Table 2.

Overview of multidomain intervention trials for the prevention of cognitive decline and dementia

Study	Design and population	Multidomain intervention	Primary outcome	Main results
The MAX trial (Barnes et al., 2013) [11]	N = 126 Adults with cognitive complaints, USA Age, 65+ years Duration, 12 weeks	Individual, home-based mental activity plus class-based physical activity—4 groups 1. Intervention (mental activity + exercise vs. 2. Intervention + control (mental activity intervention + exercise control) vs. 3. Control + intervention (mental activity control + exercise intervention) vs. 4. Control (mental activity + exercise)	Global cognitive change based on a comprehensive neuropsychological test battery	Physical plus mental activity was associated with significant improvements in global cognitive function.
Alves et al., 2013 [12]	N = 56 Healthy women, Brazil Mean age, 66.8 years Duration, 24 weeks	Creatine supplementation and exercise—4 groups 1. Creatine supplementation vs. 2. Placebo vs. 3. Creatine supplementation + strength training vs. 4. Placebo + strength training	Cognitive function (memory, selective attention, and inhibitory control)	No significant effect on cognition.
Ihle-Hansen et al., 2014 [13]	N = 195 Patients after the first stroke, Norway Mean age, 71.6 years Duration, 12 months	Outpatient stroke nurse and physician consultation 3 and 6 months post-stroke, information about lifestyle and brain health. Medical treatment optimized. Tailored advice regarding risk factor management and treatment plan sent to a general practitioner. Offered smoking cessation courses vs. care as usual	Trail-making test A and 10-word test from baseline to 12 months follow-up	No difference between the intervention and control groups.
The SMART study (Fiatarone Singh et al., 2014) [14]	N = 100 Adults with MCI, Australia Mean age, 70.1 years Duration, 18 months	2 supervised interventions, 2–3 days/week for 6 months with 18 months follow-up - Active OR sham physical training (high-intensity progressive resistance training vs. seated calisthenics) plus - Active OR sham cognitive training (computerized, multidomain cognitive training vs. watching videos/quizzes)	Global cognitive function (ADAS-Cog) and functional independence	Resistance training significantly improved global cognitive function, with the maintenance of executive and global benefits over 18 months.
Lam et al., 2015 [15]	N = 555 Adults with MCI, Hong Kong Mean age, 75.4 years Duration, 18 months	Physical exercise vs. Cognitive activity vs. Integrated cognitive and physical exercise vs. Social activity (active control) groups	Clinical Dementia Rating sum of boxes (CDR-SOB) scores	No difference between the groups for change in CDR-SOB and functional scores. Integrated physical and cognitive intervention exerted significantly better cognitive benefits on category verbal fluency test but not across all cognitive domains compared to single cognitive or physical activity intervention.
FINGER (Ngandu et al., 2015) [16]	N = 1260 Persons at-risk of dementia, Finland Age, 60 to 77 years Duration, 2 years	Lifestyle intervention (diet, exercise, cognitive training, vascular risk monitoring) vs. general health advice	Cognition on the neuropsychological test battery	Significant intervention benefit on cognition.
ASPIS (Matz et al., 2015) [17]	N = 202 Stroke patients, Austria Age, 40 to 80 years Duration, 2 years	Multidomain intervention (clinical therapy, adequate blood pressure, lipid and glycaemic control, healthy diet, regular physical activity, cognitive training) vs. standard stroke care	Cognition on Alzheimer Disease Assessment Scale and neuropsychological test battery	No difference between the intervention and control groups.
preDIVA (Moll van Charante et al., 2016) [18]	N = 3526 Community-dwelling older persons, the Netherlands Age, 70 to 78 years Duration, 6 years	Multidomain intensive vascular care vs. standard care	Incident dementia and disability score	No difference between the intervention and control groups.
MAPT (Andrieu et al., 2017) [19]	N = 1680 Community-dwelling older persons, France Mean age, 75.3 years Duration, 3 years	1. Multidomain intervention + omega-3 supplementation 2. Multidomain intervention + placebo 3. Omega-3 supplementation alone 4. Placebo alone	Cognitive decline on composite Z score	No difference between the intervention and control groups.
Look AHEAD (Espeland et al., 2018) [20]	N = 1091 Overweight or obese adults with type 2 diabetes, USA Age, 45 to 76 years Duration, 10 years	Lifestyle intervention (diet modification and physical activity) yielding long-term weight loss vs. support and education	Change in cognition (composite measure)	No difference between the intervention and control groups.
KENKOJISEICH (Bae et al., 2019) [21]	N = 83 Individuals with MCI, Japan Mean age, 76 years Duration, 24 weeks	Physical, cognitive, and social activity sessions vs. health education	Cognition on the National Center for Geriatrics and Gerontology Functional Assessment Tool	Significant intervention effect on spatial working memory.
Blumenthal et al., 2019 [22]	N = 160 Older adults with cognitive impairment and no dementia, USA Mean age, > 55 years Duration, 6 months	Diet and exercise—4 groups: 1. Aerobic exercise vs. 2. DASH diet nutritional counseling vs. 3. Combination of both aerobic exercise and DASH vs. 4. Health education	Global measure of executive cognitive functioning	The largest improvements were observed for combined aerobic exercise and DASH diet group.
Body Brain Life for Cognitive Decline (McMaster et al., 2020) [23]	N = 119 Subjective cognitive decline or mild cognitive impairment, Australia Age, 70 to 78 years Duration, 8 weeks	Educational modules covering dementia and lifestyle risk factors, Mediterranean diet, physical activity, and cognitive engagement and additional active components: dietitian sessions, an exercise physiologist session, and online brain training vs. 4 online informational modules to reduce dementia risk	Dementia risk using the Australian National University-Alzheimer’s Disease Risk Index (ANU-ADRI) and cognition	The intervention group showed a significantly lower ANU-ADRI score and a significantly higher cognition score than the control group.
DO-HEALTH (Bischoff-Ferrari et al., 2020) [24]	N = 2157 Adults having no major health events in the 5 years prior to enrolment, sufficient mobility, and good cognitive status, Europe (Switzerland, France, Germany, Portugal, and Austria) Age, 70 years or older Duration, 3 years	Supplementation and exercise—8 groups: 1. 2000 IU/day of vitamin D3, 1 g/day of omega-3s, and a strength-training exercise program vs. 2. Vitamin D3 and omega-3s vs. 3. Vitamin D3 and exercise vs. 4. Vitamin D3 alone vs. 5. Omega-3s and exercise vs. 6. Omega-3s alone vs. 7. Exercise alone vs. 8. Placebo	6 primary outcomes: change in systolic and diastolic blood pressure, Short Physical Performance Battery (SPPB), Montreal Cognitive Assessment (MoCA), and incidence rates of non-vertebral fractures and infections	No statistically significant benefits of any intervention individually or in combination for all 6 end points.

ADAS-Cog Alzheimer’s Disease Assessment Scale-Cognitive Subscale, ANU-ADRI Australian National University Alzheimer’s Disease Risk Index, ASPIS Austrian Polyintervention Study to Prevent Cognitive Decline After Ischemic Stroke, CDR-SOB Clinical Dementia Rating sum of boxes, DASH Dietary Approaches to Stop Hypertension, FINGER Finnish Geriatric Intervention Study to Prevent Cognitive Impairment and Disability, MAPT Multidomain Alzheimer Preventive Trial, MAX Mental Activity and eXercise, MoCA Montreal Cognitive Assessment, preDIVA Prevention of Dementia by Intensive Vascular Care, SMART Study of Mental and Resistance Training, SPPB Short Physical Performance Battery