Biology 4a assignment

Association of Daily Step Count and Intensity With Incident Dementia in 78 430 Adults Living in the UK Borja del Pozo Cruz, PhD; Matthew Ahmadi, PhD; Sharon L. Naismith, PhD; Emmanuel Stamatakis, PhD

IMPORTANCE Step-based recommendations may be appropriate for dementia-prevention guidelines. However, the association of step count and intensity with dementia incidence is unknown.

OBJECTIVE To examine the dose-response association between daily step count and intensity and incidence of all-cause dementia among adults in the UK.

DESIGN, SETTING, AND PARTICIPANTS UK Biobank prospective population-based cohort study (February 2013 to December 2015) with 6.9 years of follow-up (data analysis conducted May 2022). A total of 78 430 of 103 684 eligible adults aged 40 to 79 years with valid wrist accelerometer data were included. Registry-based dementia was ascertained through October 2021.

EXPOSURES Accelerometer-derived daily step count, incidental steps (less than 40 steps per minute), purposeful steps (40 steps per minute or more), and peak 30-minute cadence (ie, mean steps per minute recorded for the 30 highest, not necessarily consecutive, minutes in a day).

MAIN OUTCOMES AND MEASURES Incident dementia (fatal and nonfatal), obtained through linkage with inpatient hospitalization or primary care records or recorded as the underlying or contributory cause of death in death registers. Spline Cox regressions were used to assess dose-response associations.

RESULTS The study monitored 78 430 adults (mean [SD] age, 61.1 [7.9] years; 35 040 [44.7%] male and 43 390 [55.3%] female; 881 [1.1%] were Asian, 641 [0.8%] were Black, 427 [0.5%] were of mixed race, 75 852 [96.7%] were White, and 629 [0.8%] were of another, unspecified race) over a median (IQR) follow-up of 6.9 (6.4-7.5) years, 866 of whom developed dementia (mean [SD] age, 68.3 [5.6] years; 480 [55.4%] male and 386 [54.6%] female; 5 [0.6%] Asian, 6 [0.7%] Black, 4 [0.4%] mixed race, 821 [97.6%] White, and 6 [0.7%] other). Analyses revealed nonlinear associations between daily steps. The optimal dose (ie, exposure value at which the maximum risk reduction was observed) was 9826 steps (hazard ratio [HR], 0.49; 95% CI, 0.39-0.62) and the minimal dose (ie, exposure value at which the risk reduction was 50% of the observed maximum risk reduction) was 3826 steps (HR, 0.75; 95% CI, 0.67-0.83). The incidental cadence optimal dose was 3677 steps (HR, 0.58; 95% CI, 0.44-0.72); purposeful cadence optimal dose was 6315 steps (HR, 0.43; 95% CI, 0.32-0.58); and peak 30-minute cadence optimal dose was 112 steps per minute (HR, 0.38; 95% CI, 0.24-0.60).

CONCLUSIONS AND RELEVANCE In this cohort study, a higher number of steps was associated with lower risk of all-cause dementia. The findings suggest that a dose of just under 10 000 steps per day may be optimally associated with a lower risk of dementia. Steps performed at higher intensity resulted in stronger associations.

JAMA Neurol. 2022;79(10):1059-1063. doi:10.1001/jamaneurol.2022.2672 Published online September 6, 2022. Corrected on September 9, 2022.

Editorial page 973

Supplemental content

Author Affiliations: Author affiliations are listed at the end of this article.

Corresponding Author: Borja del Pozo Cruz, PhD, Department of Sport Sciences and Clinical Biomechanics, Centre for Active and Healthy Ageing, University of Southern Denmark, Campusvej 55, 5230 Odense M, Denmark (bdelpozocruz@ health.sdu.dk).

Research

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S tep count is a popular approach to providing physical ac- tivity targets for the general public.1 An optimal dose of 6000 to 8000 steps has been suggested to reduce the risk

of all-cause mortality.2 Higher step counts may lower the risk of cardiovascular and cancer mortality3 and incident diabetes, par- ticularly more intense steps.4 Step-based physical activity targets are easy to grasp and memorize and may be ideal for dementia-prevention guidelines.5,6 To our knowledge, no study on the dose-response association of daily steps and stepping in- tensity (ie, cadence or steps per minute) with incident demen- tia exists. Understanding this association is critical to deter- mining the optimal dose of stepping volume and intensity for dementia prevention. We examined the dose-response asso- ciation of daily step count and intensity with incident all- cause dementia in a large population sample of adults in the UK who wore wrist accelerometers.

Methods This study used data from UK Biobank (February 2013 to Decem- ber 2015)7 and followed the Strengthening the Reporting of Ob- servational Studies in Epidemiology (STROBE) reporting guideline. All participants provided written informed consent. The study was approved by the National Health Service and the National Research Ethics Service (reference 11/NW/0382). There were 236 519 eligible participants who provided a valid email address. Of these, 103 684 accepted the invitation and were instructed to wear an Axivity AX3 accelerometer on their dominant wrist 24 hours a day, 7 days a week, to measure physical activity. A total of 78 430 participants aged 40 to 79 years with at least 3 valid days (more than 16 hours wearing time) and complete data on covariates, and who were free of cardiovascular disease, cancer, or dementia at baseline were included in the analysis (Figure 1). Participants were monitored through October 31, 2021, with incident dementia (fatal and nonfatal) obtained through linkage with inpatient hospitalization or primary care records, or recorded as the underlying or contributory cause of death in the death registers.8 We identified walking activities using an accelerometer-based activity machine learning scheme9

and used a validated step-count algorithm10 for wrist acceler- ometers to estimate the number of steps. We used cadence- basedsteppingmetricsreflectiveofpaceandintensityunderfree- living conditions: incidental steps, defined as fewer than 40 steps per minute (eg, indoor walking from one room to another);11

purposeful steps, defined as 40 or more steps per minute (eg, steps while exercising);11 and peak 30-minute cadence (ie, average steps per minute recorded for the 30 highest, not necessarily consecutive, minutes in a day).12

Thesamplewasdescribedbytertilesofdailystepscountusing means (SDs) and percentages for continuous and categorical vari- ables, respectively. We assessed the dose-response association betweenstep-basedmetricsandincidentall-causedementiausing restricted cubic splines. Knots were placed at the 10th, 50th, and 90th percentiles of the exposure distribution. Nonlinearity was assessed by a Wald test. We estimated the optimal dose (ie, ex- posure value at which the maximum significant risk reduction was observed) and the minimal dose (ie, exposure value at which

the risk reduction was 50% of the observed maximum significant risk reduction). E-values associated with the optimal dose13 were calculated, estimating the plausibility of bias from unmeasured confounding. Models were adjusted for age, sex, race, education, socioeconomicalstatus,smoking,alcoholuse,fruitandvegetable consumption, family history of cardiovascular disease and can- cer, medication use, accelerometer-measured sleep, and valid accelerometer wear days. Race was included as a potential con- founderintheassociationbetweenstepsandincidenceofdemen- tia, and data were collected via self-report. Participants were of- fered multiple choice and the categories were taken from the UK Office for National Statistics. Models for incidental steps were ad- justed for purposeful steps and vice versa. For peak 30-minute cadence, models were adjusted for daily steps. To minimize chances of reverse causation, we ran a sensitivity analysis remov- ing participants who were diagnosed with dementia within the first 2 years of follow-up. An additional model was adjusted for cholesterol, hemoglobin A1c, body mass index, and mean arterial pressure. We used R version 4.2.1 (R Foundation) in our analyses. Two-tailed P values less than .05 were considered significant.

Results Among the 78 430 participants in this study, the mean (SD) age was 61.1 (7.9) years; 35 040 participants (44.7%) were male and

Figure 1. Flow Diagram of Study Participants

103 684 Participants with accelerometer data

78 430 With complete covariates included in final analytical sample

23 638 Excluded 12 068 With invalid accelerometer data

9636 With prevalent CVD, cancer, or dementia or with major health problems

1934 With <3 weekdays and 1 weekend of valid accelerometer data

CVD indicates cardiovascular disease.

Key Points Question Is there a dose-response association of daily step count and intensity with incidence of all-cause dementia among adults living in the UK?

Findings This cohort study of adults assessed with wrist-worn accelerometers found that accruing more steps per day was associated with steady declines in dementia incidence risk, up to 9800 steps per day, beyond which the benefits upturned. The dose associated with 50% of maximal observed benefit was 3800 steps per day, and steps at higher intensity (cadence) were associated with lower incidence risk.

Meaning The findings in this study suggest that accumulating more steps per day just under the popular threshold of 10 000 steps per day and performing steps at higher intensity may be associated with lower risk of dementia onset.

Research Brief Report Association of Daily Step Count and Intensity With Incident Dementia in 78 430 Adults Living in the UK

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43 390 (55.3%) were female; 881 participants were [1.1%] were Asian, 641 [0.8%] were Black, 427 [0.5%] were of mixed race, 75 852 [96.7%] were White, and 629 [0.8%] were of another, unspecified race. Over a median (IQR) follow-up of 6.9 (6.4- 7.5) years, 866 participants developed dementia (mean [SD] age, 68.3 [5.6] years; 480 [55.4%] male and 386 [54.6%] fe- male; 5 [0.6%] Asian, 6 [0.7%] Black, 4 [0.4%] mixed race, 821

[97.6%] White, and 6 [0.7%] other). Younger, healthier (de- fined as lower rates of alcohol consumption and tobacco use and higher rates of fruit and vegetable consumption) female participants took more steps in the sample (Table). We found nonlinear associations for daily steps, wherein the optimal dose was 9826 steps (hazard ratio [HR], 0.49; 95% CI, 0.39-0.62) and the minimal dose was 3826 steps (HR, 0.75; 95% CI, 0.67-

Table. Baseline Characteristics of Study Participants by Tertiles of Mean Daily Accelerometer-Measured Step Count

Characteristic

Mean (SD) P valueaOverall

Tertile 1 (1540 to <5386 steps)

Tertile 2 (5386 to <8821 steps)

Tertile 3 (≥8821 steps)

Sample size, No. 78 430 26 149 26 151 26 150 NA

Age, y 61.1 (7.9) 62.9 (7.7) 60.9 (7.8) 59.6 (7.8) <.001

Female, No. (%) 43 390 (55.3) 14 605 (55.9) 14 225 (54.4) 14 580 (55.8) .001

Male, No. (%) 35 040 (44.7) 11 544 (44.1) 11 926 (45.6) 11 570 (44.2)

Race, No. (%)b

Asian 881 (1.1)

336 (1.3)

298 (1.1)

247 (0.9)

.01

Black 641 (0.8)

221 (0.8)

203 (0.8)

217 (0.8)

Mixed race 427 (0.5)

131 (0.5)

153 (0.6)

143 (0.5)

White 75 852 (96.7)

25 221 (96.5)

25 294 (96.7) 25 337 (96.9)

Otherc 629 (0.8)

232 (0.9)

197 (0.8)

200 (0.8)

Country of origin, No. (%)

England 70326 (89.7)

23563 (90.1)

23429 (89.6) 23334 (89.3)

<.001Scotland 5190 (6.6)

1591 (6.1)

1748 (6.7) 1851 (7.1)

Wales 2914 (3.7)

987 (3.8)

968 (3.7) 959 (3.7)

University degree, No. (%) 43 356 (55.3) 14 799 (56.6) 14 253 (54.5) 14 304 (54.7) <.001

Townsend deprivation index score (lower scores indicate higher affluence)

−1.77 (2.79) −1.72 (2.82) −1.80 (2.79) −1.79 (2.76) .001

Smoking, never, No. (%) 45 330 (57.8) 14 612 (55.9) 15 213 (58.2) 15 505 (59.3) <.001

Alcohol use within guidelines,a No. (%)

28 912 (36.9) 9327 (35.7) 9768 (37.4) 9817 (37.5) <.001

Fruit consumption, servings/d 3.22 (2.49) 3.09 (2.45) 3.19 (2.38) 3.37 (2.62) <.001

Vegetable consumption, servings/d 4.89 (3.13) 4.81 (3.03) 4.89 (3.21) 4.98 (3.13) <.001

Family history of CVD, No. (%) 42 885 (54.7) 14 809 (56.7) 14 235 (54.4) 13 841 (52.9) <.001

Family history of cancer, No. (%) 19 556 (24.9) 6676 (25.5) 6552 (25.1) 6328 (24.2) .002

Cholesterol medication, No. (%) 10 645 (13.6) 4854 (18.6) 3300 (12.6) 2491 (9.5) <.001

Insulin medication, No. (%) 470 (0.6) 225 (0.9) 136 (0.5) 109 (0.4) <.001

Hypertension medication, No. (%) 12 480 (15.9) 5585 (21.4) 3909 (15.0) 2986 (11.4) <.001

HbA1c, % total hemoglobin,d mean (SD)

5.38 (0.49)

5.44 (0.58)

5.36 (0.46)

5.33 (0.41) <.001

High-density lipoprotein cholesterol, mg/dLe

57.53 (14.17) 55.60 (14.17) 57.53 (14.17) 59.46 (15.06) <.001

Low-density lipoprotein cholesterol, mg/dLe

137.84 (32.43) 138.22 (0.88) 138.22 (32.43) 137.45 (31.66) <.001

Triglycerides, mg/dLf 146.02 (84.96) 155.75 (86.73) 146.02 (85.84) 136.28 (80.53) <.001

Arterial blood pressure, mm Hg 100.56 (12.34) 101.70 (12.41) 100.46 (12.24) 99.49 (12.28) <.001

Sleep, accelerometer-measured, min/d

421.56 (85.55) 414.12 (96.92) 422.79 (86.99) 427.76 (80.41) <.001

Accelerometer wear days 6.90 (0.37) 6.89 (0.41) 6.90 (0.37) 6.92 (0.34) <.001

Total steps/dg 8040.59 (4932.97)

3761.76 (1079.93)

6982.20 (977.70)

13 377.38 (4790.68)

<.001

Incidental steps/dh 3417.60 (1266.29)

2278.90 (641.90)

3438.17 (758.25)

4535.61 (1129.85)

<.001

Purposeful steps/di 4622.99 (4160.15)

1482.86 (717.76)

3544.03 (994.41)

8841.77 (4646.91)

<.001

Peak 30-min cadence, steps/minj 84.40 (34.46) 54.47 (13.80) 81.22 (15.37) 117.51 (33.66) <.001

Abbreviations: CVD, cardiovascular disease; HbA1c, hemoglobin A1c; NA, not applicable. a Guidelines for alcohol use in the UK

recommend no more than 14 units of alcohol per week for both men and women.

b Race was included as a potential confounder in the association between steps and incidence of dementia, and data were collected via self-report using multiple choice according to the categories set by the UK Office for National Statistics.

c Included other, unspecified race if presented multiple-choice categories did not apply.

d To convert to mmol/mol, multiply by 10.93 and subtract 23.5.

e To convert to mmol/L, multiply by 0.0259.

f To convert to mmol/L, multiply by 0.0113.

g Mean number of steps accumulated in a day.

h Total daily steps at 1-39 steps/min. i Total daily steps at �40 steps/min. j Mean steps/min recorded for the 30

highest, not necessarily consecutive, minutes in a day.

Association of Daily Step Count and Intensity With Incident Dementia in 78 430 Adults Living in the UK Brief Report Research

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0.83; E-value, 3.46 [upper CI, 2.55]). For incidental steps, the optimal dose was 3677 steps (HR, 0.58; 95% CI, 0.44-0.72; E- value, 2.80 [upper CI, 1.91]). For purposeful steps, the opti- mal dose was 6315 steps (HR, 0.43; 95% CI, 0.32-0.58; E- value, 4.07 [upper CI, 2.82]). For peak 30-minute cadence, the optimal dose was 112 steps per minute (HR, 0.38; 95% CI, 0.24- 0.60; E-value, 4.65 [upper CI, 2.71]) (Figure 2). Removing par- ticipants diagnosed with dementia within the first 2 years of follow-up (eFigure 1 in the Supplement) or further adjust- ment for relevant biomarkers (eFigure 2 in the Supplement) did not change the results.

Discussion We found nonlinear associations of daily steps and intensity with incident dementia. These results may have implications for pub- lic health. We found no minimal threshold for the beneficial as-

sociation of step counts with incident dementia. Our findings suggest that approximately 9800 steps per day may be optimal to lower the risk of dementia. We estimated the minimum dose at approximately 3800 steps per day, which was associated with 25% lower incident dementia. Other studies have found 4400 steps to be associated with mortality outcomes.3,11 This finding suggests that population-wide dementia prevention might be improved by shifting away from the least-active end of the step- count distributions. Unlike previous studies investigating mor- tality outcomes,3 our analyses highlight the importance of step- ping intensity for preventing dementia. Both purposeful steps and peak 30-minute cadence (ie, an indicator of overall best natu- raleffort inafree-livingenvironment)wereassociatedwithlower risks of dementia.10

Strengths of this study are the large sample of adults with accelerometers and the use of multisource registry-based pro- spectively collected data to ascertain incident dementia. This study represents an important contribution to step count–

Figure 2. Dose-Response Association Between Different Accelerometer-Measured Step-Based Metrics and Incidence of All-Cause Dementia

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0.6

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Total steps/d and incidence of all-cause dementiaA

25 000 3000020000150001000050000

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2500020 000150001000050000

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Peak 30-min cadence and incidence of all-cause dementiaD

200150100500

Shading indicates 95% CIs; solid lines, hazard ratios, in logarithmic scale, adjusted for age, sex, race, education, Townsend deprivation index, smoking, alcohol use, fruit and vegetable consumption, family history of cardiovascular disease and cancer, medication use (cholesterol, insulin, and hypertension), accelerometer-measured sleep, and days wearing accelerometer. For incidental steps, models were further adjusted for purposeful steps (and vice versa). For peak 30-minute steps, models were additionally adjusted for total steps per

day. Total steps per day indicates the mean number of steps accumulated in a day; incidental steps, the total daily steps at 1-39 steps per minute; purposeful steps, the total daily steps at �40 steps per minute; peak 30-minute cadence, the mean steps per minute recorded for the 30 highest, not necessarily consecutive, minutes in a day. Dose-response associations were assessed with restricted cubic splines with knots at 10th, 50th, and 90th centiles of the distribution of the exposure of interest.

Research Brief Report Association of Daily Step Count and Intensity With Incident Dementia in 78 430 Adults Living in the UK

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based recommendations for dementia prevention. Step count– based recommendations have the advantage of being easy to communicate, interpret, and measure,11,14 and may be par- ticularly relevant for people who accumulate their physical ac- tivity in an unstructured manner. For such individuals, it may be otherwise challenging to track physical activity or deter- mine whether they are sufficiently active relative to current minute- and intensity-based physical activity guidelines (ie, 150 to 300 minutes per week of moderate to vigorous physi- cal activity). Therefore, step-based recommendations could provide informative supplementary information to the cur- rent physical activity guidelines.

Limitations Limitations of this study include its observational design and the low response rate (5.5%) of participants in UK Biobank, al- though studies15 have demonstrated this poor representative- ness does not necessarily influence associations between physi- cal activity and health outcomes. Reverse causation and residual confounding may still be present. However, the large E-values

showed this possibility is minimal. The inversion of the right part of the dose-response curves in this study likely reflects the sparsity of data and events rather than a genuine lack of bene- ficial association at higher levels of stepping. The age range of participants may have resulted in limited dementia cases, meaning our results may not be generalizable to older popula- tions. Because there are often considerable delays in dementia diagnosis, and this study did not include formal clinical and cog- nitive assessments of dementia, it is possible that the preva- lence of dementia in the community was much higher.

Conclusions Taking more steps per day was associated with a lower risk of incident all-cause dementia. The optimal dose was estimated at 9800 steps per day, just under the popular target of 10 000 steps. Intensity of stepping resulted in stronger associations. Future guidelines for dementia prevention may capitalize on the re- sults of this study to promote step-based recommendations.

ARTICLE INFORMATION Accepted for Publication: June 17, 2022. Published Online: September 6, 2022. doi:10.1001/jamaneurol.2022.2672 Correction: This article was corrected on September 9, 2022, to add CC-BY Open Access status. Open Access: This is an open access article distributed under the terms of the CC-BY License. © 2022 del Pozo Cruz B et al. JAMA Neurology. Author Affiliations: Department of Sports Science and Clinical Biomechanics, Centre for Active and Healthy Ageing, University of Southern Denmark, Odense, Denmark (del Pozo Cruz); Charles Perkins Centre, Faculty of Medicine and Health, School of Health Sciences, The University of Sydney, Camper- down, New South Wales, Australia (Ahmadi); Charles Perkins Centre, Faculty of Science, The Uni- versity of Sydney, Camperdown, New South Wales, Australia (Naismith); Charles Perkins Centre, Faculty of Medicine and Health, School of Health Sciences, The University of Sydney, Camperdown, New South Wales, Australia (Stamatakis). Author Contributions: Dr del Pozo Cruz had full access to all of the data in the study and takes responsibility for the integrity of the data and the accuracy of the data analysis. Drs del Pozo Cruz and Ahmadi shared co–first authorship. Concept and design: del Pozo Cruz, Ahmadi, Stamatakis. Acquisition, analysis, or interpretation of data: All authors. Drafting of the manuscript: del Pozo Cruz, Ahmadi. Critical revision of the manuscript for important intellectual content: All authors. Statistical analysis: del Pozo Cruz, Ahmadi. Obtained funding: Stamatakis. Administrative, technical, or material support: Ahmadi, Naismith, Stamatakis. Supervision: del Pozo Cruz, Stamatakis. Conflict of Interest Disclosures: Dr Naismith reported honoraria from Roche Pharmaceuticals and Nutrica and grants from the National Health and Medical Research Council, Alzheimer’s International, the US Alzheimer’s Drug Discovery Foundation, and Medical Research Future Fund

outside the submitted work. No other disclosures were reported. Funding/Support: This work was partly supported by the University of Southern Denmark (to Dr del Pozo-Cruz) and by National Health and Medical Research Council Australia investigator grant APP1194510 (to Dr Stamatakis). Role of the Funder/Sponsor: The funders had no role in the design and conduct of the study; collection, management, analysis, and interpretation of the data; preparation, review, or approval of the manuscript; and decision to submit the manuscript for publication.

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