Interactive Associations of Age, Apolipoprotein E ε4 Gene, Physical Activity, and Physical Functioning on Processing Speed

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OBJECTIVES: This study investigated the interactive associations of age, apolipoprotein E ε4 (APOE4) genetic status, physical activity energy expenditure (PAEE), and physical functioning on processing speed over a 10-year period. DESIGN: In this longitudinal study, participants underwent biennial assessments from 2002 to 2012 as part of the National Institute for Longevity Sciences-Longitudinal Study of Aging (NILS-LSA). SETTING AND PARTICIPANTS: We used data from 2518 middle-aged and older community-dwelling adults in Japan. METHODS: Processing speed was assessed using the Digit Symbol Substitution Test, and additional data included APOE4 genotyping, objective PAEE measurement via accelerometry (in kcal/d), and physical functioning assessments (handgrip strength and walking speed, dichotomized according to specific cutoffs: <18 kg for women and <28 kg for men [weakness], and <1 m/s [slowness], respectively). Mixed-effects models were used to analyze the data, accounting for time-varying covariates, including living arrangement, hypertension, hyperlipidemia, diabetes, depressive symptoms, smoking, sleep duration, energy intake, and body mass index. RESULTS: Results revealed significant 3-way interactive associations among PAEE × age × APOE4 carrier (β = 0.000025, P = .021) and among slowness × age × APOE4 carrier (β = -0.014187, P = .013) on cognitive processing speed. Higher PAEE was associated with better processing speed, whereas slowness was associated with poorer processing speed, particularly in older APOE4 carriers. Although weakness showed significant interactions with age and APOE4 carrier, no 3-way interaction was observed. CONCLUSIONS AND IMPLICATIONS: Our findings underscore the complex interplay among physical activity, physical functioning, age, and genetic risk on processing speed. The protective associations of higher PAEE levels and better physical functioning, especially in older APOE4 carriers, suggest that maintaining an active lifestyle and mobility may be crucial for individuals with a genetic predisposition to cognitive decline.

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