Causal discovery identifies pathways linking physical activity to dementia risk in the UK BioBank
Authors: Wasif Khan, Panayiotis V. Benos, Joshua K. Wong, Ruogu Fang
Organizations: J. Crayton Pruitt Family Department of Biomedical Engineering, University of Florida, Gainesville, FL, USA · Department of Epidemiology, University of Florida, Gainesville, FL, USA · Norman Fixel Institute for Neurological Diseases, University of Florida, Gainesville, FL, USA · Center for Cognitive Aging and Memory, McKnight Brain Institute, University of Florida, Gainesville, FL, USA · Department of Electrical and Computer Engineering, University of Florida, Gainesville, FL, USA
Physical Activity (PA) is consistently associated with lower risk of dementia, yet the mechanism linking PA to dementia prevention remain incomopletely understood. Here, we integrate large language model (LLM)-guided causal discovery with mediation analysis in 42,293 older adults aged 60 years or older from the UK Biobank to systematically identify pathways connecting objectively measured moderate-to-vigorous physical activity (MVPA) to dementia risk. Across behavioral, psychological, functional, and clinical domains, causal discovery consistently identified interconnected pathways linking higher MVPA to lower dementia risk through depression, functional capacity, smoking behavior, hypertension, cardiovascular disease, chronic kidney disease, and brain injury. Chain mediation analyses further identified depression as a central pathway, accounting for 15.1% of the overall association between MVPA and dementia risk. Sex-stratified analyses revealed distinct mechanistic patterns, with females exhibiting predominantly metabolic and functional pathways, while males showed behavioral and cardiometabolic cascades involving smoking and cardiovascular disease. Together, these findings suggest that the protective association between PA and dementia is mediated through interconnected behavioral, psychological, and cardiometabolic processes rather than a single pathway. Depression emerged as a prominent and potentially modifiable pathway, highlighting opportunities for integrating dementia prevention strategies that combine PA promotion with mental health and cardiovascular risk management.
Figures & tables
Figure 1: Causal pathways linking moderate-to-vigorous physical activity (MVPA) to dementia risk. (A). Causal graph derived from the PC causal discovery algorithm illustrating inferred pathways linking MVPA to dementia risk in older adults from the UK Biobank. Demographic, socioeconomic, behavioral, and clinical variables were incorporated into the causal discovery framework under domain-informed structural constraints. The resulting network identified both direct and indirect pathways connecting MVPA with dementia risk, including behavioral, functional, and psychological intermediates. Highlighted pathways indicate key mediation chains involving walking pace and depression. (B). Chain mediation analyses quantifying direct and indirect effects of MVPA on dementia risk through depression pathway. (C). Sensitivity analyses examining mediation effects across progressively longer exclusion windows (1-, 2-, 4-, and 5-year exclusions) to minimize potential reverse causation. Longer exclusion periods identified additional pathways involving hypertension, heart disease, brain injury, and chronic kidney disease (CKD). (D). Sex-specific causal pathways linking MVPA to dementia risk. Female-specific pathways primarily involved metabolic-functional mechanisms, including triglycerides, waist circumference, walking pace, depression, heart disease, and CKD, whereas male-specific pathways additionally involved smoking, PM10 exposure, hearing impairment, and a direct depression-mediated pathway. COPD, chronic obstructive pulmonary disease; CKD, chronic kidney disease; TG, triglycerides.
Figure 2: Chain mediation analyses examining the indirect pathways linking moderate-to-vigorous physical activity (MVPA) with dementia risk through depression and walking pace. The left panels represent the overall population, the middle panels represent females, and the right panels represent males. Upper panels illustrate the mediation pathway of MVPA → depression → dementia in the overall cohort and stratified by sex (females and males). Lower panels present the extended chain mediation pathway incorporating walking pace, modeled as MVPA → walking pace → depression → dementia. Standardized regression coefficients ( β ) and corresponding p-values are shown for each pathway. Models were adjusted for age, sex, ethnicity, education, deprivation index, smoking, and alcohol use.
Figure 3: Overview of the variable selection and causal mediation framework. Candidate variables from the UK Biobank were first filtered through a five-stage selection pipeline consisting of LLM-based preselection, multi-model relevance scoring, expert reviewer agents across multiple domains, census ranking and aggregation, and expert curation with data preprocessing. The final curated variables were then used for causal discovery by integrating domain knowledge, the PC algorithm, and bootstrapping to estimate a directed acyclic graph (DAG) representing pathways linking moderate-to-vigorous physical activity (MVPA) to dementia. Identified causal pathways were subsequently evaluated using chain mediation analysis to quantify direct, indirect, and total effects.
Characteristic
Total ( N = 42,293)
Female ( n = 22,526)
Male ( n = 19,767)
p -value
Age (years)
67.0±4.1
66.7±4.1
67.3±4.2
< 0.001
TDI
−2.0±2.7
−1.9±2.7
−2.0±2.6
< 0.001
Ethnicity
0.677
Others
913 (2.2%)
493 (2.2%)
420 (2.1%)
White
41,380 (97.8%)
22,033 (97.8%)
19,347 (97.9%)
Qualifications
< 0.001
Table 1: Baseline characteristics of study participants stratified by sex.