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Original Investigation
April 2018

Effect of the Apolipoprotein E Genotype on Cognitive Change During a Multidomain Lifestyle InterventionA Subgroup Analysis of a Randomized Clinical Trial

Author Affiliations
  • 1Institute of Clinical Medicine/Neurology, University of Eastern Finland, Kuopio, Finland
  • 2Aging Research Center, Karolinska Institutet, Stockholm University, Stockholm, Sweden
  • 3Division of Clinical Geriatrics, Center for Alzheimer Research, Department of Neurobiology, Care Sciences, and Society, Karolinska Institutet, Stockholm, Sweden
  • 4Chronic Disease Prevention Unit, National Institute for Health and Welfare, Helsinki, Finland
  • 5Institute of Health Sciences/Geriatrics, University of Oulu and Oulu University Hospital, Oulu, Finland
  • 6Medical Research Center Oulu, Oulu University Hospital and Oulu City Hospital, Oulu, Finland
  • 7Department of Neurology, Kuopio University Hospital, Kuopio, Finland
  • 8Institute of Public Health and Clinical Nutrition, University of Eastern Finland, Kuopio, Finland
  • 9Hospital District of North Karelia, Joensuu, Finland
  • 10Department of Public Health, Faculty of Medicine, University of Helsinki, Helskinki, Finland
  • 11Finnish Institute of Occupational Health, Helsinki, Finland
  • 12Welfare and Health Promotion Unit, National Institute for Health and Welfare, Helsinki, Finland
  • 13Department of Social and Psychological Studies, Karlstad University, Karlstad, Sweden
  • 14Department of Psychology, Umeå University, Umeå, Sweden
  • 15Department of Medicine, Geriatric Clinic, University of Helsinki and Helsinki University Central Hospital, Helsinki, Finland
  • 16Department of Public Health, University of Helsinki, Helsinki, Finland
  • 17South Ostrobothnia Central Hospital, Seinäjoki, Finland
  • 18Department of Neurosciences and Preventive Medicine, Danube-University Krems, Krems, Austria
  • 19Diabetes Research Group, King Abdulaziz University, Jeddah, Saudi Arabia
  • 20Dasman Diabetes Institute, Dasman, Kuwait
  • 21Neuroepidemiology and Ageing Research Unit, School of Public Health, Imperial College London, London, United Kingdom
JAMA Neurol. 2018;75(4):462-470. doi:10.1001/jamaneurol.2017.4365
Key Points

Question  Are the cognitive benefits of a 2-year multidomain lifestyle intervention affected by the apolipoprotein E ε4 allele?

Findings  In the Finnish Geriatric Intervention Study to Prevent Cognitive Impairment and Disability, a randomized clinical trial of 1260 at-risk elderly individuals from the general population, the cognitive benefits of a multidomain intervention (diet, exercise, cognitive training, and vascular risk management) were not significantly different between apolipoprotein E ε4 carriers and noncarriers (test of interaction). Within-group results by apolipoprotein E ε4 carrier status suggested beneficial effects, particularly among carriers.

Meaning  Healthy lifestyle changes may be beneficial for cognition in older at-risk individuals even in the presence of apolipoprotein E–related genetic susceptibility to dementia.


Importance  The role of the apolipoprotein E (APOE) ε4 allele as an effect modifier in lifestyle interventions to prevent cognitive impairment is still unclear.

Objective  To examine whether the APOE ε4 allele modifies the previously reported significant cognitive benefits of a multidomain lifestyle intervention (prespecified subgroup analysis).

Design, Setting, and Participants  The Finnish Geriatric Intervention Study to Prevent Cognitive Impairment and Disability (FINGER) was a randomized clinical trial in 6 centers across Finland (screening and randomization performed from September 7, 2009, through November 24, 2011; intervention duration, 2 years). Data analysis was performed from August 1, 2015, to March 31, 2016. The study population was at-risk older individuals from the general population. Inclusion criteria were age of 60 to 77 years; Cardiovascular Risk Factors, Aging, and Dementia risk score of at least 6 points; and cognition at a mean level or slightly lower than expected for age. Individuals with dementia or substantial cognitive impairment and conditions that prevented cooperation or safe engagement in the intervention were excluded. APOE genotype data were available for 1175 of the 1260 participants.

Interventions  Participants were randomly assigned in a 1:1 ratio to a multidomain intervention group (diet, exercise, cognitive training, and vascular risk management) or a control group (general health advice). Group allocation was not actively disclosed to participants, and outcome assessors were masked to group allocation.

Main Outcomes and Measures  Primary outcome was change in cognition measured through a comprehensive neuropsychological test battery. Analysis was based on modified intention to treat (participants with at least 1 postbaseline assessment).

Results  A total of 1109 participants (mean [SD] age, 69.3 [4.7] years; 514 [46.3%] female) were included in the analysis: 362 APOE ε4 allele carriers (173 intervention and 189 control) and 747 noncarriers (380 intervention and 367 control). The APOE ε4 carriers and noncarriers were not significantly different at baseline (except for serum cholesterol level). The difference between the intervention and control groups in annual neuropsychological test battery total score change was 0.037 (95% CI, 0.001 to 0.073) among carriers and 0.014 (95% CI, −0.011 to 0.039) among noncarriers. Intervention effect was not significantly different between carriers and noncarriers (0.023; 95% CI, −0.021 to 0.067).

Conclusions and Relevance  Healthy lifestyle changes may be beneficial for cognition in older at-risk individuals even in the presence of APOE-related genetic susceptibility to dementia. Whether such benefits are more pronounced in APOE ε4 carriers compared with noncarriers should be further investigated. The findings also emphasize the importance of early prevention strategies that target multiple modifiable risk factors simultaneously.

Trial Registration  ClinicalTrials.gov Identifier: NCT01041989