Supplementary Material for: What combinations of modifiable risk factors are most prevalent and most strongly associated with low cognition? – Results from Canadian Longitudinal Study on Aging

Introduction
Recent multidomain intervention trials for dementia showed that it is possible to improve cognition by combating combinations of risk factors. We aimed to identify the most prevalent co-occurring risk factor combinations that are strongly associated with low cognition.

Methods
This cross-sectional analysis included baseline data from 30,097 participants aged 45 to 85 in the Canadian Longitudinal Study on Aging. The five most prevalent dyad, triad, and tetrad combinations of 12 modifiable risk factors were identified. Neuropsychological test battery composite Z score was calculated to assess cognition. Multivariable linear regression was used to explore the association between the prevalent combinations of risk factors and cognition. Synergistic interaction between risk factors was assessed using interaction terms.

Results
The most prevalent combination was physical inactivity and sleep disturbance for the dyad, further including hypertension for the triad, and adding obesity for the tetrad. The dyadic combination associated with both high prevalence and the strongest association with low cognition was hearing loss and physical inactivity (prevalence 27%; mean difference -0.12, [95% CI -0.14 to -0.09]). For the triad, it was hearing loss, physical inactivity, and hypertension (14%; -0.14 [-0.16 to -0.11]), with the further addition of obesity for the tetrad (5.1%; -0.15 [-0.19 to -0.12]). The synergistic interaction effect was observed between hypertension and physical inactivity (p<0.001).

Conclusion
The most prevalent and detrimental combinations of modifiable risk factors were identified to inform targeted intervention strategies. The observed synergistic interaction between hypertension and physical inactivity highlights the need to address both risk factors simultaneously to maximize cognitive benefits.