Elsevier

The Lancet

Volume 385, Issue 9984, 6–12 June 2015, Pages 2255-2263
The Lancet

Articles
A 2 year multidomain intervention of diet, exercise, cognitive training, and vascular risk monitoring versus control to prevent cognitive decline in at-risk elderly people (FINGER): a randomised controlled trial

https://doi.org/10.1016/S0140-6736(15)60461-5Get rights and content

Summary

Background

Modifiable vascular and lifestyle-related risk factors have been associated with dementia risk in observational studies. In the Finnish Geriatric Intervention Study to Prevent Cognitive Impairment and Disability (FINGER), a proof-of-concept randomised controlled trial, we aimed to assess a multidomain approach to prevent cognitive decline in at-risk elderly people from the general population.

Methods

In a double-blind randomised controlled trial we enrolled individuals aged 60–77 years recruited from previous national surveys. Inclusion criteria were CAIDE (Cardiovascular Risk Factors, Aging and Dementia) Dementia Risk Score of at least 6 points and cognition at mean level or slightly lower than expected for age. We randomly assigned participants in a 1:1 ratio to a 2 year multidomain intervention (diet, exercise, cognitive training, vascular risk monitoring), or a control group (general health advice). Computer-generated allocation was done in blocks of four (two individuals randomly allocated to each group) at each site. Group allocation was not actively disclosed to participants and outcome assessors were masked to group allocation. The primary outcome was change in cognition as measured through comprehensive neuropsychological test battery (NTB) Z score. Analysis was by modified intention to treat (all participants with at least one post-baseline observation). This trial is registered at ClinicalTrials.gov, number NCT01041989.

Findings

Between Sept 7, 2009, and Nov 24, 2011, we screened 2654 individuals and randomly assigned 1260 to the intervention group (n=631) or control group (n=629). 591 (94%) participants in the intervention group and 599 (95%) in the control group had at least one post-baseline assessment and were included in the modified intention-to-treat analysis. Estimated mean change in NTB total Z score at 2 years was 0·20 (SE 0·02, SD 0·51) in the intervention group and 0·16 (0·01, 0·51) in the control group. Between-group difference in the change of NTB total score per year was 0·022 (95% CI 0·002–0·042, p=0·030). 153 (12%) individuals dropped out overall. Adverse events occurred in 46 (7%) participants in the intervention group compared with six (1%) participants in the control group; the most common adverse event was musculoskeletal pain (32 [5%] individuals for intervention vs no individuals for control).

Interpretation

Findings from this large, long-term, randomised controlled trial suggest that a multidomain intervention could improve or maintain cognitive functioning in at-risk elderly people from the general population.

Funding

Academy of Finland, La Carita Foundation, Alzheimer Association, Alzheimer's Research and Prevention Foundation, Juho Vainio Foundation, Novo Nordisk Foundation, Finnish Social Insurance Institution, Ministry of Education and Culture, Salama bint Hamdan Al Nahyan Foundation, Axa Research Fund, EVO funding for University Hospitals of Kuopio, Oulu, and Turku and for Seinäjoki Central Hospital and Oulu City Hospital, Swedish Research Council, Swedish Research Council for Health, Working Life and Welfare, and af Jochnick Foundation.

Introduction

Late-life cognitive impairment and dementia have become serious human, social, and economic burdens.1 WHO1 and the G8 Dementia Summit (2013)2 emphasised prevention as a key element to counteract the dementia epidemic. Findings from observational studies have linked several vascular and lifestyle-related risk factors with increased risk of late-life cognitive impairment and Alzheimer's disease, the most common cause of dementia.3 A third of Alzheimer's disease cases worldwide are estimated to be attributable to seven modifiable factors (low education, midlife hypertension, midlife obesity, diabetes, physical inactivity, smoking, and depression), providing prevention opportunities.3 However, randomised controlled trials are desperately needed to confirm these associations and investigate strategies to maintain cognitive functioning and prevent cognitive impairment.4, 5

Previous single-domain prevention trials for cognitive impairment and dementia have yielded mainly negative results.4 Some positive associations with cognition were reported for physical activity, cognitive training, or both in smaller and shorter intervention studies.6, 7, 8, 9, 10, 11 Cognitive impairment, dementia, and Alzheimer's disease are complex, multifactorial disorders, and multidomain interventions targeting several risk factors and disease mechanisms simultaneously could be needed for optimum preventive effects. Successful prevention trials for cardiovascular disease and type 2 diabetes have emphasised the importance of a multidomain approach.12, 13 Further, randomised controlled trials in individuals at risk of dementia have been recommended as an effective and feasible approach.4

Research in context

Systematic review

We searched ClinicalTrials.gov and WHO's International Clinical Trial Registry Platform up to Jan 31, 2015, to identify larger multidomain randomised controlled trials. Search terms were “prevention of dementia OR prevention of Alzheimer disease”. Further selection criteria included primary outcome cognitive impairment or dementia; at least two combined interventions (eg, physical exercise, cognitive training, social activities, dietary intervention, drug or dietary supplement); age 40 years or older; duration at least 1 year; and size 500 participants or greater. We based criteria on the 2010 National Institutes of Health Evidence Report on Preventing Alzheimer's Disease and Cognitive Decline. We identified two ongoing randomised controlled trials, the Multidomain Alzheimer Preventive Trial (MAPT; NCT00672685) and Prevention of Dementia by Intensive Vascular Care (Pre-DIVA; ISRCTN29711771). Results are not yet available.

Added value of the study

To our knowledge, the Finnish Geriatric Intervention Study to Prevent Cognitive Impairment and Disability (FINGER) is the first large, longer-term, and methodologically robust trial showing that a multidomain intervention can improve or maintain cognitive functioning and reduce the risk of cognitive decline among older at-risk individuals. FINGER targeted the at-risk segment of the general elderly population, not patients in a clinical setting. Results are thus most appropriately interpreted in a public health context, where small long-term changes can have large effects. The FINGER extended follow-up will provide further knowledge about intervention effects on incidence of dementia and Alzheimer's disease.

Interpretation

After many negative dementia trials, the focus has shifted to presymptomatic and predementia disease stages and at-risk states when intervention might not be too late. In these early stages, no other trials have so far provided references for expected cognitive effects, and these references cannot be simply extrapolated from dementia trials. FINGER provides a first reference, and also a novel and pragmatic model, for dementia prevention trials that can be tested and adapted in various other settings and populations.

In a proof-of-concept trial, we aimed to investigate the effects of a 2 year multidomain intervention on cognition in at-risk elderly people from the general population.

Section snippets

Study design and participants

The Finnish Geriatric Intervention Study to Prevent Cognitive Impairment and Disability (FINGER) is a 2 year population-based multidomain randomised controlled trial done in six centres in Finland (Helsinki, Vantaa, Kuopio, Oulu, Seinäjoki, and Turku). The study protocol14 and baseline population characteristics15 have been published previously.

Participants were recruited from previous population-based non-interventional surveys.16, 17 To be eligible for participating in the trial, individuals

Results

Between Sept 7, 2009, and Nov 24, 2011, 2654 individuals were screened and 1260 were randomly assigned to the intensive intervention group (n=631) or control group (n=629; figure 1). 1168 (93%) participants completed the 12 month assessments, and 1105 (88%) participants completed the 24 month assessments. 16 individuals who withdrew from the study came to the final cognitive evaluation. The intervention was completed in February, 2014. The mITT analyses included 1190 participants (94% of all

Discussion

To our knowledge, FINGER is the first large-scale, longer-term randomised controlled trial to assess a multidomain intervention for improvement or maintenance of cognitive functioning and reduction in the risk of cognitive decline in elderly at-risk individuals from the general population. The main hypothesis was that simultaneous changes in several risk factors (even of smaller magnitude) would lead to a protective effect on cognition. We noted significant intervention effects on the primary

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