Neighborhoods, Networks, and Neurodegeneration: A Call for Population-Level Policy and Advancing the Exposome

The past three decades of aging research has rapidly grown with significant federal funding from the National Institutes of Health/National Institutes on Aging, which has been matched by exponential growth in identifying and measuring various risk factors for mild cognitive impairment (MCI) and dementia [1]. While preclinical AD and MCI have received significant interest in screening and early assessment, limited studies have examined the role of social and environmental factors in risk prediction across diverse samples. Structural and social determinants of health (S/SDOH) are social, economic, and political conditions exerting synergistic direct/indirect effects on health outcomes [2]. Micro-to-macro-level factors like greenspace, air pollution, poverty, mobility, crime, and interpersonal biases interact within S/SDOH across the life course to create and intensify disparities for specific groups [3].

This timely and compelling study [4] by Dr. Mary Ganguli and colleagues leveraged two well-characterized, diverse, population-based cohorts (Monongahela-Youghiogheny Healthy Aging Team [MYHAT], Seniors Project 15104 [SP15104]) to examine the intersections of social and environment-level factors on the risk of MCI among older adults. The study's cross-sectional analysis of over 2800 older adults reveals striking associations between MCI and several community-level factors, including neighborhood disadvantage, schooling, air pollution, limited greenspace, and elevated local violent crime/homicide rates. The results emphasize how systemic inequities and chronic environmental exposures accumulate and compound to increase vulnerabilities in cognitive functioning among participants recruited from under-resourced, post-industrial towns in Pennsylvania. Key findings show that area deprivation and air pollution disproportionately affected participants racialized as Black, demonstrating the interplay of race as a social construct, geographic location, and environmental exposure. These findings resonate with the broader public health literature, which consistently identifies the compounding effects of systemic racism and poverty on health outcomes and dementia risk [5]. The study also highlights the consideration of early-life education, specifically schooling in the southern United States, which was linked to elevated odds of MCI, centralizing the role of historical inequities in education quality and their long-term health implications.

The study's emphasis on S/SDOH challenges the paradigm that cognitive health can be preserved solely through individual-level interventions, such as lifestyle modifications or obtaining regular clinical care. While encouraging older adults to adopt brain-healthy behaviors remains crucial, these findings emphasize addressing distal upstream factors, such as urban planning, environmental regulations, and community safety. For example, the association between green space and reduced odds of MCI spotlights urban planning opportunities to design age-friendly environments with diverse green space. Policymakers can draw on these findings to advocate for increased investment in public parks, forestation and green-scaping initiatives, and equitable access to green areas in historically marginalized neighborhoods, particularly in urban settings. Similarly, addressing air pollution—a modifiable risk factor—requires stringent and sustained enforcement of environmental regulations, particularly in regions where industrial emissions remain high and are often in neighborhoods with a more significant proportion of minoritized populations [6].

The study's methodological rigor adopted an intersectional lens, comprehensively examining multiple S/SDOH variables. By disentangling the differential effects of S/SDOH across age, race, gender, and educational attainment, The investigator's approach advances a more nuanced understanding of health inequities. The elevated liklihood of MCI linked to education in Southern states, particularly among Black participants, replicates prior findings [7, 8] and confirms the enduring impact of segregated and underfunded schools in the mid-20th century. This history has a measurable effect on the intergenerational inheritance of health and disease decades later. Additionally, this intersectional approach had implications for designing tailored interventions. Older minoritized adults residing in areas with high deprivation may benefit from targeted cognitive health programs incorporating cultural competence, awareness, and education about dementia. Simultaneously, addressing disparities in educational quality at a structural level could yield long-term benefits for future generations. The study's compelling insights are balanced by its cross-sectional design, which is limited from establishing causality between S/SDOH and MCI. However, these results provide a robust foundation for longitudinal research to elucidate specific temporal relationships and explore mechanisms underlying these associations. The study also highlights gaps in publicly available datasets. Factors like structural racism, food insecurity, and healthcare access and quality—while undoubtedly influential—would be critical for prospective research to quanitfy and establish causal relationships with cognitive decline. Expanding data collection efforts to capture these dimensions will further illuminate the pathways linking S/SDOH to better brain health.

This cross-sectional design across the two prospective cohorts, MYHAT and SP15104, offers a unique advantage, the intentional oversampling of Black participants, to address a long-standing gap in ethnoracial representation in AD research [9]. This inclusivity strengthens the study's external validity and ensures its relevance for diverse populations and newer studies [10] that examine within-group variability across S/SDOH and minoritized populations. The implications extend beyond research to public health, environmental regulation, healthcare policy, urban design, and precision medicine. To combat the cognitive health disparities illuminated in this research, stakeholders across sectors must collaborate on bold, systemic solutions. Public health professionals can advocate for integrated policies that address individual, structural, and social factors [11]. Meanwhile, clinicians should be equipped to consider patients' social and environmental contexts when assessing cognitive functioning and providing treatments tailored to their environment.

The exposome or “exposure” framework [12] conceptualizes an internal-external interaction between a person's experience, behavior, and social-cultural-natural environment interacting with biological systems to impact health outcomes. It encompasses a spectrum of factors, including chemical, physical, and social environments, lifestyle behaviors, diet, and psychosocial stressors. Internal exposures, such as inflammation, oxidative stress, and microbiome composition, are also integral, reflecting the body's biological responses to external influences. The exposome recognizes exposures' dynamic and cumulative nature across different life stages and examines the complex interplay between environment and biology influencing health outcomes. The updated 2024 Lancet Commission on Dementia identified 14 modifiable risk factors across early (n = 1), mid (n = 10), and late-life (n = 3) [13]. The putative risk factors for dementia include lower education, hearing loss, physical inactivity, and air pollution, with the majority being classified as medical conditions. Superimposing these risk factors onto the exposome provides an informed approach to guide precise measurement and development of assessments for dementia. A conceptual exposome for dementia is proposed to organize and begin outlining and quantifying the dynamic relationships in operationalizing the measurement of S/SDOH in AD (Figure 1). To improve diagnostic accuracy, it is essential to study how exposure and dosage of S/SDOH impact brain health for heterogeneous populations across race, ethnicity, gender, sex, and geographic residence. This research by Ganguli et al. is a pivotal addition to geriatrics, psychology, and neurology, advancing our understanding of how S/SDOH shapes cognitive trajectories and contributing evidence of the exposome of MCI and dementia.

Finally, the findings of this study underscore that the enterprise of brain health equity in aging populations of older adults must traverse the broader landscape of social and environmental justice. By addressing the root causes of health inequities, we can pave the way for healthier aging across diverse communities at the population level. This study by Ganguli and colleagues is a clarion call for an interdisciplinary research agenda that centers on health equity and S/SDOH in cognitive aging. Future studies will require the deployment of mixed methods designs, incorporating quantitative and qualitative data to capture the lived experiences of individuals navigating disadvantaged environments. Such approaches must elucidate the complex, intersectional mechanisms underlying observed associations between S/SDOH and dementia risk to address actionable and scalable strategies toward risk reduction.

G.M.B. contributed to the drafting, revision, and approval of this editorial.

The sponsor played no role in the drafting, revision, and approval of this editorial.

The author declares no conflicts of interest.