- Email: [email protected]
Building the evidence for an ecological model of cognitive health
Health and Place 60 (2019) 102206
Contents lists available at ScienceDirect
Health & Place journal homepage: www.elsevier.com/locate/healthplace
Commentary
Building the evidence for an ecological model of cognitive health Ester Cerin a b
T
a,b
Mary MacKillop Institute for Health Research, Australian Catholic University, Melbourne, Australia School of Public Health, The University of Hong Kong, Hong Kong, China
A R T I C LE I N FO
A B S T R A C T
Keywords: Built environment Natural environment Apolipoprotein E genotype Walkability Cognitive function
This is a commentary on Besser and colleagues’ article “Associations between neighbourhood built environment and cognition vary by apolipoprotein E genotype: Multi-Ethnic Study on Atherosclerosis” published in Health & Place. Unlike previous studies, the authors found significant environment-cognition associations in apolipoprotein E (APOE) ε2 carriers and no significant associations in ε4 carriers. This commentary discusses the possible reasons for these findings and, in doing so, proposes an ecological model of cognitive health. The model highlights the importance of accounting for multiple environmental influences including the built and natural environment and air and noise pollution indicators. It also stresses the importance of studying the underlying biological mechanisms explaining differences in environment-cognition associations across APOE genotype categories.
1. Commentary Neighbourhood environments are considered major contributors to mortality and morbidity by national and international health organisations (World Health Organization, 2009). A plethora of studies have reported significant associations of aspects of the neighbourhood environment with physical inactivity (Barnett et al., 2017; Cerin et al., 2017a), depression (Barnett et al., 2018), obesity, hypertension and diabetes (Chandrabose et al., 2019), which are established mid- or late life risk factors for dementia (Livingston et al., 2017). However, as highlighted by Besser and colleagues (Besser et al., 2019), the contribution of neighbourhood environments to dementias and, more broadly, brain and cognitive health has received little attention (Besser et al., 2017; Cerin et al., 2017b). This is unfortunate for multiple reasons. Firstly, with over 44 million cases worldwide in 2016 (GBD, 2016 Dementia Collaborators, 2019), dementia is a global health priority and one of the leading causes of disability and overall burden of disease for ageing populations in developed and developing countries (GBD, 2016 Dementia Collaborators, 2019; Prince et al., 2014). Second, mild cognitive impairment (MCI) that is not severe enough to meet a diagnosis of dementia also causes significant disability and increased medical costs (Zissimopoulos et al., 2014). Third, no effective pharmacological treatment for dementia and MCI is yet available and risk reduction and prevention remains the best strategy to lower their incidence, associated disability and cost. The Global Observatory for Ageing and Dementia Care (Prince et al., 2014) and the Global Burden of Disease Dementia Collaborators have
E-mail address: [email protected]. https://doi.org/10.1016/j.healthplace.2019.102206 Received 10 September 2019; Accepted 10 September 2019 1353-8292/ © 2019 Elsevier Ltd. All rights reserved.
recently stressed the need for evidence-based, multi-level, multi-sectoral (urban planning and design, transportation, residential aged care, food industry) strategies to yield significant, large-scale, sustainable delays in cognitive decline and reductions in incidence of dementia. However, empirical evidence to inform these strategies is lacking because most research in the field of cognitive health has focused on individual-level factors, such as lifestyle behaviours and biomarkers. Besser and colleagues' paper (Besser et al., 2019) makes an important contribution to addressing the dearth of evidence on neighbourhood environmental influences on cognitive health by specifically focusing on multiple aspects of the built environment and examining the moderating effects of a genetic risk factor for Alzheimer's disease. Because cognitive function and cognitive decline are bound to be determined by environmental as well as genetic factors (Prince et al., 2014), it makes sense to study them conjointly. Apolipoprotein E (APOE) genotype is the main genetic risk factor for dementia (Livingston et al., 2017) and a likely strong moderator of the effects of environmental factors and lifestyle behaviours on cognitive health (Cerin et al., 2017b; Prince et al., 2014). The study of gene-environment interactions on cognitive health is essential not only for a better understanding of the effects of the environment and their underlying pathways but also for the identification of vulnerable population segments and the development of effective individually-tailored lifestyle interventions that may offset harmful environmental influences. In fact, evidence suggests that APOE and a few other genotypes modify the effects of cognition-promoting lifestyle activities, such as engagement in physical activity (Brown et al., 2013) and high intake of dietary
Health and Place 60 (2019) 102206
E. Cerin
Fig. 1. A simplified ecological model of cognitive health.
being damaged and eventually dying (Prince et al., 2014). APOE ε4 carriers are primarily at increased risk of Alzheimer's disease rather than vascular dementia, while APOE ε2 carriers appear to have higher risk of obesity (Duman et al., 2004), type 2 diabetes (Anthopoulos et al., 2010) and peripheral vascular disease, including carotid atherosclerosis (de Andrade et al., 1995) and cerebrovascular disease (Couderc et al., 1993). APOE ε2 genotype is also associated to elevated postprandial triglyceride levels which, in turn, promote systemic inflammation and increase the risk of metabolic diseases (Rivellesse et al., 2009). Given that obesity and diabetes are major risk factors for dementia (Livingston et al., 2017) and activity-friendly neighbourhoods have been associated with better cardio-metabolic health (Chandrabose et al., 2019) by facilitating regular engagement in physical activity (Barnett et al., 2017; Cerin et al., 2017a), Besser and colleagues' findings on APOE ε2 carriers make logical sense. They also highlight the need for a more in-depth examination of the moderating role of APOE genotype on the effects of the environment and lifestyle behaviours on cognitive health that transcend the examination of differences between APOE ε4 carriers vs non-carriers. While the observed associations between environmental attributes and cognitive function in APOE ε2 carriers may be plausible, we are left to wonder why Besser and colleagues did not find an association in APOE ε4 carriers. As the authors noted, it is possible that the risk of cognitive decline in the latter may be too difficult to be overcome by activity-friendly environments (Besser et al., 2019). However, other factors may have also contributed to these findings. For example, only the more resilient APOE ε4 carriers with lower levels of cognitive decline and living in more activity-friendly environments might have remained in the analytical sample of the study. In fact, albeit only approaching statistical significance, when compared to those excluded from the sample, the analytical sample had ~5% fewer APOE ε4 carriers and tended to live in neighbourhoods with higher intersection density (Besser et al., 2019). A recent study found that intersection density was one of the strongest predictors of changes in amyloid β depositions in the brain of APOE ε4 carriers. Further, as the Besser and colleagues noted, an analysis of longitudinal data (i.e., cognitive decline) might have yielded different results. In this regard, it is noteworthy that Cerin and colleagues did not find significant differences in associations of activity-friendly environments with average brain volumetric measures between APOE ε4 carriers and non-carriers but found significant between-group differences in associations of the environment with changes in brain volumes (brain atrophy). Another limitation that may have yielded biased estimates of
omega-3 fatty acids (van de Rest et al., 2016), and those of environmental factors (Besser et al., 2019; Lee et al., 2011). Genetic factors may also determine how individuals interact with the environment and the biological pathways via which the environment affects cognition (Nithianantharajah and Hannan, 2006). To gather information of practical value, an interactionist approach is needed that establishes the extent to which environment-cognition relationships depend on genetic risk of dementia and whether this is due to individual differences in reactions to the environment, effects of behaviour on biological mechanisms, or biological pathways affecting cognitive function (Fig. 1). While previous studies examining APOE genotype by environmental exposure interactions on brain or cognitive health in later life found stronger associations in APOE ε4 carriers than non-carriers (Boardman et al., 2012; Lee et al., 2011; Cerin et al., 2017b), Besser and colleagues (Besser et al., 2019) observed significant positive confounder-adjusted associations between activity-friendly environmental attributes and cognitive function in APOE ε2 carriers only. In support of their findings, the authors cited another study that observed significant associations between activity-friendly environments (green spaces) and cognitive decline in APOE ε4 non-carriers only (Cherrie et al., 2019). However, with only 76 APOE ε4 carriers and 205 non-carriers, the latter study was underpowered to detect associations in carriers. Also, it is noteworthy that the same study found that early and mid-life, rather than late-life, exposure to green spaces were predictive of slower cognitive decline in later life, while Besser et al. examined late-life environmental exposures. Given that early, mid- and late-life risk factors of dementia substantially differ (Livingston et al., 2017), there also may be differences in the effects of various environmental exposures on cognitive health across life stages. Thus, evidence of an effect of an early-life environmental exposure on late-life cognitive function is not necessarily comparable to the evidence of an effect of a late-life exposure on cognitive function. Notwithstanding the above issues, the fact that Besser and colleagues found significant associations only in APOE ε2 carriers is interesting and worth further consideration. It is possible that the effects of environmental factors on cognitive function and decline in different APOE genotypes are underpinned by distinct biological mechanisms. Firstly, cognitive decline can be caused by different pathological processes. For example, vascular dementia results from reduced blood supply to the brain due to diseased blood vessels, while dementia caused by Alzheimer's disease is believed to develop due to problems with brain proteins that function abnormally, disrupt the work of neurons and trigger a cascade of toxic events that result in neurons 2
Health and Place 60 (2019) 102206
E. Cerin
References
associations of activity-friendly attributes of the neighbourhood built environment and cognitive function in Besser et al.‘s study (and earlier similar studies) pertains to the lack of adjustment for green spaces and pollution. As depicted in Fig. 1, high levels of density and access to a wide range of destinations and amenities is typically accompanied by higher levels of traffic-related air pollution and other environmental stressors and reductions in green spaces. If we assume that exposure to green spaces and pollution are, respectively, beneficial and detrimental to cognitive health, their omission from statistical models is likely to underestimate the positive associations of density and destination accessibility with cognitive health. Hence, it is suggested that future studies on cognitive health should strive to account for all these environmental aspects in multiple-exposure models. Other key issues that should be addressed in future studies of environmental determinants of cognitive health are the shape of the doseresponse relationships, the effect of environmental exposures on specific facets of cognitive function (e.g., visuospatial memory, attention and executive functions), the identification of lifestyle behaviours and biological processes mediating the effects of the environment and the assessment of personal activity spaces beyond residential neighbourhoods. Specifically, there is some evidence that the relationship of measures of access to destinations and green spaces with cognitive impairment may be U-shaped and that both lack and overload of environmental stimulation may be detrimental to cognitive health (Wu et al., 2017). Thus, it is important to establish the levels of specific environmental exposures that yield optimal health outcomes. Most studies on the effects of the environment on cognitive health have used single general measures of cognitive function (Besser et al., 2017). However, it is reasonable to assume that different types of environmental attributes may affect different aspects of cognitive function by promoting specific lifestyle behaviours or cognitive processes, as Besser et al.‘s study suggests. For example, exposure to urban environments with intricate street networks may lead to better visuospatial working memory. There is a general dearth of studies on the mediating effects of lifestyle behaviours - including physical activity, sedentary behaviour, sleep, socialising, mental activities, navigational activities and dietary behaviour – on the relationships between environmental attributes and cognitive health (Fig. 1). The same holds true for biological pathways linking the environment and cognitive health. Finally, although individuals spend a substantial part of their day in their residential neighbourhood, it is not the only place they are regularly exposed to. For example, a recent study on adults aged 18–94 years reported that over 60% of outdoor physical activity took place outside of the proximal home neighbourhood (defined as a 800m radius buffer around the home). Moreover, substantial inter-individual differences were observed in the distances from home where physical activity was undertaken (Hillsdon et al., 2015). To more accurately characterise individual exposure to environmental stimulation, pollution and other stressors, there is a need for studies on environmental determinants of cognitive health to capture the whole range of habitual activity spaces individuals are exposed to rather than focus solely on their home neighbourhood. In summary, despite its potential importance for cognitive health promotion, the field of environmental determinants of cognitive health is still in its infancy. Besser and colleagues’ study on the moderating effects of APOE genotype on the associations between aspects of the neighbourhood built environment and cognitive function moves the field forward by providing novel, valuable findings that open new venues for research. Undoubtedly, many important questions related to environmental influences on cognitive health remain unanswered. Decades of substantial international multidisciplinary investigative efforts will be required to gain a satisfactory understanding of these issues.
Anthopoulos, P.G., Hamodrakas, S.J., Bagos, P.G., 2010. Apolipoprotein E polymorphisms and type 2 diabetes: a meta-analysis of 30 studies including 5423 cases and 8197 controls. Mol. Genet. Metab. 100 (3), 283–291. https://doi.org/10.1016/j.ymgme.2010.03.008. Barnett, A., Zhang, C.J.P., Johnston, J.M., Cerin, E., 2018. Relationships between the neighborhood environment and depression in older adults: a systematic review and meta-analysis. Int. Psychogeriatr. 30 (8), 1153–1176. https://doi.org/10.1017/ S104161021700271X. Barnett, D.W., Barnett, A., Nathan, A., Van Cauwenberg, J., Cerin, E., 2017. Council on Environment and Physical Activity (CEPA) – older Adults working group. Built environmental correlates of older adults' total physical activity and walking: a systematic review and meta-analysis. Int. J. Behav. Nutr. Phys. Act. 14 (1), 103. https://doi.org/10.1186/ s12966-017-0558-z. Besser, L., Galvin, J.E., Rodriguez, D., Seeman, T., Kukull, W., Rapp, S.R., Smith, J., 2019. Associations between Neighborhood Built Environment and Cognition Vary by Apolipoprotein E Genotype: Multi-Ethnic Study of Atherosclerosis. Health Place (in press). Besser, L.M., McDonald, N.C., Song, Y., Kukull, W.A., Rodriguez, D.A., 2017. Neighborhood environment and cognition in older adults: a systematic review. Am. J. Prev. Med. 53 (2), 241–251. https://doi.org/10.1016/j.amepre.2017.02.013. Boardman, J.D., Barnes, L.L., Wilson, R.S., Evans, D.A., Mendes de Leon, C.F., 2012. Social disorder, APOE-E4 genotype, and change in cognitive function among older adults living in Chicago. Soc. Sci. Med. 74 (10), 1584–1590. https://doi.org/10.1016/j.socscimed.2012. 02.012. Brown, B.M., Peiffer, J.J., Taddei, K., Lui, J.K., Laws, S.M., Gupta, V.B., Taddei, T., Ward, V.K., Rodrigues, M.A., Burnham, S., Rainey-Smith, S.R., Villemagne, V.L., Bush, A., Ellis, K.A., Masters, C.L., Ames, D., Macaulay, S.L., Szoeke, C., Rowe, C.C., Martins, R.N., 2013. Physical activity and amyloid-β plasma and brain levels: results from the Australian Imaging, Biomarkers and Lifestyle Study of Ageing. Mol. Psychiatry 18 (8), 875–881. https://doi.org/10.1038/mp.2012.107. Cerin, E., Nathan, A., van Cauwenberg, J., Barnett, D.W., Barnett, A., 2017a. Council on Environment and Physical Activity (CEPA) – older Adults working group. The neighbourhood physical environment and active travel in older adults: a systematic review and meta-analysis. Int. J. Behav. Nutr. Phys. Act. 14 (1), 15. https://doi.org/10.1186/s12966017-0471-5. Cerin, E., Rainey-Smith, S.R., Ames, D., Lautenschlager, N.T., Macaulay, S.L., Fowler, C., Robertson, J.S., Rowe, C.C., Maruff, P., Martins, R.N., Masters, C.L., Ellis, K.A., 2017b. Associations of neighborhood environment with brain imaging outcomes in the Australian Imaging, Biomarkers and Lifestyle cohort. Alzheimers Dement 13 (4), 388–398. https:// doi.org/10.1016/j.jalz.2016.06.2364. Chandrabose, M., Rachele, J.N., Gunn, L., Kavanagh, A., Owen, N., Turrell, G., Giles-Corti, B., Sugiyama, T., 2019. Built environment and cardio-metabolic health: systematic review and meta-analysis of longitudinal studies. Obes. Rev. 20 (1), 41–54. https://doi.org/10.1111/ obr.12759. Cherrie, M.P.C., Shortt, N.K., Ward Thompson, C., Deary, I.J., Pearce, J.R., 2019. Association between the activity space exposure to parks in childhood and adolescence and cognitive aging in later life. Int. J. Environ. Res. Public Health 16 (4), E632. https://doi.org/10. 3390/ijerph16040632. Couderc, R., Mahieux, F., Bailleul, S., Fenelon, G., Mary, R., Fermanian, J., 1993. Prevalence of apolipoprotein E phenotypes in ischemic cerebrovascular disease. A case-control study. Stroke 24 (5), 661–664. Duman, B.S., Oztürk, M., Yilmazer, S., Hatemi, H., 2004. Apolipoprotein E polymorphism in Turkish subjects with Type 2 diabetes mellitus: allele frequency and relation to serum lipid concentrations. Diabetes Nutr. Metab. 17 (5), 267–274. GBD 2016 Dementia Collaborators, 2019. Global, regional, and national burden of Alzheimer's disease and other dementias, 1990-2016: a systematic analysis for the Global Burden of Disease Study 2016. Lancet Neurol. 18 (1), 88–106. https://doi.org/10.1016/S14744422(18)30403-4. Hillsdon, M., Coombes, E., Griew, P., Jones, A., 2015. An assessment of the relevance of the home neighbourhood for understanding environmental influences on physical activity: how far from home do people roam? Int. J. Behav. Nutr. Phys. Act. 12, 100. https://doi. org/10.1186/s12966-015-0260-y. Lee, B.K., Glass, T.A., James, B.D., Bandeen-Roche, K., Schwartz, B.S., 2011. Neighborhood psychosocial environment, apolipoprotein E genotype, and cognitive function in older adults. Arch. Gen. Psychiatr. 68 (3), 314–321. https://doi.org/10.1001/archgenpsychiatry. 2011.6. Livingston, G., Sommerlad, A., Orgeta, V., Costafreda, S.G., Huntley, J., Ames, D., Ballard, C., Banerjee, S., Burns, A., Cohen-Mansfield, J., Cooper, C., Fox, N., Gitlin, L.N., Howard, R., Kales, H.C., Larson, E.B., Ritchie, K., Rockwood, K., Sampson, E.L., Samus, Q., Schneider, L.S., Selbæk, G., Teri, L., Mukadam, N., 2017. Dementia prevention, intervention, and care. Lancet 390 (10113), 2673–2734. https://doi.org/10.1016/S0140-6736(17)31363-6. Nithianantharajah, J., Hannan, A.J., 2006. Enriched environments, experience-dependent plasticity and disorders of the nervous system. Nat. Rev. Neurosci. 7 (9), 697–709. Prince, M., Albanese, E., Guerchet, M., Prina, M., 2014. World Alzheimer Report 2014: Dementia and Risk Reduction: an Analysis of Protective and Modifiable Risk Factors. Alzheimer's Disease International, London. Rivellesse, A.A., Bozzetto, L., Annuzzi, G., 2009. Postprandial lipidemia, diet, and cardiovascular risk. Curr Cardiovasc Risk Rep 3, 5–11. van de Rest, O., Wang, Y., Barnes, L.L., Tangney, C., Bennett, D.A., Morris, M.C., 2016. APOE ε4 and the associations of seafood and long-chain omega-3 fatty acids with cognitive decline. Neurology 86 (22), 2063–2070. https://doi.org/10.1212/WNL.0000000000002719. World Health Organization, 2009. Global Health Risks: Mortality and Burden of Disease Attributable to Selected Major Risks. WHO, Geneva. Wu, Y.T., Prina, A.M., Jones, A., Matthews, F.E., Brayne, C., Medical Research Council, 2017. Cognitive function and ageing study collaboration. The built environment and cognitive disorders: results from the cognitive function and ageing study II. Am. J. Prev. Med. 53 (1), 25–32. https://doi.org/10.1016/j.amepre.2016.11.020. Zissimopoulos, J., Crimmins, E., St Clair, P., 2014. The value of delaying Alzheimer's Disease onset. Forum Health Econ. Policy 18 (1), 25–39.
3
Contents lists available at ScienceDirect
Health & Place journal homepage: www.elsevier.com/locate/healthplace
Commentary
Building the evidence for an ecological model of cognitive health Ester Cerin a b
T
a,b
Mary MacKillop Institute for Health Research, Australian Catholic University, Melbourne, Australia School of Public Health, The University of Hong Kong, Hong Kong, China
A R T I C LE I N FO
A B S T R A C T
Keywords: Built environment Natural environment Apolipoprotein E genotype Walkability Cognitive function
This is a commentary on Besser and colleagues’ article “Associations between neighbourhood built environment and cognition vary by apolipoprotein E genotype: Multi-Ethnic Study on Atherosclerosis” published in Health & Place. Unlike previous studies, the authors found significant environment-cognition associations in apolipoprotein E (APOE) ε2 carriers and no significant associations in ε4 carriers. This commentary discusses the possible reasons for these findings and, in doing so, proposes an ecological model of cognitive health. The model highlights the importance of accounting for multiple environmental influences including the built and natural environment and air and noise pollution indicators. It also stresses the importance of studying the underlying biological mechanisms explaining differences in environment-cognition associations across APOE genotype categories.
1. Commentary Neighbourhood environments are considered major contributors to mortality and morbidity by national and international health organisations (World Health Organization, 2009). A plethora of studies have reported significant associations of aspects of the neighbourhood environment with physical inactivity (Barnett et al., 2017; Cerin et al., 2017a), depression (Barnett et al., 2018), obesity, hypertension and diabetes (Chandrabose et al., 2019), which are established mid- or late life risk factors for dementia (Livingston et al., 2017). However, as highlighted by Besser and colleagues (Besser et al., 2019), the contribution of neighbourhood environments to dementias and, more broadly, brain and cognitive health has received little attention (Besser et al., 2017; Cerin et al., 2017b). This is unfortunate for multiple reasons. Firstly, with over 44 million cases worldwide in 2016 (GBD, 2016 Dementia Collaborators, 2019), dementia is a global health priority and one of the leading causes of disability and overall burden of disease for ageing populations in developed and developing countries (GBD, 2016 Dementia Collaborators, 2019; Prince et al., 2014). Second, mild cognitive impairment (MCI) that is not severe enough to meet a diagnosis of dementia also causes significant disability and increased medical costs (Zissimopoulos et al., 2014). Third, no effective pharmacological treatment for dementia and MCI is yet available and risk reduction and prevention remains the best strategy to lower their incidence, associated disability and cost. The Global Observatory for Ageing and Dementia Care (Prince et al., 2014) and the Global Burden of Disease Dementia Collaborators have
E-mail address: [email protected]. https://doi.org/10.1016/j.healthplace.2019.102206 Received 10 September 2019; Accepted 10 September 2019 1353-8292/ © 2019 Elsevier Ltd. All rights reserved.
recently stressed the need for evidence-based, multi-level, multi-sectoral (urban planning and design, transportation, residential aged care, food industry) strategies to yield significant, large-scale, sustainable delays in cognitive decline and reductions in incidence of dementia. However, empirical evidence to inform these strategies is lacking because most research in the field of cognitive health has focused on individual-level factors, such as lifestyle behaviours and biomarkers. Besser and colleagues' paper (Besser et al., 2019) makes an important contribution to addressing the dearth of evidence on neighbourhood environmental influences on cognitive health by specifically focusing on multiple aspects of the built environment and examining the moderating effects of a genetic risk factor for Alzheimer's disease. Because cognitive function and cognitive decline are bound to be determined by environmental as well as genetic factors (Prince et al., 2014), it makes sense to study them conjointly. Apolipoprotein E (APOE) genotype is the main genetic risk factor for dementia (Livingston et al., 2017) and a likely strong moderator of the effects of environmental factors and lifestyle behaviours on cognitive health (Cerin et al., 2017b; Prince et al., 2014). The study of gene-environment interactions on cognitive health is essential not only for a better understanding of the effects of the environment and their underlying pathways but also for the identification of vulnerable population segments and the development of effective individually-tailored lifestyle interventions that may offset harmful environmental influences. In fact, evidence suggests that APOE and a few other genotypes modify the effects of cognition-promoting lifestyle activities, such as engagement in physical activity (Brown et al., 2013) and high intake of dietary
Health and Place 60 (2019) 102206
E. Cerin
Fig. 1. A simplified ecological model of cognitive health.
being damaged and eventually dying (Prince et al., 2014). APOE ε4 carriers are primarily at increased risk of Alzheimer's disease rather than vascular dementia, while APOE ε2 carriers appear to have higher risk of obesity (Duman et al., 2004), type 2 diabetes (Anthopoulos et al., 2010) and peripheral vascular disease, including carotid atherosclerosis (de Andrade et al., 1995) and cerebrovascular disease (Couderc et al., 1993). APOE ε2 genotype is also associated to elevated postprandial triglyceride levels which, in turn, promote systemic inflammation and increase the risk of metabolic diseases (Rivellesse et al., 2009). Given that obesity and diabetes are major risk factors for dementia (Livingston et al., 2017) and activity-friendly neighbourhoods have been associated with better cardio-metabolic health (Chandrabose et al., 2019) by facilitating regular engagement in physical activity (Barnett et al., 2017; Cerin et al., 2017a), Besser and colleagues' findings on APOE ε2 carriers make logical sense. They also highlight the need for a more in-depth examination of the moderating role of APOE genotype on the effects of the environment and lifestyle behaviours on cognitive health that transcend the examination of differences between APOE ε4 carriers vs non-carriers. While the observed associations between environmental attributes and cognitive function in APOE ε2 carriers may be plausible, we are left to wonder why Besser and colleagues did not find an association in APOE ε4 carriers. As the authors noted, it is possible that the risk of cognitive decline in the latter may be too difficult to be overcome by activity-friendly environments (Besser et al., 2019). However, other factors may have also contributed to these findings. For example, only the more resilient APOE ε4 carriers with lower levels of cognitive decline and living in more activity-friendly environments might have remained in the analytical sample of the study. In fact, albeit only approaching statistical significance, when compared to those excluded from the sample, the analytical sample had ~5% fewer APOE ε4 carriers and tended to live in neighbourhoods with higher intersection density (Besser et al., 2019). A recent study found that intersection density was one of the strongest predictors of changes in amyloid β depositions in the brain of APOE ε4 carriers. Further, as the Besser and colleagues noted, an analysis of longitudinal data (i.e., cognitive decline) might have yielded different results. In this regard, it is noteworthy that Cerin and colleagues did not find significant differences in associations of activity-friendly environments with average brain volumetric measures between APOE ε4 carriers and non-carriers but found significant between-group differences in associations of the environment with changes in brain volumes (brain atrophy). Another limitation that may have yielded biased estimates of
omega-3 fatty acids (van de Rest et al., 2016), and those of environmental factors (Besser et al., 2019; Lee et al., 2011). Genetic factors may also determine how individuals interact with the environment and the biological pathways via which the environment affects cognition (Nithianantharajah and Hannan, 2006). To gather information of practical value, an interactionist approach is needed that establishes the extent to which environment-cognition relationships depend on genetic risk of dementia and whether this is due to individual differences in reactions to the environment, effects of behaviour on biological mechanisms, or biological pathways affecting cognitive function (Fig. 1). While previous studies examining APOE genotype by environmental exposure interactions on brain or cognitive health in later life found stronger associations in APOE ε4 carriers than non-carriers (Boardman et al., 2012; Lee et al., 2011; Cerin et al., 2017b), Besser and colleagues (Besser et al., 2019) observed significant positive confounder-adjusted associations between activity-friendly environmental attributes and cognitive function in APOE ε2 carriers only. In support of their findings, the authors cited another study that observed significant associations between activity-friendly environments (green spaces) and cognitive decline in APOE ε4 non-carriers only (Cherrie et al., 2019). However, with only 76 APOE ε4 carriers and 205 non-carriers, the latter study was underpowered to detect associations in carriers. Also, it is noteworthy that the same study found that early and mid-life, rather than late-life, exposure to green spaces were predictive of slower cognitive decline in later life, while Besser et al. examined late-life environmental exposures. Given that early, mid- and late-life risk factors of dementia substantially differ (Livingston et al., 2017), there also may be differences in the effects of various environmental exposures on cognitive health across life stages. Thus, evidence of an effect of an early-life environmental exposure on late-life cognitive function is not necessarily comparable to the evidence of an effect of a late-life exposure on cognitive function. Notwithstanding the above issues, the fact that Besser and colleagues found significant associations only in APOE ε2 carriers is interesting and worth further consideration. It is possible that the effects of environmental factors on cognitive function and decline in different APOE genotypes are underpinned by distinct biological mechanisms. Firstly, cognitive decline can be caused by different pathological processes. For example, vascular dementia results from reduced blood supply to the brain due to diseased blood vessels, while dementia caused by Alzheimer's disease is believed to develop due to problems with brain proteins that function abnormally, disrupt the work of neurons and trigger a cascade of toxic events that result in neurons 2
Health and Place 60 (2019) 102206
E. Cerin
References
associations of activity-friendly attributes of the neighbourhood built environment and cognitive function in Besser et al.‘s study (and earlier similar studies) pertains to the lack of adjustment for green spaces and pollution. As depicted in Fig. 1, high levels of density and access to a wide range of destinations and amenities is typically accompanied by higher levels of traffic-related air pollution and other environmental stressors and reductions in green spaces. If we assume that exposure to green spaces and pollution are, respectively, beneficial and detrimental to cognitive health, their omission from statistical models is likely to underestimate the positive associations of density and destination accessibility with cognitive health. Hence, it is suggested that future studies on cognitive health should strive to account for all these environmental aspects in multiple-exposure models. Other key issues that should be addressed in future studies of environmental determinants of cognitive health are the shape of the doseresponse relationships, the effect of environmental exposures on specific facets of cognitive function (e.g., visuospatial memory, attention and executive functions), the identification of lifestyle behaviours and biological processes mediating the effects of the environment and the assessment of personal activity spaces beyond residential neighbourhoods. Specifically, there is some evidence that the relationship of measures of access to destinations and green spaces with cognitive impairment may be U-shaped and that both lack and overload of environmental stimulation may be detrimental to cognitive health (Wu et al., 2017). Thus, it is important to establish the levels of specific environmental exposures that yield optimal health outcomes. Most studies on the effects of the environment on cognitive health have used single general measures of cognitive function (Besser et al., 2017). However, it is reasonable to assume that different types of environmental attributes may affect different aspects of cognitive function by promoting specific lifestyle behaviours or cognitive processes, as Besser et al.‘s study suggests. For example, exposure to urban environments with intricate street networks may lead to better visuospatial working memory. There is a general dearth of studies on the mediating effects of lifestyle behaviours - including physical activity, sedentary behaviour, sleep, socialising, mental activities, navigational activities and dietary behaviour – on the relationships between environmental attributes and cognitive health (Fig. 1). The same holds true for biological pathways linking the environment and cognitive health. Finally, although individuals spend a substantial part of their day in their residential neighbourhood, it is not the only place they are regularly exposed to. For example, a recent study on adults aged 18–94 years reported that over 60% of outdoor physical activity took place outside of the proximal home neighbourhood (defined as a 800m radius buffer around the home). Moreover, substantial inter-individual differences were observed in the distances from home where physical activity was undertaken (Hillsdon et al., 2015). To more accurately characterise individual exposure to environmental stimulation, pollution and other stressors, there is a need for studies on environmental determinants of cognitive health to capture the whole range of habitual activity spaces individuals are exposed to rather than focus solely on their home neighbourhood. In summary, despite its potential importance for cognitive health promotion, the field of environmental determinants of cognitive health is still in its infancy. Besser and colleagues’ study on the moderating effects of APOE genotype on the associations between aspects of the neighbourhood built environment and cognitive function moves the field forward by providing novel, valuable findings that open new venues for research. Undoubtedly, many important questions related to environmental influences on cognitive health remain unanswered. Decades of substantial international multidisciplinary investigative efforts will be required to gain a satisfactory understanding of these issues.
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