Introduction
According to the 2015 World Alzheimer Report, over 46 million people worldwide have dementia, with an anticipated increase to 152 million individuals by 2050 (Patterson,
2018). Mild cognitive impairment (MCI) is considered the intermediate stage between normal cognitive aging and dementia. MCI constitutes a high risk state for progression to dementia, and its prevalence is estimated to range between 12% and 18% in persons aged ≥ 60 years (Petersen,
2016). Research has increasingly focused on modifiable lifestyle factors such as physical activity that may be effective in preventing or delaying the onset of cognitive impairment in the context of brain aging (Lautenschlager, Cox, & Ellis,
2019), and especially early disease stages such as subjective cognitive impairment or MCI are regarded as a “window of opportunity” for a potentially protective effect of physical activity on cognitive decline.
In line with this, the authors and others have reported that engaging in physical activity is associated with a decreased risk of developing new onset of MCI (Laurin, Verreault, Lindsay, MacPherson, & Rockwood,
2001; Yoneda et al.,
2020; Krell-Roesch et al.,
2016) and dementia (Podewils et al.,
2005; Tan et al.,
2017; Krell-Roesch et al.,
2018), with a recent meta-analysis indicating a dose–response relationship between a higher degree of physical activity and lower risk of incident dementia (Xu et al.,
2017). In turn, lack of engagement in physical activity and sedentary behavior is associated with higher odds of having MCI (Vancampfort et al.,
2018), and is also regarded as a risk factor for cognitive decline in old age (Falck, Davis, & Liu-Ambrose,
2017); albeit, conflicting (Maasakkers et al.,
2020) or only sex-specific findings (Whitaker et al.,
2021) have been reported. Nevertheless, a recently published report by the Lancet commission lists physical inactivity as one of 12 modifiable risk factors for dementia (Livingston et al.,
2020). In addition, neuropsychiatric symptoms such as depression, apathy, or anxiety are very common in older adults with or without cognitive impairment (Geda et al.,
2008; Lyketsos et al.,
2002). Furthermore, these are also well-established risk factors of incident MCI or dementia (Forrester, Gallo, Smith, & Leoutsakos,
2016; Geda et al.,
2014; Pink et al.,
2015; Teng, Lu, & Cummings,
2007).
Little is known about the longitudinal association and interaction between physical activity and neuropsychiatric symptoms in predicting the risk of incident MCI in older community-dwelling adults. The aim of this study was thus to examine the association between lack of engaging in late-life physical activity and presence of neuropsychiatric symptoms, both separately and combined, with the outcome of incident MCI. The authors hypothesized that participants who do not report engaging in physical activity and have neuropsychiatric symptoms would be at higher risk of developing incident MCI than participants who report engaging in physical activity and do not have neuropsychiatric symptoms.
Results
A total of 3083 participants with a mean (standard deviation) age of 72.41 (9.72) years were included in this study; 50.9% of the sample were males and 27.8% were APOE ε4 carriers. After a median follow-up of 6.3 years, 599 participants developed incident MCI. In all, 14.2% of participants reported not engaging in light intensity physical activity, 42.0% reported not engaging in moderate intensity physical activity, and 85.6% reported not engaging in vigorous intensity physical activity within 1 year prior to baseline assessment. The most frequent neuropsychiatric symptoms present in the total sample were depression (9.2%), irritability (6.8%), sleep/nighttime disturbance behavior (5.8%), anxiety (4.8%), and apathy (3.8%). Clinical depression (BDI-II total score ≥ 13) was present in 5.4% and clinical anxiety (BAI total score ≥ 10) was present in 6.0% of participants (Table
1).
Table 1
Participant demographics at baseline
Age |
Mean (SD) | 70.85 (9.83) | 78.85 (6.84) | 72.41 (9.72) |
Median (IQR) | 72.21 (63.74, 77.62) | 79.75 (74.47, 83.76) | 73.62 (65.37, 79.75) |
Male sex, N (%) | 1279 (51.5) | 291 (48.6) | 1570 (50.9) |
Education, years |
Mean (SD) | 14.83 (2.58) | 13.79 (2.71) | 14.63 (2.64) |
Median (IQR) | 15.00 (12.00, 16.00) | 13.00 (12.00, 16.00) | 14.00 (12.00, 16.00) |
APOE ε4 carrier, N (%) | 647 (26.0) | 209 (34.9) | 856 (27.8) |
Charlson Index |
Mean (SD) | 2.62 (2.78) | 3.74 (3.10) | 2.84 (2.88) |
Median (IQR) | 2.00 (1.00, 4.00) | 3.00 (2.00, 5.00) | 2.00 (1.00, 4.00) |
Global cognition z‑score |
Mean (SD) | 0.22 (0.89) | −0.90 (0.93) | 0.00 (1.00) |
Median (IQR) | 0.26 (−0.40, 0.86) | −0.89 (−1.45, −0.31) | 0.05 (−0.66, 0.70) |
Light intensity PA, N (%) |
Not engaging | 328 (13.2) | 111 (18.5) | 439 (14.2) |
Engaging | 2156 (86.8) | 488 (81.5) | 2644 (85.8) |
Moderate intensity PA, N (%) |
Not engaging | 1002 (40.3) | 292 (48.7) | 1294 (42.0) |
Engaging | 1482 (59.7) | 307 (51.3) | 1789 (58.0) |
Vigorous intensity PA, N (%) |
Not engaging | 2098 (84.5) | 542 (90.5) | 2640 (85.6) |
Engaging | 386 (15.5) | 57 (9.5) | 443 (14.4) |
Agitation, N (%) | 52 (2.1) | 14 (2.3) | 66 (2.1) |
Anxiety, N (%) | 117 (4.7) | 30 (5.0) | 147 (4.8) |
Apathy, N (%) | 71 (2.9) | 46 (7.7) | 117 (3.8) |
Appetite change, N (%) | 80 (3.2) | 27 (4.5){1} | 107 (3.5){1} |
Nighttime behavior, N (%) | 105 (4.7){266} | 54 (10.8){98} | 159 (5.8){364} |
Delusions, N (%) | 2 (0.1) | 3 (0.5) | 5 (0.2) |
Depression, N (%) | 204 (8.2){1} | 81 (13.5) | 285 (9.2){1} |
Disinhibition, N (%) | 15 (0.6) | 10 (1.7) | 25 (0.8) |
Euphoria, N (%) | 11 (0.4) | 3 (0.5) | 14 (0.5) |
Hallucinations, N (%) | 0 (0.0) | 1 (0.2) | 1 (0.0) |
Irritability, N (%) | 162 (6.5) | 48 (8.0) | 210 (6.8) |
Motor behavior, N (%) | 14 (0.6) | 3 (0.5) | 17 (0.6) |
BDI-II score ≥ 13 | 117 (4.7){12} | 49 (8.2){2} | 166 (5.4){14} |
BAI score ≥ 10 | 131 (5.3){5} | 52 (8.7){3} | 183 (6.0){8} |
Individuals who did not engage in moderate intensity physical activity (HR [95% CI]; 1.18 [1.00, 1.39],
p = 0.047) had a statistically significantly increased risk of incident MCI. Having anxiety (1.52 [1.05, 2.20],
p = 0.028), apathy (1.92 [1.41, 2.60],
p < 0.001), and depression (1.71 [1.35, 2.16],
p < 0.001), as well as clinical depression (1.47 [1.09, 1.97],
p = 0.012), were also associated with an increased risk of incident MCI (Table
2).
Table 2
Associations between lack of physical activity and incident mild cognitive impairment (MCI), as well as between neuropsychiatric symptoms and incident MCI
Lack of physical activity |
No light PA | 1.22 (0.98, 1.50) | 0.070 |
No moderate PA | 1.18 (1.00, 1.39) | 0.047 |
No vigorous PA | 1.27 (0.96, 1.67) | 0.095 |
Neuropsychiatric symptoms |
Agitation | 1.24 (0.73, 2.12) | 0.428 |
Anxiety | 1.52 (1.05, 2.20) | 0.028 |
Apathy | 1.92 (1.41, 2.60) | < 0.001 |
Appetite change | 1.21 (0.82, 1.79) | 0.335 |
Nighttime behavior | 1.29 (0.96, 1.71) | 0.088 |
Depression | 1.71 (1.35, 2.16) | < 0.001 |
Irritability | 1.20 (0.89, 1.62) | 0.226 |
BDI-II score ≥ 13 | 1.47 (1.09, 1.97) | 0.012 |
BAI score ≥ 10 | 1.26 (0.94, 1.68) | 0.118 |
There were no significant additive interactions between light intensity physical activity and neuropsychiatric symptoms or between moderate intensity physical activity and neuropsychiatric symptoms in predicting the risk of incident MCI. There were statistically significant additive interactions between vigorous intensity physical activity and sleep/nighttime disturbance behavior, clinical depression, and clinical anxiety in predicting the risk of incident MCI, i.e., participants who did not engage in vigorous intensity physical activity in the presence of sleep/nighttime disturbance behavior (1.61 [1.07, 2.43],
p = 0.021), clinical depression (1.98 [1.34, 2.92],
p < 0.001), or clinical anxiety (1.63 [1.11, 2.41],
p = 0.013) had an increased risk of incident MCI as compared to the reference group (Table
3).
Table 3
Associations between the combination of neuropsychiatric symptoms and vigorous intensity physical activity and the outcome of incident mild cognitive impairment
Night. behavior−/PA+ | 388 | 46 | Reference | N/A | 0.011 |
Night. behavior+/PA+ | 22 | 4 | 0.46 (0.16, 1.28) | 0.136 | N/A |
Night. behavior−/PA− | 2172 | 401 | 1.07 (0.78, 1.46) | 0.670 | N/A |
Night. behavior+/PA− | 137 | 50 | 1.61 (1.07, 2.43) | 0.021 | N/A |
BDI-II−/PA+ | 423 | 57 | Reference | N/A | < 0.001 |
BDI-II+/PA+ | 19 | 0 | N/A | N/A | N/A |
BDI-II−/PA− | 2480 | 491 | 1.09 (0.82, 1.44) | 0.551 | N/A |
BDI-II+/PA− | 147 | 49 | 1.98 (1.34, 2.92) | < 0.001 | N/A |
BAI−/PA+ | 429 | 56 | Reference | N/A | 0.001 |
BAI+/PA+ | 13 | 1 | 0.19 (0.03, 1.41) | 0.105 | N/A |
BAI−/PA− | 2463 | 488 | 1.15 (0.87, 1.52) | 0.338 | N/A |
BAI+/PA− | 170 | 51 | 1.63 (1.11, 2.41) | 0.013 | N/A |
Discussion
Here the authors report a synergistic additive interaction between lack of engaging in vigorous intensity physical activity and sleep/nighttime disturbance behavior, clinical depression, or clinical anxiety in increasing the risk of incident MCI in community-dwelling persons aged 50 years and older. Thus, the combined presence of lack of vigorous intensity physical activity with sleep/nighttime disturbance behavior, clinical depression, or clinical anxiety was greater than the expected arithmetic sum of their independent effects. However, statistically significant additive interactions between light or moderate intensity physical activity and neuropsychiatric symptoms in predicting the risk of incident MCI were not observed. In general, neuropsychiatric symptoms appear to be a stronger driving force of incident MCI than lack of physical activity.
To date, little is known about the longitudinal association and potential interactions between physical activity and neuropsychiatric symptoms in predicting the risk of incident MCI. Few studies have been published that examined interactions between physical inactivity or sedentary behavior and other lifestyle factors with cognitive decline. For example, US investigators reported that low sedentary behavior and high cardiorespiratory fitness interacted in preserving cognitive function in persons aged ≥ 60 years (Edwards & Loprinzi,
2017). Researchers from the Rush Memory and Aging Project observed that accelerometer-measured physical activity and self-reported cognitive activity had significant interactive effects on memory in older cognitively unimpaired adults (Halloway, Schoeny, Wilbur, & Barn,
2020). With regard to neuropsychiatric symptoms, a cross-sectional study from South Korea found that depression mediates the inverse relationship between physical activity and cognitive impairment among older adults (Jin et al.,
2018); and another study from China reported that a higher amount of leisure-time physical activity was associated with less neuropsychiatric symptoms in community-dwelling adults with cognitive impairment (Chiu et al.,
2014). Similarly, US researchers reported that an intensive continuous activity programming in dementia patients was associated with decreased agitation and improved sleep (Volicer, Simard, Pupa, Medrek, & Riordan,
2006). One intervention study revealed a reduction in aggressive behavior in dementia patients after they underwent a walking program (Holmberg,
1997), and a randomized clinical trial showed that an intervention combining physical activity with nighttime environment improvement had a beneficial impact on sleep and agitation in nursing home residents (Alessi, Yoon, Schnelle, Al-Samarrai, & Cruise,
1999). In line with this, a recent review concluded that engagement in physical activity had a positive impact on neuropsychiatric symptoms, particularly depression and sleep disturbance, in patients with Alzheimer’s disease (Veronese, Solmi, Basso, Smith, & Soysal,
2019), and researchers from Japan reported that a combination of poor sleep quality and physical inactivity was associated with significantly decreased cognitive performance in a large sample of over 5000 community-dwelling older adults (Nakakubo et al.,
2017). These studies are partly in line with the authors’ observation that lack of engaging in vigorous intensity physical activity and sleep/nighttime disturbance behavior or clinical depression are associated with higher risk of developing MCI. Of note, the present study considered participants who reported engaging in physical activity at a given intensity level (i.e., light, moderate and vigorous) 2–3 times per month or less as having a lack of physical activity. This must be distinguished from sedentary behavior, which includes, for example, sitting activities such as watching TV or working on a computer. Lack of engaging in physical activity, as assessed in this research, and sedentary behavior are thus different constructs. More research is needed to also examine the association between sedentary behavior, neuropsychiatric symptoms, and the risk of incident MCI.
The authors did not examine potential mechanisms that may explain the observed interaction between lack of vigorous intensity physical activity and sleep/nighttime disturbance behavior, clinical depression, or clinical anxiety in increasing the risk of incident MCI. Previous research has shown that engaging in physical activity may be associated with brain health through various mechanisms (Cabral et al.,
2019), including but not limited to increased release of neurotrophic brain factors such as brain-derived neurotrophic factor (Knaepen, Goekint, Heyman, & Meeusen,
2010), enhanced synaptogenesis and neurogenesis (Vecchio et al.,
2018), increased cerebral blood flow (Nishijima, Torres-Aleman, & Soya,
2016), decreased vascular risk factors (Barnes & Corkery,
2018), and a generally healthy lifestyle of physically active persons that may also show in abstaining from smoking and adhering to a healthy diet or other health-enhancing behaviors. In contrast, persons who do not engage in physical activity may not benefit from these effects. Furthermore, the presence of neuropsychiatric symptoms has been linked to cognitive impairment via different pathways, i.e.,: 1) an etiologic pathway indicating that neuropsychiatric symptoms lead to cognitive impairment by affecting the pathology of the brain; 2) a shared risk factor pathway indicating that neuropsychiatric symptoms are not directly associated with cognitive impairment but that there is another genetic or environmental factor (confounder) that causes both emergence of neuropsychiatric symptoms and cognitive impairment; 3) a reverse causality pathway indicating that neuropsychiatric symptoms may be a non-cognitive manifestation of, or psychological reaction to, cognitive impairment and its underlying effect on brain pathology; and 4) an interaction pathway indicating the existence of a synergistic interaction between neuropsychiatric symptoms and a biological factor that leads to cognitive impairment (Geda et al.,
2013). Of note, as this was an observational study, reverse causality is also a possible explanation of its findings. According to this, persons who are in the very early disease stages without symptoms of MCI may engage in physical activity, particularly of vigorous intensity, to a lesser extent and may be more likely to report neuropsychiatric symptoms than persons who are not in early disease stages. In addition, the authors’ conclusion that neuropsychiatric symptoms appear to be a stronger driving force of incident MCI than lack of physical activity could also be due to a potentially more robust assessment of neuropsychiatric symptoms than physical activity in this study. Another potential explanation might be that a large number of distinct neuropsychiatric symptoms was investigated, whereas only three rather broad physical activity parameters were utilized.
The strengths of this study include its large, population-based sample and a rigorous analysis with adjustment for traditional confounders as well as cognition, medical comorbidities, and APOE ε4 genotype status which is a genetic risk factor for Alzheimer’s disease. Limitations pertain to the observational study design. Thus, the authors are not able to make conclusions regarding cause and effect based on their findings. As mentioned above, their findings imply that a combination of lack of physical activity, particularly of vigorous intensity, and the presence of neuropsychiatric symptoms may lead to increased risk of MCI, or that persons who will eventually develop MCI are more likely to not engage in physical activity and report neuropsychiatric symptoms several years before MCI onset. Another main limitation pertains to the physical activity assessment, which was carried out using a self-reported questionnaire and may thus be prone to recall bias. The questionnaire items were derived from validated surveys that were used in other studies before and, as previously reported by the authors, their questionnaire has moderate to good internal consistency (Geda et al.,
2010). However, the questionnaire only assesses frequency of engaging in physical activity at three different intensities. It does not record volume or duration of physical activity (e.g., minutes per session), even though the volume of physical activity engagement is commonly used in recommendations on physical activity such as the World Health Organization (WHO) or American College of Sports Medicine (ACSM) guidelines and would be necessary to estimate energy expenditure. In addition, the intensity examples provided in the questionnaire might be misleading to some participants, e.g., one can swim with high intensity and play tennis singles with moderate intensity. This could have introduced a certain amount of bias, and the concepts of the different physical activity intensities may not have been clear to all participants.
In conclusion, the authors observed an additive interaction between lack of engaging in vigorous intensity physical activity and sleep/nighttime disturbance behavior, clinical depression, or clinical anxiety in further increasing the risk of incident MCI among cognitively unimpaired, community-dwelling adults aged 50 years and older. More research, preferably with longitudinal design, is needed to confirm these findings and to also examine potential mechanisms that may underlie this relationship.
Declarations
All procedures performed in studies involving human participants or on human tissue were in accordance with the ethical standards of the institutional and/or national research committee and with the 1975 Helsinki declaration and its later amendments or comparable ethical standards. Informed consent was obtained from all individual participants included in the study.