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 show it is possible to improve cognition by targeting 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 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 dyadic combination was physical inactivity and sleep disturbance, with hypertension added for the triad, and obesity added 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]), and with the addition of obesity for the tetrad (5.1%; -0.15 [-0.19 to -0.12]). Synergistic interaction was observed between hypertension and physical inactivity (p < 0.001). CONCLUSION: Prevalent and detrimental combinations of modifiable risk factors for dementia were identified to inform targeted intervention strategies. The synergistic interaction between hypertension and physical inactivity highlights the benefit of addressing both risk factors simultaneously to maximize cognitive benefits.