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The effect of adherence on cognition in a multidomain lifestyle intervention (FINGER)

Lifestyle interventions may prevent cognitive decline, but the sufficient dose of intervention activities and lifestyle changes is unknown. We investigated how intervention adherence affects cognition in the FINGER trial (pre‐specified subgroup analyses).


BACKGROUND
Healthy lifestyles are associated with a lower risk of cognitive impairment, including dementia and Alzheimer's disease. 1 Emerging evidence from randomized controlled trials suggests that lifestyle interventions may reduce the risk of cognitive decline. 2 Given the multifactorial nature of old-age cognitive impairment, multidomain interventions are a promising prevention strategy.
Adherence to lifestyle intervention is crucial to have an effect on cognition; not only participation in the proposed activities, but also adopting healthy lifestyles in everyday life. What constitutes a sufficient dose of lifestyle intervention remains unclear. Although some lifestyle trials targeting prevention of cognitive decline have reported attendance to intervention visits 3,4 or change in lifestyle, [5][6][7] few studies have investigated how adherence impacts cognitive outcomes, with indication of positive association. 8,9 Knowledge of the magnitude of intervention activities needed would improve the efficacy of future trials.
The Finnish Geriatric Intervention Study to Prevent Cognitive Impairment and Disability (FINGER) was the first large multidomain lifestyle trial reporting beneficial effects on cognitive function among older adults. 10 The aim of the current study is to investigate how intervention adherence explains the observed degree of cognitive change (prespecified subgroup analyses). The analyses examine adherence defined as (1) participation in the intervention activities and (2) achieved changes in lifestyles during the 2-year intervention.

Setting and population
FINGER is a multidomain lifestyle intervention trial conducted in six areas in Finland (ClinicalTrials.gov NCT01041989). 11 The study comprises a population-based sample aged 60 to 77 years, with an elevated risk for dementia. Persons with CAIDE (Cardiovascular Risk Factors, Aging, and Dementia) risk score 12 ≥6 were invited to a screening visit where they underwent brief neuropsychological testing and a medical examination. They were eligible if free of dementia and conditions affecting safe engagement in the intervention, and with cognitive performance at an average level or slightly below expected. 10 The study was approved by the Coordinating Ethics Committee of Helsinki and Uusimaa Hospital District, and all participants gave written informed consent. The study flowchart is presented as Figure S1 in supporting information. Participants were randomized 1:1 to multidomain lifestyle (intervention) or regular health advice (control) groups using computerized algorithm in blocks of four (two individuals randomly allocated to each group) at each site after baseline by the study nurse. Doubleblinding was pursued as much as possible: The outcome assessors were blinded, and the randomization group was not actively told to the participants.

Interventions
Participants in the multidomain group received all four intervention components: dietary counseling, exercise training, cognitive training, and management of cardiovascular and metabolic factors (vascular management).
The dietary intervention was based on national recommendations 13 and included nutrient intake goals operationalized by using foodlevel recommendations, for example increased consumption of fruits, berries, vegetables, wholegrain cereal, vegetable fats, and fish; individually tailored for each participant. The intervention comprised three individual counseling and six to eight group sessions with a study nutritionist. 6 The physical exercise intervention followed international guidelines and previous Finnish trials. 14 16,17 Intensive management of metabolic and vascular risk factors (vascular intervention) was based on national guidelines aimed at improving blood pressure, lipids, glucose, and body weight with improving lifestyles. Study physicians did not prescribe medication, but strongly recommended contacting local health care if needed. The intervention group met a study nurse (at 3, 9, and 18 months), and the study physician (at 3, 6, and 12 months) for additional measurement and advice.
All participants received mini-intervention with the study nurse at baseline and written feedback on their vascular risk factors.

Adherence measures
Adherence to the intervention comprises two aspects: (1) participation in offered activities in the intervention group (prespecified definition) and (2)

Lifestyles
Self-reported lifestyles and measured vascular factors were collected annually for both intervention and control groups. Diet score was based on 3-day food records ranging from none to all dietary goals (0-9). 6 Average number of weekly moderate to vigorous physical activity sessions was calculated based on a validated questionnaire. 18 An average number of weekly cognitive and social activities (cognitive activity) was collected with a frequency-based questionnaire. Cardiovascular risk was assessed with the validated Finnish FINRISK score divided by the score of age-and sex-matched person without vascular risk factors. 19 Healthy lifestyle pattern at baseline was based on tertiles of each component: 0 points for low (unfavorable), 1 for intermediate, and 2 for upper tertile (favorable); and the healthy multidomain lifestyle composite (multi-lifestyle score) was calculated as the sum (range 0-8).
Multi-lifestyle score is used as outcome and predictor in the analyses.
Change in each lifestyle was defined as the difference score between baseline and 2-year visit as worsening (0 points), stable (1 point), or improvement (2 points; cut-offs in Table S1). Measure for multi-lifestyle change from worsening in all to improvement in all lifestyle components ranged from 0 to 8.

Neuropsychological examination
A trained study psychologist blinded to group allocation administered the Neuropsychological Test Battery (NTB) 10,20 at baseline and annually thereafter. Primary outcome was a composite score reflecting global cognition, calculated as an average of 14 tests standardized to Z scores with higher scores indicating better performance as described.
Secondary outcomes included cognitive domain Z scores for executive function, processing speed, and memory.

Statistical analyses
Baseline characteristics were compared using t-tests for continuous

Baseline characteristics and lifestyle changes
The mean age of the 1259 participants was 68.9 years, and 54% were men; 12% dropped out.
Most intervention participants met the prespecified definition for adherent participation in diet (n = 557, 88%) and vascular (n = 587, 93%) intervention components; and approximately one half in exercise (n = 361, 57%) and cognitive training (n = 295, 47%) components. Altogether 37% were adherent to all intervention components (adherent multi-participation), 42% at least in two components (partially adherent), and 21% less (non-adherent). The intervention and control groups were similar, but adherent intervention participants were younger, more often married, less often had diabetes, and had fewer depressive symptoms and faster processing speed than non-adherent ones (Table 1), who in turn had several less favorable characteristics than the control group. Compared to the control group, the non-adherent or partially adherent participants in the intervention group had lower multi-lifestyle score at baseline, and adherent participants had higher.

Change in cognition in relation to multi-participation and multi-lifestyle changes
Adherent multi-participation predicted more improvement in global cognition compared to the non-adherent or the control group (Figure 2) and was related to improvement in all cognitive domains, especially executive function and memory ( Table 2). Memory improved less in the non-adherent group than in the control group. Results remained largely unchanged after adjusting for observed lifestyle changes. Adherent multi-participation was related to more improvement in global cognition even compared to the control group participants who improved their lifestyle (n = 214 with imputation; annual difference in change 0.06 points; P = 0.001).
A multi-lifestyle score at baseline predicted improvement in global cognition, processing speed, and memory (  (16) 140 (17) 140 (18) 140 (17) 140 (16) Total cholesterol (mmol/l) Body mass index (kg/m2) 28 at baseline also showed cross-sectional association with better global cognition and all cognitive domains (results not shown). Improvement in multi-lifestyle score was associated with improvement in global cognition and executive function. These results were similar in the observed data (Model A) and also imputed data (Model B). Intervention allocation modified the association between lifestyle and executive function (time x group x lifestyle interaction P = 0.020 for lifestyle change), but not for other cognitive domains, such that improvement in lifestyles was associated with improvement in executive function in the intervention group only ( Figure S2 and Table S2 in supporting information).

DISCUSSION
In a 2-year multidomain intervention trial comprising dietary and vascular risk counseling, and exercise and cognitive training, adherent participation resulted in improvement in both cognitive performance and lifestyles. Improved lifestyles were linked to cognitive improvement.
Lifestyle changes measured in this study did not, however, explain the participation-related improvement, suggesting that both played a role in the observed cognitive changes. Participation may have benefits beyond the observed measures, for example through social stimulation; and all lifestyle changes induced by the participation may not be captured by these measures.
Several lifestyle interventions have been conducted for the prevention of cognitive impairment, 2,21 but only a few have shown effects on cognitive outcomes, 2 and most have not analyzed cognition in relation to adherence. In earlier analyses of FINGER, adherence to the dietary goals was linked to improvement in executive function. 9 In other trials active memory training was associated with immediate benefits on memory but not on subsequent cognitive trajectories among participants without cognitive impairement, 22 and adherence to physical and cognitive training among persons with mild cognitive impairment was linked to some cognitive improvement. 8 In an uncontrolled clinicbased study, participants with lower or higher adherence to preventive recommendations improved in cognition more than observational controls but did not differ from each other. 23 Today, it is unclear how intensive an intervention has to be to influence cognitive performance. Two other previous long-term lifestyle trials, the Multidomain Alzheimer Preventive Trial 24 and the Prevention of Dementia by Intensive Vascular Care, 25 both less intensive than FIN-GER, showed no effect in main analyses, although the latter showed reduced dementia risk among adherent participants with untreated hypertension or no previous cardiovascular disease. 25 In the Finnish Diabetes Prevention study, achieving lifestyle intervention goals was associated with better cognition 9 years after the intervention. 26 Considering the current results showing greatest benefits among those who participated in at least half of all proposed activities, or improved in at least two lifestyle components, evidence suggests quite an intensive program and high adherence. Participants with low adherence differed from those with higher level of adherence in some characteristics, for example they had less favorable lifestyles to begin with. Determinants of adherence to FINGER intervention have been investigated previously. 3,16 Additional tailored support for participants at risk of low adherence may improve intervention outcomes.
Participation in all intervention components contributed to the observed effects on cognition in all cognitive domains, but their relative importance cannot be estimated due to a strong multicollinearity. Actual changes in lifestyle were more independent of each other, and all observed associations remained significant after being included in the same model. Lifestyle changes were linked mainly to changes in executive functioning and global cognition but not to changes in other cognitive domains. Executive functions could be more sensitive for effects of lifestyle modification in early prevention trials as they are suggested to be the first cognitive changes observed in preclinical dementia. 27 Diet, vascular risk control, and cognitive activity, but not physical activity, contributed to associations. Given that physical activity has the strongest previous evidence for beneficial effects, 21 this might indicate that scales used to measure physical activity in the current study were not optimal.
No gold standard for defining adherence to lifestyle intervention has been established, and it is unlikely that one definition would fit all studies. Most often participation in intervention sessions is used, 3,4,28 or sometimes actual lifestyle changes. 5,29 Participation in intervention visits that mainly include counseling is not a direct indicator of targeted behavior change. Therefore, in addition to measuring participation (prespecified analyses), we also investigated the effect of the achieved lifestyle changes. For all intervention components correlations between intervention participation and changes in self-reported lifestyles were relatively low, indicating that they may represent different aspects of the same lifestyle components. It is plausible that similar lifestyle changes would produce similar effects in both intervention and control groups.
Overall, lifestyles improved in both intervention and control groups, which may be to some extent due to a mini-intervention at the start of the trial or regular monitoring of risk factors and lifestyles during the trial. However, lifestyle changes were larger in the intervention group.
Active or partially active intervention group participants showed similar magnitude of lifestyle changes and they did not significantly differ from the non-active participants, which may be due to lack of statistical power, lack of sensitivity in the lifestyle measures used, or the fact that participants even in the non-active group often were active in some of the intervention components. Compared to the control group, the active and partially active intervention groups both improved their lifestyles.
The strengths of this study include the carefully designed and longterm randomized controlled trial, low drop-out rate, careful measurement of standardized cognitive outcomes, and inclusion of a representative sample of older adults at increased risk of dementia. 30 The main limitation is that the trial was not designed to study different intensities of intervention, and thus the groups with different participation rates differed in many characteristics. This may explain the fact that for some cognitive outcomes, the non-adherent intervention group participants had worse trajectories than the control group. Data from drug trials show that adherence to placebo can be associated with better outcomes, supporting the "healthy adherer" effect, 31 and we also detected healthier baseline lifestyle among the adherent people. We adjusted the analyses for several potential confounders but residual confounding is possible. However, cognitive improvement among the adherent intervention participants was greater than for control group participants with the most improvement in lifestyle, who supposedly would be the "healthy adherers" in their group.
The variables for each component were not directly comparable: for diet and vascular risk, the intervention visits were easy to attend, but participation did not automatically mean any improvement in lifestyle, whereas participation in exercise and cognitive training was already an indicator of lifestyle change. Data on lifestyle were all self-reported, and some of the scales were not optimal for measuring changes, for example diet score was based on dichotomous cut-offs, and the cognitive and physical activity scales focused on frequency rather than on changes in content or intensity. The cognitive activity scale did not include activities that were initiated within the intervention. Thus, con- show if the adopted healthier lifestyles will be sustained, and if the adherence affects the longer term outcomes. or in the writing of the report. We sincerely thank all participants of the FINGER study and all people involved in the data collection, particularly the nurses, psychologists, physicians, nutritionists and physiotherapists conducting the field work.

CONFLICTS OF INTEREST
Research grants received outside the submitted work from European