Objectively Measured Cardiorespiratory Fitness as a Potential Biomarker for Alzheimer’s Disease Risk in Older Adults: Evidence from the Generation 100 Study

PURPOSE: Cardiorespiratory fitness is a modifiable physiological trait linked to dementia risk, but whether objectively measured peak oxygen uptake (VO2peak) and short-term changes fitness in older adults associates with Alzheimer's disease (AD) remains unknown. We examined whether baseline levels and one-year changes in VO2peak were associated with subsequent risk of AD in older adults. METHODS: This prospective cohort study included participants from the Generation 100 Study. VO2peak was measured at baseline (2012-13) and 1-year follow-up. Participants were categorized as unfit (<80% of the sex-specific mean VO2peak), moderately fit (80-99%), or fit (≥100%). Incident AD was identified through national health registries, hospital records, and the Norwegian Prescribed Drug Registry. Cox proportional hazards models estimated associations between VO2peak and incident AD. RESULTS: A total of 1491 participants free from dementia, aged 70-77 years were included. Mean VO2peak at baseline was 28.7 mL/kg/min. During a median follow-up of 8.7 years, 77 developed AD. Compared with unfit, moderately fit (aHR 0.54, 95% CI 0.29-0.98) and fit (aHR 0.52, 95% CI 0.29-0.93) participants had a lower AD risk. Each 1 mL/kg/min higher baseline VO2peak was associated with a 4% lower risk of AD (HR 0.96, 95% CI 0.92-1.00). Staying above 80% of sex-specific mean VO2peak (25.1 mL/kg/min for men and 20.9 mL/kg/min for women) was identified as a threshold of AD risk stratification of which below the risk increased substantially. Weaker associations were observed between one-year changes in VO2peak and subsequent AD risk. CONCLUSIONS: Higher VO2peak in older adults was associated with a substantially lower risk of developing AD, whereas short-term changes in fitness did not confer additional benefit. These findings suggest that entering older age with fitness >80% of sex-specific mean may be more important for reducing late-life AD risk than achieving short-term improvements after the age of 70. CRF emerged as a clinically relevant biomarker for AD, that may help stratify risk and inform preventive strategies in ageing populations.