSF are all under evaluation and might become available for clinical trials in the short to medium term. Such biomarkers could be used for selection and possibly also stratification of prevention trial participants but, even so, prevention trials are likely to remain relatively large, long, and correspondingly expensive. To ascertain which individuals are most likely to benefit from preventive interventions and to ensure that these individuals are recruited to trials is important. Mass media or mailing campaigns are often used for recruitment, because they can reach large numbers of people quite quickly, but the recruited participants are generally a highly selected sample of the target population, often in better health and with higher levels of education than the rest of the population, which can lead to lower-thanexpected rates of dementia or cognitive decline and therefore underpowered trials (the healthy participant effect).38,113,133,134 Furthermore, the course of cognitive decline before dementia diagnosis might differ by level of education,135 and the probability of improving cognitive function in individuals with a higher level of education through any intervention might be quite low. Finally, the generalisability of the results of trials done in highly selected populations is questionable. Recruitment websites or internet-based registries of people interested in participating in prevention trials (eg, Brain Initiative, Alzheimer’s Prevention Registry, and TrialMatch) are being set up to try to increase recruitment. These registries could help to more widely disseminate information about prevention trials, identify eligible participants, and even to perform initial cognitive testing via the internet, but might further increase selection bias in older age groups as a consequence of selection associated with ability to use the internet. To avoid healthy participant bias during recruitment, so-called self-selection of trial participants needs to be reduced, such as by avoiding recruitment strategies based on advertising or mass media campaigns. Recruitment of participants via family doctors or targeting of individuals with specific risk factors from population registries or previous cohorts might help to recruit populations that are as representative as possible of the true target population.

Statistical aspects Statistical aspects of trial design are often overlooked, but the need for sufficient statistical power to detect an intervention effect and use of the most adequate method of analysis are crucial design features.

www.thelancet.com/neurology Published online July 24, 2015 http://dx.doi.org/10.1016/S1474-4422(15)00153-2

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For more on the European Prevention of Alzheimer’s Dementia consortium see http://www.synapse-managers. com/epad

Figure 1 shows the timeline of completed trials. Notably, with the exception of some of the more recent trials of lifestyle interventions,50,54,57,63,65 most of the completed prevention trials did not have any published data available from previous trials testing the same type of intervention on which to base their sample size calculations and other features of study design. Such elements were therefore based mainly on data from observational studies. To combine hypotheses from observational studies with the wealth of data and experience obtained in previous prevention trials and data from simulation studies should help investigators to do more realistic sample size (power) calculations based on more reasonable assumptions for future prevention trials.136 Binary primary outcomes, such as incident dementia, are typically analysed by time-to-event (survival) analysis, generally using the log-rank test but, given the length of follow-up in dementia prevention trials and the likely modest effects of potentially disease-modifying interventions, treatment effects could vary over time or might only be detectable after a specific period of exposure to the intervention. Indeed, the GuidAge38 and Alzheimer’s Disease Anti-Inflammatory Prevention Trial (ADAPT)98 studies both showed evidence of non-constant treatment effects over time. In such cases (known as nonproportional hazards in statistical terms), other methods

Search strategy and selection criteria We searched PubMed for papers published up to May 11, 2015, using the following search terms: “(Alzheimer* OR dementia OR memory OR cognit*) AND prevent* AND “Randomized Controlled Trial” [Publication Type]” to identify completed dementia prevention trials with published results for the primary outcome or ongoing dementia prevention trials. We also searched the reference lists of selected reports and papers in our own files. We reviewed only papers published in English; we included those presenting the methods or results of randomised controlled trials testing the efficacy of any type of intervention for the prevention of dementia or cognitive decline. Trials done in children, pregnant women, or those judged to be off topic (eg, studies of depression, smoking prevention, HIV/AIDS, substance abuse, cognitive development, or postoperative or cancer-related cognitive impairment) were excluded, as were prevention trials undertaken in patients diagnosed with Alzheimer’s disease at either the dementia or the prodromal stage, or with dementia of any cause. We also excluded trials with non-randomised, non-efficacy, or crossover study designs; pilot studies; and those that were not specifically designed to assess efficacy on cognition or dementia or a relevant biomarker (ie, if a-priori sample size calculation was not reported for cognitive outcomes, or if such outcomes were not assessed at baseline). We identified additional ongoing trials in the ClinicalTrials.gov and Current Controlled Trials registries and the WHO International Clinical Trials Registry Platform using the following search criteria: “(prevent OR prevention OR preventive) AND (cognition OR cognitive OR dementia OR Alzheimer OR Alzheimer’s OR memory)”, with the interventional studies filter activated, when available. As above, prevention trials in people diagnosed with prodromal Alzheimer’s disease or dementia of any cause, those judged to be off topic, and those with non-randomised or non-efficacy study designs were excluded, as were those that did not measure cognition, dementia, or a relevant biomarker as a primary outcome, and those that were already completed. We also excluded ongoing trials with published methods that did not report an a-priori sample size calculation for cognitive outcomes.

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of statistical analysis might be more suitable than the classical log-rank test.137,138 Trials measuring cognitive decline using repeated measures need fewer participants than those measuring binary endpoints. Longitudinal mixed-effects models are preferred for the analysis of such data over repeatedmeasures analysis of variance or generalised estimating equations, especially because of the more realistic assumptions made about missing data.136,139 In all cases, sensitivity analyses using different assumptions about missing data are recommended.

Conclusions and future directions Several Alzheimer’s disease prevention trials have shown some evidence of efficacy of a physical activity, cognitive training, nutritional, multidomain lifestyle, or pharmacological antihypertensive intervention on a primary endpoint, but overall the trials have provided no consistent evidence of efficacy for any specific intervention. Notably, follow-up periods were generally short (no more than 1 year for more than half of these trials) and nearly all trials measured cognitive performance or cognitive decline as the primary endpoint. There was not a reasonably sized trial with a positive result on a clearly prespecified analysis of a clinically meaningful endpoint, such as a direct or indirect (as measured by a validated surrogate endpoint) reduction of Alzheimer’s disease dementia incidence. Thus, the trials showing beneficial results so far can be regarded as proof-of-concept studies that need further confirmation in larger and longer trials in well-characterised study populations and using clinically meaningful endpoints. Our Review draws attention to substantial heterogeneity in Alzheimer’s disease prevention trials, in terms of intervention content and duration, study populations, length of follow-up, and outcome measures. These methodological differences hinder comparisons across studies and could also explain variations in trial results.7 Standardisation of trial methods, especially in terms of duration of follow-up, comparators, target population definitions, and outcome measures, would enable the comparison of effect sizes across different types of interventions. New study designs, especially adaptive trials, which are beginning to be advocated in the Alzheimer’s disease specialty,140 could accelerate the process of identifying effective preventive interventions for Alzheimer’s disease by testing several different interventions simultaneously in different groups within the same trial, some of which could be discontinued based on the results of predefined interim analyses. Although adaptive designs are already beginning to be used in Alzheimer’s disease prevention by industry (ClinicalTrials.gov identifier NCT01767311) and by the European Prevention of Alzheimer’s Dementia consortium, a public–private partnership, their use is limited by an absence of validated surrogate endpoints that could be used as a short-term primary endpoint.

www.thelancet.com/neurology Published online July 24, 2015 http://dx.doi.org/10.1016/S1474-4422(15)00153-2

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Experience and knowledge gained from previous and ongoing prevention trials should be used to improve the design of future trials. The Alzheimer’s Disease Neuroimaging Initiative (ADNI)141 has pioneered the concept of data sharing within the Alzheimer’s disease specialty to accelerate new biomarker discoveries. We now need to exploit data gathered in prevention trials to improve outcome measures, better define target populations, and do realistic sample size calculations, and to develop and apply improved methods of statistical analysis, as is being promoted by the Healthy Ageing Through Internet Counselling in the Elderly (HATICE) project, which is part of the European Dementia Prevention Initiative, and the A4 trial.14,142 The new generation of prevention trials is addressing some of the problems encountered in previous trials by testing interventions during the optimum window of exposure (ie, earlier in the course of the disease, even in the preclinical phase), using multidomain rather than single-domain intervention strategies, or through the use of enrichment strategies based on biomarker or genetic criteria. The simultaneous evaluation of novel interventions and trial methods, as initiated by some ongoing trials, is to be encouraged. In view of the many challenges associated with the development and clinical application of pharmacological therapies for the prevention of Alzheimer’s disease, we should not neglect lifestyle interventions, which present substantial cost and safety advantages and offer benefits against other diseases (ie, by reducing disease risk).143 Pharmacological treatments, especially if their indication depends on biomarker criteria, might be prohibitively expensive in low-income countries, whereas lifestyle interventions are applicable in almost any setting. Further research is needed to establish the optimum type, duration, timing, and intensity of lifestyle-based interventions, and the clinical meaningfulness of any beneficial effects. Observational research has suggested that the mid-life period could be a crucial time for dementia risk factors,144 and interventional studies should also take this into account. However, we might need to rethink the classical randomised controlled study design in this case, because although this approach provides the highest level of evidence, it should be remembered that the initial goal of such trials was to show effects on symptoms over short follow-up periods rather than preventive effects over longer periods, which are generally more modest and might only become apparent after several years of exposure to the intervention. Furthermore, they were designed to measure individual effects in a strict setting, rather than long-term population effects, which might be of more interest for lifestyle interventions. Other study designs—eg, beforeand-after studies—might be more suitable for the study of this sort of effect. However, the results of such studies are difficult to interpret because of a high risk of bias. To be effective worldwide, preventive interventions must be feasible, inexpensive, and easy to implement in a wide range of settings, in addition to being safe. Lifestyle

interventions, particularly multidomain interventions targeting physical exercise, cognitive training, and management of vascular risk factors, could be a key component of our efforts to reduce the prevalence of Alzheimer’s disease dementia. We know that at the collective level a very moderate decrease in exposure to some risk factors could lead to a drastic reduction in the number of cases of Alzheimer’s disease because exposure to these lifestyle factors is widespread. Furthermore, since many lifestyle risk factors are linked, simultaneous reductions in several factors could provide even greater benefits. The success of these preventive strategies will be linked to the capacity of the scientific community to involve other influential actors, such as policy makers and industrial partners, to facilitate access to specific interventions for the entire population. In estimating the effect of lifestyle changes on the future prevalence of Alzheimer’s disease, the feasibility of achieving longterm changes in behaviour must be taken into account. Contributors SA and NC conceived the structure of the Review. NC did the literature search. SA and NC created the figures and wrote the Review. SA, NC, SL, PSA, and BV critically revised the original and subsequent versions of the Review. Declaration of interests SA has received a grant from Beaufour Ipsen Pharma; speaker’s fees, travel expenses, or consulting fees from Beaufour Ipsen Pharma, Elan, Lilly, Nestlé, Pierre Fabre, Sanofi, and Servier; and non-financial support from Biogen, Icon, Nutrition Santé, and Pfizer, outside the submitted work. SL has received grants from the EU through the Innovative Medicines Initiative during the writing of this Review; and personal fees from Lundeck Neuroscience Foundation, outside the submitted work. SL is named as an inventor on a patent for biomarkers for Alzheimer’s disease held by King’s College London and by Proteome Sciences (ref: 1322094.2). Aspects of this work have been licensed out. PSA has received grants from the US Alzheimer’s Association, Janssen, Lilly, the US National Institute on Aging, and Toyama; and consulting fees from Abbott, Abbvie, Amgen, Anavex, AstraZeneca, Biogen Idec, Biotie, Bristol-Myers Squibb, Cardeus, Cohbar, Eisai, Elan, Eli Lilly, Genentech, Ichor, iPerian, Janssen, Lundbeck, Medivation, Merck, NeuroPhage, Novartis, Pfizer, Probiodrug, Roche, Somaxon, and Toyama, outside the submitted work. BV has received grants from Lilly, Lundbeck, MSD, Otsuka, Pierre Fabre, Regeneron, Roche, and Sanofi; and consulting fees from Biogen, Lilly, Lundbeck, Medivation, MSD, Nestlé, Roche, Sanofi, Servier, and TauRx Therapeutics, outside the submitted work. NC declares no competing interests. References 1 Wimo A, Jonsson L, Bond J, Prince M, Winblad B. The worldwide economic impact of dementia 2010. Alzheimers Dement 2013; 9: 1–11.e3. 2 Schrijvers EM, Verhaaren BF, Koudstaal PJ, Hofman A, Ikram MA, Breteler MM. Is dementia incidence declining? Trends in dementia incidence since 1990 in the Rotterdam Study. Neurology 2012; 78: 1456–63. 3 Lutz W, Sanderson W, Scherbov S. The coming acceleration of global population ageing. Nature 2008; 451: 716–19. 4 Prince M, Bryce R, Albanese E, Wimo A, Ribeiro W, Ferri CP. The global prevalence of dementia: a systematic review and metaanalysis. Alzheimers Dement 2013; 9: 63–75.e2. 5 Brookmeyer R, Johnson E, Ziegler-Graham K, Arrighi HM. Forecasting the global burden of Alzheimer’s disease. Alzheimers Dement 2007; 3: 186–91. 6 Norton S, Matthews FE, Barnes DE, Yaffe K, Brayne C. Potential for primary prevention of Alzheimer’s disease: an analysis of population-based data. Lancet Neurol 2014; 13: 788–94. 7 Coley N, Andrieu S, Gardette V, et al. Dementia prevention: methodological explanations for inconsistent results. Epidemiol Rev 2008; 30: 35–66.

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