Background Fibroblast growth factor 23 is an emerging vascular biomarker, recently associated with cerebral small vessel disease and poor cognition in patients on dialysis. It also interacts with klotho, an anti-aging and cognition enhancing protein. Objective To determine if circulating Fibroblast growth factor 23 (FGF23) is associated with new-onset cognitive outcomes in a community-based cohort of cognitively healthy adults with long-term follow-up. Methods We measured serum FGF23 levels in 1537 [53% women, mean age 68.7 (SD 5.7)] dementia-free Framingham Offspring participants at their 7th quadrennial examination (1998–2001), and followed these participants for the development of clinical all-cause dementia and Alzheimer’s disease (AD). Secondary outcomes included MRI-based structural brain measures, and neurocognitive test performance at exam 7. Results During a median (Q1, Q3) 12-year (7.0, 13.3) follow up, 122 (7.9%) participants developed dementia, of whom 91 (5.9%) had AD. Proportional-hazards regression analysis, adjusted for age, sex, education, systolic blood pressure, antihypertensive medication, prevalent cardiovascular disease, diabetes mellitus, smoking status and apoE ε4 carrier status, revealed that higher serum FGF23 levels were associated with an increased risk of incident dementia and AD (Hazard ratio [HR] per 1 standard deviation increment in inverse transformed FGF23 level 1.25, 95% CI 1.02–1.53, and 1.32, 95% CI 1.04–1.69, respectively). There was no significant interaction according to presence/absence of significant renal impairment (eGFR <30 versus 30ml/min) and risk of dementia (based on 1537; p = 0.97). Conclusions Higher circulating FGF23 is associated with an increased risk of dementia, suggesting that FGF23-related biological pathways may play a role in the development of dementia.
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