Associations between physical frailty and dementia incidence: a prospective study from UK Biobank – Authors' reply
Authors: Fanny Petermann-Rocha, Donald M Lyall, Terence J Quinn, Frederick K Ho, Jill P Pell, Carlos Celis-Morales
Journal: The Lancet Healthy Longevity (2021)

We thank Martin Kopp and Martin Burtscher and Alberto Sardella and colleagues for their interest in our work.1Petermann-Rocha F Lyall DM Gray SR et al.Associations between physical frailty and dementia incidence: a prospective study from UK Biobank.Lancet Healthy Longev. 2020; 1: e58-e68Summary Full Text Full Text PDF Scopus (16) Google Scholar Kopp and Burtscher raised the issue that the finding of no association between low levels of physical activity (PA) and dementia risk reported in our study could send the wrong message to the public, by discoursing and negatively affecting adherence to regular PA. Despite reporting no association between the level of PA and dementia risk in our study, we cannot deny the health benefits of being physically active.2Strain T Brage S Sharp SJ et al.Use of the prevented fraction for the population to determine deaths averted by existing prevalence of physical activity: a descriptive study.Lancet Glob Health. 2020; 8: e920-e930Summary Full Text Full Text PDF PubMed Scopus (33) Google Scholar Therefore, our finding should not discourage people from engaging in PA, because PA has been extensively associated with several health benefits beyond reduced dementia risk.2Strain T Brage S Sharp SJ et al.Use of the prevented fraction for the population to determine deaths averted by existing prevalence of physical activity: a descriptive study.Lancet Glob Health. 2020; 8: e920-e930Summary Full Text Full Text PDF PubMed Scopus (33) Google Scholar However, there are several factors that could explain why no association between PA and dementia risk was reported in our study, including differences in how the PA exposure was defined, self-reported bias related to the PA variable, and reverse causation. In our study,1Petermann-Rocha F Lyall DM Gray SR et al.Associations between physical frailty and dementia incidence: a prospective study from UK Biobank.Lancet Healthy Longev. 2020; 1: e58-e68Summary Full Text Full Text PDF Scopus (16) Google Scholar to derive a metric compatible with the Fried frailty criteria, a threshold that defined low PA had to be chosen. We dichotomised the population by using the lowest 20th percentile to signify low PA. Other studies have used more extreme cutpoints and comparison groups to estimate whether the risk of dementia and the level of PA are associated. No association between PA and dementia could also be attributable to the potential effect of misreporting and dilution bias related to the PA information derived from the International Physical Activity Questionnaire.3Ekelund U Dalene KE Tarp J Lee I-M Physical activity and mortality: what is the dose response and how big is the effect?.Br J Sports Med. 2020; 54: 1125-1126Crossref PubMed Scopus (20) Google Scholar Such types of bias could obscure the true magnitude of the association between PA and dementia risk. Kopp and Burtscher suggest the collinearity between PA, grip strength, and gait speed could explain why no association between PA and dementia risk was found. However, there was no evidence to suggest that collinearity assumptions were violated in our Cox proportional hazard models. Moreover, our results suggest that low PA level was not associated with dementia risk even for the minimally adjusted model when neither gait speed nor grip strength was included as covariates in our analyses.1Petermann-Rocha F Lyall DM Gray SR et al.Associations between physical frailty and dementia incidence: a prospective study from UK Biobank.Lancet Healthy Longev. 2020; 1: e58-e68Summary Full Text Full Text PDF Scopus (16) Google Scholar Reverse causation is another important source of bias that should be carefully considered when interpreting a link between PA and dementia. Most of the evidence on dementia and PA has been derived from observational studies that do not necessarily support a causal link.4Sabia S Dugravot A Dartigues JF et al.Physical activity, cognitive decline, and risk of dementia: 28 year follow-up of Whitehall II cohort study.BMJ. 2017; 357j2709Crossref PubMed Scopus (165) Google Scholar Although Kopp and Burtscher mention evidence5Xu W Wang HF Wan Y Tan CC Yu JT Tan L Leisure time physical activity and dementia risk: a dose-response meta-analysis of prospective studies.BMJ Open. 2017; 7e014706Crossref PubMed Scopus (65) Google Scholar that supports an association between PA and dementia risk, this evidence is not conclusive nor unequivocal; more high quality, well-controlled, large-scale randomised controlled trials are required. Most of the studies that are in support of a link between dementia and PA, including those mentioned by Kopp and Burtscher, have a relatively short follow-up (ie, less than 10 years).4Sabia S Dugravot A Dartigues JF et al.Physical activity, cognitive decline, and risk of dementia: 28 year follow-up of Whitehall II cohort study.BMJ. 2017; 357j2709Crossref PubMed Scopus (165) Google Scholar, 5Xu W Wang HF Wan Y Tan CC Yu JT Tan L Leisure time physical activity and dementia risk: a dose-response meta-analysis of prospective studies.BMJ Open. 2017; 7e014706Crossref PubMed Scopus (65) Google Scholar This factor is particularly important if we consider that PA levels decline even 9 years before dementia is typically diagnosed, suggesting that reverse causation might have an important role in the link between PA and dementia.4Sabia S Dugravot A Dartigues JF et al.Physical activity, cognitive decline, and risk of dementia: 28 year follow-up of Whitehall II cohort study.BMJ. 2017; 357j2709Crossref PubMed Scopus (165) Google Scholar Kopp and Burtscher also suggested that low PA levels in people with frailty supports the link between PA and dementia. However, this suggestion should be carefully considered, because the association between low levels of PA and dementia could be attributable to being frail, indicating reverse causation. We agree with the suggestions made by Sardella and colleagues on the role of cognitive reserve on dementia risk. In our study, the profile of pre-frail and frail individuals (ie, lower education, lower socioeconomic status, and reduced engagement in social activities) indirectly suggests that these individuals have a lower cognitive reserve compared with non-frail individuals, and our findings showed that pre-frail and frail individuals had a higher risk of dementia incidence. However, as Sardella and colleagues mentioned, research regarding cognitive reserve has proven to be challenging. If a consensus on the definition of cognitive reserve emerges in the future, it will be highly relevant to investigate its interplay with frailty and dementia risk. We declare no competing interests. Associations between physical frailty and dementia incidence: a prospective study from UK BiobankIndividuals with pre-frailty and frailty were at a higher risk of dementia incidence even after adjusting for a wide range of confounding factors. Early detection and interventions for frailty could translate into prevention or delayed onset of dementia. Full-Text PDF Open AccessAssociations between physical frailty, physical activity and dementia incidenceWe read with great interest the excellent study on the association between physical frailty and dementia that was recently published in The Lancet Healthy Longevity.1 Based on a large cohort, the authors showed that four of five components defining frailty—ie, weight loss, tiredness, low grip strength, and slow gait speed—were independently associated with a higher risk of dementia incidence. Although grip strength and gait speed had the largest contributions, no association was shown between physical activity (PA) and the risk of dementia incidence. Full-Text PDF Open AccessCan cognitive reserve protect frail individuals from dementia?Fanny Petermann-Rocha and colleagues1 reported the findings of a large prospective study, which was aimed at investigating the association of physical frailty and all-cause dementia incidence. The principal finding was that individuals clustered as pre-frail and frail (according to the diagnostic criteria of the Fried frailty phenotype) showed a higher risk of dementia incidence than non-frail individuals. This study investigated the potential predictive role of physical frailty in the development of dementia for the first time, and thus substantially improved the current knowledge that was often limited to the investigation of sole components of physical frailty, such as handgrip strenght and gait speed, as potential predictors of dementia. 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