Physical inactivity, cardiometabolic disease, and risk of dementia: an individual-participant meta-analysis
BMJ 2019; 365 doi: https://doi.org/10.1136/bmj.l1495 (Published 17 April 2019) Cite this as: BMJ 2019;365:l1495Linked BMJ Opinion
Reflections on null findings: the case of physical activity and risk of dementia
All rapid responses
Rapid responses are electronic comments to the editor. They enable our users to debate issues raised in articles published on bmj.com. A rapid response is first posted online. If you need the URL (web address) of an individual response, simply click on the response headline and copy the URL from the browser window. A proportion of responses will, after editing, be published online and in the print journal as letters, which are indexed in PubMed. Rapid responses are not indexed in PubMed and they are not journal articles. The BMJ reserves the right to remove responses which are being wilfully misrepresented as published articles or when it is brought to our attention that a response spreads misinformation.
From March 2022, the word limit for rapid responses will be 600 words not including references and author details. We will no longer post responses that exceed this limit.
The word limit for letters selected from posted responses remains 300 words.
Kivimäki et al. (1) conducted a meta-analysis of prospective observational cohort studies, concluding that physical activity (PA) is not associated with all-cause dementia or Alzheimer’s disease (AD), and that the previously found associations mostly reflect reverse causality. This surprisingly strong conclusion is partly misleading for several reasons:
1) Dementia outcomes were based on register diagnoses, resulting in very low incidence numbers: 0.3 per 1000 person-years in the total population, and only 1.1% of participants among the 60+ year old sub-group developed dementia. Although this may be a central determinant for the observed lack of association between PA and dementia, the major limitations of this approach are never addressed in the article. Compared with the register accuracy for acute vascular events, e.g. myocardial infarction and stroke, dementia diagnoses have substantially poorer sensitivity, leading to outcome misclassification and the observed discrepancy in the impact of PA.
Register-based dementia diagnoses are affected by multiple factors: developments in diagnostic criteria over time, drug availability, prescription and reimbursement regulations, changes in register-entry guidelines and practice, and population awareness and attitudes towards dementia and seeking help for cognitive symptoms. Recording of dementia as cause of death in mortality registries has only started to increase in recent years. The differences between individuals with dementia who were identified versus not identified in the registers are unclear. If the healthy and more physically active participants were also more prone to seek help early for cognitive symptoms, this would substantially bias the associations.
2) Varying operationalization of PA definition across studies. Physical inactivity was defined as no or very little moderate or vigorous PA or exercise. This means that even relatively inactive persons who do not meet the PA recommendations are categorized as active. Since it is known that vigorous PA has most beneficial effects on cognition, using this crude categorization naturally weakens the possible association between PA and dementia risk. Higher levels of PA (500 kcal or 10 MET-h increase/week) have been associated with lower risk of all-cause dementia (10%) and AD (13%) (2).
3) Quality of evidence provided by observational studies, where the risk of bias is high compared to randomized controlled trials (RCTs) (3). Large sample sizes do not automatically mitigate this problem (4). A recent review of systematic reviews on PA interventions concluded that there was moderate quality of evidence supporting beneficial effects on cognition (5). This formed the basis of the recently released World Health Organization (WHO) guidelines on risk reduction of cognitive decline and dementia (5). WHO concluded that PA interventions should be recommended to adults with normal cognition to reduce the risk of cognitive decline. This recommendation was strong, i.e. the guideline development group was confident that the desirable effects of PA interventions outweigh any undesirable effects, and most individuals should receive the intervention (5). Consensus Study Report by the National Academies of Sciences, Engineering, and Medicine also concluded that evidence from RCTs is encouraging (6). Biomarker and imaging evidence from RCTs also support a protective effect of PA on cognition (7).
4) Impact of PA in midlife. The authors showed that inactivity was associated with dementia when the follow-up was <10 years, but not longer, and concluded that this finding reflects the presence of preclinical disease (reverse causation). Although pre-clinical disease may indeed influence PA habits, this does not completely exclude PA benefits within ten years before dementia diagnosis. Persons in early disease stages may still benefit from PA and could maintain their cognitive abilities longer, even if dementia onset is not fully averted (8). Due to these multiple benefits, pre-clinical populations should not be automatically excluded from PA interventions. Furthermore, older populations are most likely a mixture of healthy individuals, and individuals in preclinical disease stages. Assuming everyone had preclinical disease based on the 10-year cut-off alone, without any biomarker evidence or cognitive scores, is rather crude.
It is true that no RCTs have shown that PA interventions can prevent dementia or AD, as such studies would need long-term intervention and follow-up times given the long preclinical/prodromal phase before dementia onset. We also agree with the authors that focusing only on PA may not be the optimal way to prevent dementia. Given the multifactorial etiology of dementia and AD, interventions targeting multiple risk factors simultaneously may provide additional benefits in terms of dementia prevention. The Finnish Geriatric Intervention Study to Prevent Cognitive Impairment and Disability (FINGER)-intervention focusing on physical, cognitive and social activity, diet and cardiovascular risk factor management reported significant benefits on cognition among elderly persons at-risk of dementia (9). In view of these encouraging results, FINGER-type interventions that have been adapted in diverse geographical and cultural settings are currently ongoing (10). In the following years, new evidence on the effects of PA and multidomain interventions towards dementia prevention will be available.
References:
1. Kivimaki M, Singh-Manoux A, Pentti J, et al. Physical inactivity, cardiometabolic disease, and risk of dementia: an individual-participant meta-analysis. BMJ. 2019;365:l1495.
2. Xu W, Wang HF, Wan Y,et al. Leisure time physical activity and dementia risk: a dose-response meta-analysis of prospective studies. BMJ Open 2017;7:e014706.
3. Stephen R, Hongisto K, Solomon A, Lonnroos E. Physical Activity and Alzheimer's Disease: A Systematic Review. J Gerontol A Biol Sci Med Sci. 2017;72:733-739.
4. Keyes KM, Westreich D. UK Biobank, big data, and the consequences of non-representativeness. Lancet. 2019;393:1297-6736(18)33067-8.
5. Risk reduction of cognitive decline and dementia: WHO guidelines. Geneva: World Health Organization; 2019. Licence: CC BY-NC-SA 3.0 IGO.
6. National Academies of Sciences, Engineering, and Medicine. 2017. Preventing cognitive decline and dementia: A way forward. Washington, DC: The National Academies Press. doi: https://doi.org/10.17226/24782
7. Erickson KI, Voss MW, Prakash RS, et al. Exercise training increases size of hippocampus and improves memory. Proc Natl Acad Sci U S A. 2011;108:3017-3022.
8. Song D, Yu DSF, Li PWC, Lei Y. The effectiveness of physical exercise on cognitive and psychological outcomes in individuals with mild cognitive impairment: A systematic review and meta-analysis. Int J Nurs Stud. 2018 Mar;79:155-164.
9. Ngandu T. 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. Lancet. 2015 Jun 6;385(9984):2255-63.
10. Kivipelto M, Mangialasche F, Ngandu T, World Wide Fingers Network (2017). World Wide Fingers will advance dementia prevention. Lancet Neurology. 17(1):27.
Competing interests: No competing interests
Dementia carries many risk factors from nutritional deficiency to genetic susceptibility to loss of cognitive function. Physical inactivity is one of the many geriatric problems faced by the elderly due to a physical cause or mental condition. The loss of communication, the loss of a sense of belonging or the sudden demise of one's spouse influence the mental attitude of a geriatric patient. The loss of interest in carrying out day to day activities and the period of retirement from an active profession add up to the loss of mental acuity as well as the need to remember things to be done routinely. We have witnessed elderly people measuring and placing their bed at a distance suitable for them to reach the bathroom for their daily chores. These small adjustments are related to their mental as well as to their slowing down metabolic processes that need to trigger their neuronal activity to process information and relay it.
A person who keeps himself or herself with intellectual activity like processing information or data or say research findings sharpens their faculty of reasoning and keeps their cognitive as well as other higher domains of learning and experience.
Physical inactivity may result in cardio-metabolic disease. Yet if these patients are given an opportunity to continue their profession actively or keep their learning activity or analytical capacity it will take care of their physical as well as mental health in a positive way. Elders require to be recognized and given their due respect as well as their due place in society to create healthy solutions to physical as well as mental health problems.
Competing interests: No competing interests
The IPD-Work consortium did not find that dementia related to physical activity. 1 However excessive physical activity can cause magnesium deficiency in red blood cells and muscle damage although serum magnesium levels can be normal. 2 Dementia is most commonly related to zinc, magnesium and B vitamin deficiencies as the number of references in PubMed for dementia and separate nutritional deficiencies are:
3143 references for zinc deficiency
2530 for vitamin B12 deficiency
1638 for vitamin B6 deficiency
1449 for folic acid deficiency
1245 for magnesium deficiency
1177 for vitamin D deficiency
193 PUFA deficiencies
Monitored repletion of essential nutrient deficiencies should be more widely available, especially zinc levels in white blood cells and functional tests for B vitamin deficiencies. It is safer and more physiological to supplement B12 deficiency with methylcobalamin rather than cyanocobalamin.
There is also at least moderate evidence implicating increases in environmental risk factors: air pollution, aluminium, silicon, selenium, pesticides and electric and magnetic fields, as risk factors for dementia. 3
In 1989 we reported in the BMJ that all of the dyslexic children tested were zinc deficient in their sweat (measured to parts per billion) although their serum zinc levels were in the normal range. Age and sex matched control children had sweat and serum zinc levels in the normal range. 4,5
It is important that dementia and learning difficulties are most commonly related to zinc and B vitamin deficiencies.
1 Kivimäki M, Singh-Manoux A, Pentti J, Sabia S, Nyberg ST, Alfredsson L, Goldberg M, Knutsson A, Koskenvuo M, Koskinen A, Kouvonen A, Nordin M, Oksanen T, Strandberg T, Suominen SB, Theorell T, Vahtera J, Väänänen A, Virtanen M, Westerholm P, Westerlund H, Zins M, Seshadri S, Batty GD, Sipilä PN, Shipley MJ, Lindbohm JV, Ferrie JE, Jokela M; IPD-Work consortium. Physical inactivity, cardiometabolic disease, and risk of dementia: an individual-participant meta-analysis. BMJ 2019; 365: l1495.
2 Howard J. Muscle Action, Trace Elements and Related Nutrients: The Myothermogram. In: Chazot G, Abdulla M, Arnaud P, eds. Current Trends in Trace Element Research: Proceedings of International Symposium on Trace Elements. Paris, 1987, Smith-Gordon, London,1989, pp79-85.
3 Killin LOJ. Starr JM, Shiue IJ, RussTC, Environmental risk factors for dementia: a systematic review. BMC Geriatr. 2016; 16: 175. Published online 2016 Oct 12. doi: 10.1186/s12877-016-0342-y
4 Grant ECG, Howard JM, Davies S, Chasty H, Hornsby B, Galbraith J. Zinc deficiency in children with dyslexia: concentrations of zinc and other minerals in sweat and hair. BMJ 1989;296:607-609.
5 Howard JMH. Serum, Leucocyte, Sweat and Hair Zinc Levels - a correlational Study. J.Nutr.Med. 1990;1:119-126.
Competing interests: No competing interests
Congratulation to Kivimäki et al for showing that there is probably no effect of physical activity on dementia risk [1]. On the one hand, this is of course a bad news for population health as there was hope that physical activity could help prevent dementia [2]; we will have to find other preventive strategies for dementia. On the other hand, this could be a good news for evidence-informed public health. Indeed, using an interesting data analysis approach, the author could limit the risk of reverse causation, that is, dementia causing a reduction of physical activity. With this approach, the authors could move from a prediction exercise to a true causal inference study. Observational epidemiology aiming to address causal relationship has suffered major drawbacks, notably in the domains of nutrition or environmental science, where numerous findings were eventually not confirmed [3, 4]; the null finding in the study by Kivimäki et al, if confirmed, could reveal a new drawback of observational studies. Such failures are a real danger for public health. To better inform evidence for public health, it is necessary to move toward a post-modern epidemiology, clearly distinguishing description, prediction, and causal inference in observational studies, and taking advantage of new methods in causal analyses [5].
References
1. Kivimäki M, Singh-Manoux A, Pentti J, Sabia S, Nyberg ST, Alfredsson L, Goldberg M, Knutsson A, Koskenvuo M, Koskinen A, Kouvonen A, Nordin M, Oksanen T, Strandberg T, Suominen SB, Theorell T, Vahtera J, Väänänen A, Virtanen M, Westerholm P, Westerlund H, Zins M, Seshadri S, Batty GD, Sipilä PN, Shipley MJ, Lindbohm JV, Ferrie JE, Jokela M; IPD-Work consortium. Physical inactivity, cardiometabolic disease, and risk of dementia: an individual-participant meta-analysis. BMJ 2019; 365: l1495.
2. Livingston G, Sommerlad A, Orgeta V, Costafreda SG, Huntley J, Ames D, Ballard C, Banerjee S, Burns A, Cohen-Mansfield J, Cooper C, Fox N, Gitlin LN, Howard R, Kales HC, Larson EB, Ritchie K, Rockwood K, Sampson EL, Samus Q, Schneider LS, Selbæk G, Teri L, Mukadam N. Dementia prevention, intervention, and care. Lancet 2017; 390(10113): 2673-34.
3. Chiolero A. Counterfactual and interventionist approach to cure risk factor epidemiology. Int J Epidemiol 2016; 45(6): 2202-3.
4. Ioannidis JP. Why most published research findings are false. PLoS Med 2005; 2(8): e124.
5. Hernán MA, Hsu J, Healy B. A second chance to get causal inference right: A classification of data science tasks. Chance 2019; 32(1):42-9.
Competing interests: No competing interests
Re: Physical inactivity, cardiometabolic disease, and risk of dementia: an individual-participant meta-analysis - Authors’ response
We thank Stephen and colleagues for their comments on our paper.[1] We refer interested readers to the BMJ opinion accompanying our paper that anticipated criticism of inadequate measurement of exposure or outcome.[2] Briefly, measurement issues are an unlikely explanation as the short-term associations between physical inactivity and dementia in our study were similar to those in previous studies with more comprehensive dementia ascertainment. An important advantage of dementia ascertainment from linkage to electronic records is that it allows analysis on everyone recruited to the study rather than those who continue to participate over the long course of the follow-up.
Stephen and colleagues’ argument that only vigorous physical activity is protective against Alzheimer’s disease and all-cause dementia is based on a meta-analysis of studies with short follow-ups.[3] The analysis does not consider bias arising from preclinical dementia leading to reduction of physical activity. In our sensitivity analyses where reverse causation is taken into account by stratification of the follow-up period, we used a 3-level measure of physical activity and found no reduction in dementia risk in the top category that reflects vigorous physical activity.[1]
Population studies show evidence of cognitive decline starting before the age of 60.[4] Physical activity is correlated with cognitive performance in dementia-free people, but these data cannot be extrapolated to infer a “causal” protective effect of physical activity for Alzheimer’s disease and related dementias, which are a consequence of major pathophysiological changes in the brain. Analogously, it would be wrong to conclude that physical inactivity is a risk factor for ALS (a disease preceded by loss of muscle strength) based on correlation between physical inactivity and declining muscle mass.
Our aim was to evaluate physical inactivity as a risk factor and target for primary prevention after explicit consideration of reverse causation, a major source of bias in dementia research. Given the long preclinical phase of dementia, separating measurement of physical activity and dementia diagnosis by a minimum 10 years is not perfect but it is certainly a major step forward compared to studies that ignore reverse causation altogether.
Whether physical activity during the preclinical phase of dementia can be a target for secondary prevention with the aim of delaying onset of clinically diagnosed dementia, as Stephen et al. suggest, is a different question and needs to be examined in intervention studies. Current evidence does not support this hypothesis. In the DAPA trial of dementia patients, cognitive decline was more rapid in the exercise group than in the usual-care arm.[5]
It is worth highlighting that the PreDIVA trial, a multidomain intervention with individually tailored lifestyle advise on physical activity and other cardiovascular risk factors, did not show reduced incidence of dementia.[6] Stephen et al. refer to FINGER trial, starting date 2009, which did not only target physical inactivity but combined lifestyle advice, management of cardiovascular disease risk, and cognitive training in a multimodal intervention.[7] The trial was pre-registered with a hypothesis that the intervention would reduce dementia incidence after 7-year follow-up; results ought to be due soon and could help move the field forward. In a FINGER substudy, no difference in brain changes on MRI between the intervention and control groups were detected.[8]
Making ‘strong’ recommendations for dementia prevention based on weak and indirect evidence is risky as it may expose people to ineffective strategies that divert attention and resources from strategies that are more effective; lead to misleading public health messages that are difficult to correct later; and affect confidence in evidence-based guidelines among health professionals, patients and the general public. In contrast, recognising what we do not know will lead to progress by meaningful research. We hope that our findings and commentaries will encourage cautious interpretation of the evidence and a more critical evaluation of the association between physical activity and dementia.
1. Kivimaki M, Singh-Manoux A, Pentti J, et al. Physical inactivity, cardiometabolic disease, and risk of dementia: an individual-participant meta-analysis. BMJ 2019;365:l1495.
2. Kivimaki M, Singh-Manoux A. Reflections on null findings—the case of physical activity and risk of dementia. BMJ Opinion (https://blogs.bmj.com/bmj/2019/04/18/reflections-null-findings-case-phys...)
3. Xu W, Wang HF, Wan Y, et al. Leisure time physical activity and dementia risk: a dose-response meta-analysis of prospective studies. BMJ Open 2017;7:e014706.
4. Singh-Manoux A, Kivimaki M, Glymour MM, et al. Timing of onset of cognitive decline: results from Whitehall II prospective cohort study. BMJ 2012;344:d7622.
5. Lamb S, Sheehan B, Atherton N et al. Dementia and physical activity (DAPA) trial of moderate to high intensity exercise training for people with dementia: randomised controlled trial. BMJ 2018;361:k1675.
6. Moll van Charante EP, Richard E, Eurelings LS, et al. Effectiveness of a 6-year multidomain vascular care intervention to prevent dementia (preDIVA): a cluster-randomised controlled trial. Lancet 2016;388:797-805.
7. Finnish Geriatric Intervention Study to Prevent Cognitive Impairment and Disability (FINGER). ClinicalTrials.gov, number NCT01041989 (https://clinicaltrials.gov/ct2/show/NCT01041989 , accessed 14/06/2019).
8. Stephen R, Liu Y, Ngandu T, et al. Brain volumes and cortical thickness on MRI in the Finnish Geriatric Intervention Study to Prevent Cognitive Impairment and Disability (FINGER). Alzheimers Res Ther 2019;11:53.
Competing interests: No competing interests