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Combining modifiable risk factors and risk of dementia: a systematic review and meta-analysis
  1. Ruth Peters1,2,3,
  2. Andrew Booth4,
  3. Kenneth Rockwood5,
  4. Jean Peters4,
  5. Catherine D’Este6,7,
  6. Kaarin J Anstey1,3
  1. 1 Neuroscience Research Australia, Sydney, New South Wales, Australia
  2. 2 School of Public Health, Imperial College London, London, UK
  3. 3 University of New South Wales, Sydney, New South Wales, Australia
  4. 4 School of Health and Related Research (ScHARR), University of Sheffield, Sheffield, UK
  5. 5 Dalhousie University, Halifax, Nova Scotia, Canada
  6. 6 Australian National University (ANU), Canberra, Australian Capital Territory, Australia
  7. 7 University of Newcastle, Callaghan, New South Wales, Australia
  1. Correspondence to Dr Ruth Peters; r.peters{at}


Objective To systematically review the literature relating to the impact of multiple co-occurring modifiable risk factors for cognitive decline and dementia.

Design A systematic review and meta-analysis of the literature relating to the impact of co-occurring key risk factors for incident cognitive decline and dementia. All abstracts and full text were screened independently by two reviewers and each article assessed for bias using a standard checklist. A fixed effects meta-analysis was undertaken.

Data sources Databases Medline, Embase and PsycINFO were searched from 1999 to 2017.

Eligibility criteria For inclusion articles were required to report longitudinal data from participants free of cognitive decline at baseline, with formal assessment of cognitive function or dementia during follow-up, and an aim to examine the impact of additive or clustered comorbid risk factor burden in with two or more core modifiable risk factors.

Results Seventy-nine full-text articles were examined. Twenty-two articles (18 studies) were included reporting data on >40 000 participants. Included studies consistently reported an increased risk associated with greater numbers of intraindividual risk factors or unhealthy behaviours and the opposite for healthy or protective behaviours. A meta-analysis of studies with dementia outcomes resulted in a pooled relative risk for dementia of 1.20 (95% CI 1.04 to 1.39) for one risk factor, 1.65 (95% CI 1.40 to 1.94) for two and 2.21 (95% CI 1.78 to 2.73) for three or more, relative to no risk factors. Limitations include dependence on published results and variations in study outcome, cognitive assessment, length of follow-up and definition of risk factor exposure.

Conclusions The strength of the reported associations, the consistency across studies and the suggestion of a dose response supports a need to keep modifiable risk factor exposure to a minimum and to avoid exposure to additional modifiable risks. Further research is needed to establish whether particular combinations of risk factors confer greater risk than others.

PROSPERO registration number 42016052914.

  • dementia
  • risk factors
  • cognitive decline
  • scores
  • clustering

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  • Contributors RP conceived and designed the study, carried out the data extraction, analysis and drafted the manuscript. AB helped design the study and the search strategy and commented on the manuscript. KR helped design the study, and commented on the manuscript. JP helped design the study, extracted the data and commented on the manuscript. CDE advised on the statistical methods and commented on the manuscript. KJA helped design the study and commented on the manuscript. All authors had full access to study data.

  • Funding No funding was received specifically for this work. RP is funded by the Australian Dementia Collaborative Research Centre. AB’s input into the literature search and review design was undertaken under his University of Sheffield employment contract. KR is funded through the Dalhousie Medical Research Foundation as the Kathryn Allen Weldon Professor of Alzheimer’s Research and receives research funding from the Canadian Institutes of Health Research, the Canadian Frailty Network and the Fountain Family Research Fund of the Queen Elizabeth II Health Sciences Centre. JP received no support from any organisation for the submitted work. KJA is funded by NHMRC Fellowship APP1102694.

  • Competing interests RP, AB, JP, CDE, KJA report no disclosures. KR founded DGI Clinical, which has contracts with pharma for individualised outcome measurement and for data analytics, including in dementia studies with Otsuka and Roche. In 2017, he participated in an Advisory Board meeting on dementia for Lundbeck and in 2014 spoke at a satellite symposium at the Alzheimer Association International Conference, sponsored by Nutricia.

  • Patient consent Not required.

  • Provenance and peer review Not commissioned; externally peer reviewed.

  • Data sharing statement The data supporting the results are publicly available in the published literature. RP affirms that the manuscript is an accurate honest and transparent account of the study being reported. No important aspects of the study have been omitted, any discrepancies between the study as planned and registered are explained. Funding bodies had no role in the inception, design, completion or publication of this work.