The Association of increased Body Mass Index on Cardiorespiratory Fitness, Physical Activity, and Cognition in adults with Down Syndrome

Abstract

Background:

Obesity is a significant risk factor for Alzheimer’s disease; however, this association has not been explored in adults with Down syndrome.

Objective:

To examine the association of obesity, assessed by body mass index (BMI), with factors related to Alzheimer’s disease risk including cardiorespiratory fitness, physical activity, and cognition in adults with Down syndrome.

Methods:

Adults with Down syndrome attended a laboratory visit where BMI, cardiorespiratory fitness (VO_{2 peak}), and cognitive function (CANTAB^® DS Battery) were obtained. Physical activity (accelerometer) was collected over the week following the laboratory visit. Wilcoxon rank sum tests were used to evaluate differences in cardiorespiratory fitness, sedentary time, moderate-to-vigorous physical activity (MVPA), and cognition between adults with obesity (BMI≥ 30 kg/m²) and those with healthy weight or overweight (BMI <30 kg/m²). Spearman correlations and linear regressions were used to measure the impact of BMI on cardiorespiratory fitness, MVPA, sedentary time, and cognition.

Results:

Data was collected for 79 adults with Down syndrome (26.7 ± 9.0 years of age, 54% female, 54% with obesity). VO_{2 peak} was significantly lower in participants with obesity (18.4 ± 2.5 ml/kg/min) compared to those with healthy weight or overweight (22.9 ± 4.0 ml/kg/min, p < 0.001). BMI was negatively associated with cardiorespiratory fitness (rho = −0.614, p<0.001). No associations were observed between BMI and physical activity or cognition.

Conclusions:

Lower BMI was associated with improved cardiorespiratory fitness. However, no associations were observed between BMI and cognition or physical activity.

INTRODUCTION

Down syndrome (DS), a genetic condition caused by an extra chromosome 21, is the most common chromosomal abnormality associated with an intellectual disability ¹, with an estimated incidence of 1 per 650 live births and prevalence of ~251,000 individuals ². Most adults with DS will develop pathology associated with Alzheimer’s disease beginning at ~30 years of age ^{3, 4}. By age 65 the cumulative incidence of Alzheimer’s disease in adults with DS exceeds 90% ⁴ and is the leading cause of death in individuals with DS ⁵. High rates of Alzheimer’s disease in DS are hypothesized to be associated with the overproduction of amyloid-beta from the additional copy of the amyloid precursor protein found on chromosome 21 which accelerates neurodegeneration, oxidative stress, plaque deposition, and early development of Alzheimer’s disease-like pathology in individuals with DS ^{3, 6}.

Evidence from both epidemiological and clinical observations in typically developed adults suggest that obesity is a significant risk factor for later-life dementia, including Alzheimer’s disease, independent of comorbidities such as hypertension and diabetes ^{7, 8}. A 2022 report lists mid-life obesity as the top modifiable risk factor associated with Alzheimer’s disease in adults without DS⁹. Obesity is thought to contribute to Alzheimer’s disease and cognitive impairment via a range of mechanisms including impaired cerebral metabolism ¹⁰, elevated leptin ^{11, 12}, inflammation and oxidative stress ¹³, and neuronal degradation ¹³. Additionally, in typically developed adults obesity is associated with decreased moderate-to-vigorous physical activity (MVPA) and lower cardiorespiratory fitness, factors also associated with the development of Alzheimer’s disease ⁹.

Previous research in typically developed adults suggests that obesity may be associated with impaired cognition, low MVPA, and decreased cardiorespiratory fitness, all factors associated with the development of Alzheimer’s disease. Given the high prevalence of obesity in adults with DS (~54%) ¹⁴, research examining the impact of obesity on factors associated with Alzheimer’s disease in adults with DS including cognition, MVPA and cardiorespiratory fitness is warranted. The current report utilized baseline data from a physical activity trial in adults with DS to examine the differences in cardiorespiratory fitness, MVPA and cognition between participants with obesity and those with healthy weight or overweight.

METHODS

Participants

This is a cross-sectional analysis using baseline data from a physical activity trial in adults with DS (NCT04048759)¹⁵, conducted in the Kansas City metropolitan area (United States). This study was approved by the University’s Institutional Review Board. Informed consent and assent were obtained from participants and their parent/legal guardians prior to data collection.

Participants were adults with DS (age ≥ 18 years) who were living at home with a parent or guardian, or in a supported living environment with a caregiver who agreed to serve as a study partner. Additional inclusion criteria were sufficient functional ability to understand directions, ability to communicate through spoken language, ability to participate in physical activity and walk 10 feet unassisted, and access to the internet in the home. Potential participants were excluded if they had dementia as determined by the Dementia Screening Questionnaire for Individuals with Intellectual Disabilities (DSQIID) ¹⁶, participated in a regular exercise program, i.e., ≥ 20 min/d ≥ 3 d/wk., had a serious medical risk, such as cancer or a recent cardiac event, or were unable to participate in MVPA. Participants were recruited using flyers, list-serves, and social media posts by local community organizations that provide services to adults with DS. Caregivers of potential participants were asked to contact the study coordinator who answered questions about the study and administered the initial participant eligibility screener which included the DSQIID. A home visit or video conference meeting was scheduled with those remaining interested and potentially eligible to determine final eligibility, and to obtain consent. All participants were also required to get physician approval to participate.

Outcomes

BMI, cardiorespiratory fitness, and cognition were assessed in our laboratory by trained staff familiar with working with individuals with DS. Physical activity was collected over a 7 day period at the participants home. All data were collected between January 2020 and November 2022.

Body Mass Index.

Weight was measured in light clothing on a calibrated scale (Model #PS6600, Belfour, Saukville, WI) to the nearest 0.1 kg. Standing height was measured with a portable stadiometer (Model #IP0955, Invicta Plastics Limited, Leicester, UK). BMI was calculated as weight (kg)/height (m²).

Cardiorespiratory Fitness.

Cardiorespiratory fitness (VO₂ mL/kg^/min) was assessed using a maximal treadmill test, following the protocol described by Fernhall et al. ¹⁷. The protocol started with a 2-minute warm-up at 0% grade at a comfortable walking speed. Following the warm-up, the speed was adjusted to an individualized brisk walking speed (~2.4mph). After 2 minutes of walking at a brisk speed at 0% grade, the grade increased by 2.5% every 2 minutes until reaching a grade of 12.5% grade when the treadmill speed was increased by 1 mph (1.6 km/hr) each minute until exhaustion. Heart rate (Polar RS 400, Kempele, Finland) and expired O₂ and CO₂ (ParvoMedics TrueOne 2300, Salt Lake City, Utah), calibrated prior to each test, were measured continuously across the treadmill protocol and averaged in 20 second intervals. The exercise test was terminated if participants were unable to maintain the treadmill speed or requested that the test be stopped at any time during the treadmill protocol, and this data was not included in the analysis. Otherwise, tests were terminated when participants achieved two or more of the following criteria: 1) volitional exhaustion, 2) a plateau in VO₂, i.e., < 150 mL/min or heart rate (HR) < 2 beats/min with increased work rate 3) HR_peak within 5 beats/min of HR_peak predicted using the formula of Fernhall et al. ¹⁷, and 4) a respiratory exchange ratio ≥ 1.0. Only participants who achieved a respiratory exchange ratio ≥ 1.0 or had a HR within 10 beats/min of their HR_peak were included in the analysis.

Physical Activity.

MVPA and sedentary time were assessed using an ActiGraph wGT3XBT tri-axial accelerometer (ActiGraph LLC, Pensacola, FL), an elastic belt worn over the non-dominant hip at the anterior axillary line during waking hours for 7 consecutive days, with the exception of bathing, swimming, and contact sports. Vertical axis data aggregated over 60 second epochs from ActiGraphs initialized and downloaded using ActiLife Software version 6.13.3 (ActiGraph LLC, Pensacola, FL) were collected at 60 HZ and processed using a custom R program developed by our group. Non-wear time was defined as at least 90 consecutive minutes of zero counts, with allowance for 1-2 minutes of counts between zero and 100 ¹⁸. Counts ≥ 20,000·min⁻¹ were considered spurious ¹⁹. A wear time of ≥ 8 hours on at least 3 days which included at least 1 weekend day was required for inclusion in the analysis. Vertical axis ActiGraph cut points used for adults in the 2003-2004 and 2005-2006 cycles of NHANES were used to classify minutes of sedentary (< 1.0 MET; ≤ 100 counts/min) and MVPA (≥ 3 METs; ≥ 2020 counts/min) ^{20, 21}.

Cognitive Function.

Cognitive outcomes were assessed using the Cambridge Neuropsychological Test Automated Battery for DS (CANTAB^®, Cambridge Cognition, LTD, Cambridge, UK) ^{22, 23} administered on an iPad^® in a quiet room following manufacturer’s instructions. The CANTAB^® DS Battery, which has been used in previous trials in individuals with DS ^{24, 25}, includes measures of executive function (multitasking task), episodic memory (paired associates learning), and processing speed (reaction time). CANTAB^® DS Battery measures have demonstrated sensitivity to disease-specific cognitive deficits in DS, including those related to hippocampal dysfunction, and sensitivity to changes in cognitive function associated with AD ²⁶.

Multitasking.

Multitasking task, a measurement of executive function, assessed the ability of participants to ignore task-irrelevant information. An arrow was presented on either side of the screen pointing in either direction (right or left). Participants had to pay attention to either the side of the screen where the arrow appears or the direction of the arrow (indicated by SIDE or DIRECTION on the screen), by pressing a button on the left or right corner on the screen, respectively. Four key outcomes were collected from the multitasking task: Incongruency cost, which is the difference (in milliseconds) between the median latency of response (from stimulus appearance to button press) on the trials that were congruent versus the trials that were incongruent; Reaction latency, which is the median latency of response (from stimulus appearance to button press); Multitasking cost, which is the difference (seconds) between the median latency of response (from stimulus appearance to button press) during assessed blocks in which both rules are used versus assessed blocks in which only a single rule is used; and total incorrect, which is the number of trials for which the outcome was an incorrect response.

Paired associates learning.

The paired associates learning task assessed visual episodic memory. Participants were presented with boxes on the screen in which different visual patterns are shown one by one. After the encoding phase, the different patterns were shown in the middle of the screen and participants had to select the box in which the pattern was previously presented. Two key outcome measures were collected from this task: the first attempt memory score, which assessed the number of times a participant was able to correctly recall a pattern previously displayed on the computer screen on their first attempt with higher scores indicating better memory; and the total errors, which is the number of times the subject chose the incorrect box for a stimulus on assessment problems plus an adjustment for the estimated number of errors they would have made on any problems, attempts, and recalls they did not reach.

Reaction time.

The reaction time task, a measure of attention and psychomotor speed, assessed reaction times for motor and mental responses. During the task, circles (one for the simple task and five for the five-choice mode) were shown at the top of the screen in which a random yellow light appears. Participants had to hold a button on the bottom of the screen and release it to select the circle above in which they detected the yellow light as fast as possible and then return their finger to the hold button. Four key outcome measures were collected from this task: simple and five-choice reaction time, which is the medium duration required for participants to release the response button following presentation of the target stimulus (milliseconds) calculated across trials when the stimulus could appear in only one location or in any one of five locations, respectively; and simple and five-choice movement time, which is the median time (milliseconds) taken for a subject to release the response button and select the target stimulus after it flashed yellow on screen, calculated across trials when the stimulus could appear in only one location or in any one of five locations.

Statistical Analysis.

Mean ± standard deviation and frequency (percentage) were used to describe continuous and dichotomous variables in the sample, respectively. We created 2 independent groups from the baseline data by separating the adults with DS into healthy weight or overweight (BMI < 30 kg/m²) and obese (BMI ≥ 30 kg/m²) categories. After the data were checked for normality using histograms, Q-Q plots, and Shapiro-Wilk tests, we used Wilcoxon rank sum tests to assess the differences in cardiorespiratory fitness, physical activity, and cognition for those who had a BMI <30 kg/m² compared to adults with DS who had a BMI ≥ 30 kg/m². P-values from the Wilcoxon rank sum tests were adjusted for multiple comparisons using the Holm method²⁷ to lower the chance of type I error. Spearman correlations were used to estimate the association between BMI and cardiorespiratory fitness, physical activity, and cognition. Given a significant Spearman correlation, we used an age-and sex-adjusted linear regression to quantify the impact of BMI on the cardiorespiratory fitness, physical activity, or cognition outcome of interest. Statistical significance was set at p < 0.05 and all analyses were performed using R version 4.2.2.

RESULTS

Participants.

Baseline data was collected from 82 adults with DS, however, only 79 had BMI data and were included in this analysis. Participants were 26.7 ± 9.0 years of age, 54% female and 76% non-Hispanic white with an average BMI of 32.5 ± 7.0 kg/m². Forty-three participants were classified as having obesity (BMI ≥ 30 kg/m²) and 36 as having a healthy weight or being overweight (BMI < 30 kg/m²). Demographic characteristics of the adults with DS are presented in Table 1.

Table 1.

Demographic Characteristics of Adults with Down Syndrome

	Overall N = 79	Obese N = 43	Healthy Weight or Overweight N = 36
Age	26.7 ± 9.0	28.6 ± 9.4	24.5 ± 8.1
Gender: Female	43 (54%)	27 (63%)	16 (44%)
Non-Hispanic White	60 (76%)	31 (72%)	29 (81%)
Height (cm)	151.1 ± 8.8	149.8 ± 8.5	152.6 ± 9.0
Weight (kg)	74.3 ± 17.7	84.7 ± 16.7	61.9 ± 8.6
Body Mass Index (kg/m2)	32.5 ± 7.0	37.5 ± 5.5	26.5 ± 2.4

Mean ± SD or n (%)

Wilcoxon rank sum tests and Spearman correlations for cardiorespiratory fitness, physical activity, and cognition are presented in Table 2.

Table 2.

Differences in cardiorespiratory fitness, physical activity, and cognition by Body Mass Index (BMI) Status in adults with Down syndrome

			Wilcoxon Rank Sum Test		Spearman Correlations
	Obese N = 43	Healthy Weight or Overweight N = 36	P-Value	Adjusted P-Value 2	Rho	P-Value
Cardiorespiratory Fitness
VO2 Max (ml/kg/min)	18.4 ± 2.5	22.9 ± 4.0	<0.001	< 0.001	−0.614	< 0.001
Multitasking Cost
Incongruency cost	37.4 ± 111.3	−16.7 ± 194.5	0.348	0.695	0.025	0.827
Reaction latency	901.2 ± 200.0	834.7 ± 190.4	0.224	0.672	0.119	0.297
Multitasking cost	−72.0 ± 161.4	7.6 ± 184.6	0.115	0.459	−0.144	0.210
Total Incorrect	49.2 ± 18.1	47.3 ± 21.0	0.677	0.695	0.086	0.456
Paired Associates
First Attempt Memory	5.3 ± 4.1	4.7 ± 4.2	0.473	0.946	0.052	0.647
Total Errors	41.6 ± 19.9	43.0 ± 21.7	0.749	0.946	0.022	0.849
Reaction Time
Five-choice movement	473.8 ± 253.0	430.5 ± 141.0	0.914	> 0.999	0.062	0.590
Five-choice reaction	581.0 ± 416.7	468.8 ± 138.1	0.493	> 0.999	0.198	0.085
Simple movement	493.1 ± 307.9	443.1 ± 194.0	0.920	> 0.999	0.092	0.422
Simple reaction	591.8 ± 466.5	475.7 ± 209.4	0.960	> 0.999	0.082	0.477
Physical Activity 3
Sedentary time	495.8 ± 143.0	474.2 ± 113.6	0.808	> 0.999	−0.028	0.826
Light Activity	268.8 ± 75.0	276.3 ± 92.6	0.901	> 0.999	0.054	0.668
MVPA	12.0 ± 11.7	20.6 ± 28.8	0.230	0.919	−0.237	0.057

¹Mean ± standard deviation

²Holm correction for multiple testing

³Sedentary time, light activity, and MVPA (moderate-to-vigorous physical activity) measured in minutes per valid day.

Cardiorespiratory Fitness.

Forty-seven participants completed the maximal treadmill test and had a respiratory exchange ratio ≥ 1.0 or had a HR within 10 beats/min of their HR_peak. VO_{2 peak} was significantly lower in participants with obesity compared to those with healthy weight or overweight (18.4 ± 2.5 ml/kg/min vs. 22.9 ± 4.0 ml/kg/min, p < 0.001). BMI and cardiorespiratory fitness were negatively correlated (rho: −0.614, p < 0.001), and we found a significant negative association between BMI and cardiorespiratory fitness using the age- and sex-adjusted linear regressions (β = −0.34, p < 0.001). This association suggests a decrease in VO₂ by 0.34 ml/kg/min for a 1 kg/m² increase in BMI. Figure 1 shows the association between cardiorespiratory fitness and BMI by obesity status for adults with DS participating in this study.

Figure 1.

The association between body mass index (BMI) and cardiorespiratory fitness

Physical activity.

Sixty-five participants had valid accelerometer data. Participants with obesity accumulated ~12 mins/day of MVPA while participants with healthy weight or overweight obtained ~21 mins/day, however, this difference was not statistically significant (p=0.23) and there was some variability between subjects (Figure 2). Additionally, no association was observed between BMI and MVPA (rho: −0.237, p=0.06). No significant differences in light activity or sedentary time were observed between participants with obesity compared to those with healthy weight or overweight (all p>0.05). There were also no significant associations between BMI and light activity or sedentary time (all p>0.05).

Figure 2.

Individual minutes of MVPA (mins/day) for adults with Down syndrome by BMI status

Cognition.

Seventy-eight participants completed the multitasking task, 79 completed the paired associates learning task, and 77 completed the reaction time task. No significant differences in cognition were observed between participants with obesity compared to those with healthy weight or overweight (all p>0.05). There were also no significant correlations between BMI and any of the cognitive outcomes (all p>0.05).

DISCUSSION

Previous research in typically developed adults suggests that obesity may be associated with impaired cognition, lower daily MVPA, and decreased cardiorespiratory fitness; all of which are factors associated with the development of Alzheimer’s disease. The results of this study observed an association between obesity and cardiorespiratory fitness. However, no associations were observed between physical activity or cognition.

Research in typically developed adults has demonstrated that obesity is associated with decreased cardiorespiratory fitness ²⁸. However, the limited findings examining obesity and cardiorespiratory fitness in adults with DS are mixed. A study conducted by Wee et al ²⁹ in 151 adults with DS reported that those with obesity had lower VO_{2 peak} (24.3 ± 6.9 ml/kg/min, p = 0.001) compared to those with normal weight (26.7 ± 7.1 ml/kg/min) or overweight (27.0 ± 6.1 ml/kg/min). Additionally, Nordstrom et al ³⁰ observed a negative association between BMI and physical capacity assessed by a 6-minute walk test in 87 adults with ID (40 with DS). Conversely, Beck et al ³¹ reported that obesity, assessed by both BMI and body composition (DXA), was not associated with cardiorespiratory fitness in 10 adults with DS. The results of the current analysis observed that cardiorespiratory fitness was significantly lower in participants classified as obese compared to those classified as non-obese, and BMI was negatively associated with cardiorespiratory fitness even when controlling for age and sex, providing additional evidence that obesity is associated with decreased cardiorespiratory fitness in adults with DS.

The results of the current analysis observed that MVPA was 9 mins/day lower in participants with obesity compared to those with healthy weight or overweight; while this difference was not statistically significant, it is may be clinically meaningful. Eight participants with healthy weight or overweight obtained the Physical Activity Guidelines for Americans ³² recommended 150 mins/wk. of MVPA, while only 2 participants with obesity only obtained the recommended level. Notably, the limited previous research in adults with DS, has observed that obesity is significantly associated with decreased MVPA. For example, Nordstrom et al ³⁰ observed that individuals with obesity obtained ~22 mins/day of MVPA, assessed by accelerometry, while those with overweight obtained ~33 mins/day and those with normal weight obtained ~29 mins/day. Thus, additional adequality powered analysis are needed to examine the association between obesity and MVPA in adults with DS.

The results of the current study found no association between BMI and any of the cognitive variables in adults with DS. We are only aware of one other study which examined BMI and cognitive function in adults with DS. Fleming et al ³³ observed a relationship between BMI and Free and Cued Recall, which assess memory, in 66 non-demented adults with DS; however, there was no association between BMI and the other 8 cognitive outcomes which measured executive function, visuospatial ability, and motor planning and control. In typically developed adults, research has produced substantial evidence of a correlation between high BMI and lower cognitive function in typically developed adults ^{34, 35}. For example, in a study of 213 young adults without DS, Huang et al ³⁴ observed that BMI (p = 0.02) and body fat percentage (p = 0.02) were significantly correlated with larger global switch costs of accuracy in women, and body fat percentage was significantly correlated with larger local switch costs of reaction time in men (p = 0.01). A systematic literature review ⁷ examining the relationship between obesity and cognitive function in typically developed adults concluded that obesity certainly has a significant relationship with cognitive function, although, due to methodology limitations, they were unable to confirm an independent relationship between obesity and cognitive function. Given the limited number of studies examining the association between BMI and cognition in adults with DS, the conflicted findings, and the of evidence that suggest BMI is associated with cognition in adults without DS, future research is needed to better understand the association between BMI and cognition in adults with DS.

This study benefits from the use of device-based assessments of MVPA and sedentary time, and use of directly measured cardiorespiratory fitness (i.e., VO_{2 peak}), as well as a diverse (e.g., 54% females, 54% with obesity) sample of adults with DS. However, it is limited as the data is cross-sectional and all participants were from a sample of adults with DS who had agreed to participate in a program focused on the promotion of physical activity. This participant population was sedentary at baseline as part of the criteria for inclusion in the clinical trial. Therefore, there was a smaller range of MVPA and cardiorespiratory fitness in this population compared with the general population of individuals with DS. Similarly, all participants were cognitively stable, thus, we were unable to examine cognitive function of adults with DS who had already progressed to Alzheimer’s disease. Thus, the specific population used in this study may limit its external validity. Additionally, while BMI is currently used as the standard for weight status, it is widely known that body fat percentage may be a more accurate standard than BMI. For example, Pitchford et al ³⁶ found correlations between MVPA and body fat percentage rather than BMI in adolescents with DS ³⁶. Further research should include body composition as well as BMI in order to determine more accurate weight statuses of the participants.

CONCLUSIONS

In summary, the results of this analysis observed that in adults with DS increased BMI was associated with decreased cardiorespiratory fitness. We did not observe any significant relationships between BMI and cognition or BMI and physical activity. Given the increased risk of Alzheimer’s disease in adults with DS, longitudinal trials examining the impact of obesity on risk factors related to Alzheimer’s disease are warranted .