Research Article: Circulating fibroblast growth factor 23 levels and incident dementia: The Framingham heart study

Date Published: March 4, 2019

Publisher: Public Library of Science

Author(s): Emer R. McGrath, Jayandra J. Himali, Daniel Levy, Sarah C. Conner, Matthew P. Pase, Carmela R. Abraham, Paul Courchesne, Claudia L. Satizabal, Ramachandran S. Vasan, Alexa S. Beiser, Sudha Seshadri, Stephen D. Ginsberg.


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.

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.

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.

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). 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.

Partial Text

Dementia is a major health problem. An estimated 35 million people worldwide have dementia and this number is expected to triple over the next three decades due to an aging population[1]. Genetic factors, such as the apoE ε4 allele, and vascular risk factors, such as hypertension, can explain a proportion of dementia risk. However, a large proportion of dementia risk remains unexplained, necessitating the identification of additional underlying pathways and newer biomarkers for dementia.

The study cohort included 1537 participants for the primary outcome of incident dementia. During a median (Q1, Q3) 12 (7.0, 13.3) year follow up, 122 (7.9%) participants were diagnosed with dementia, 91 of whom were diagnosed with clinical AD. 74 (4.8%) of individuals died from cardiovascular disease during follow-up. The mean age of participants at baseline was 68.7 years (SD 5.7) and 53% were women. Baseline characteristics are shown in Table 1. Patients in the top quartile of FGF23, compared to the bottom quartile, were more likely to be female, have a history of diabetes, prior CVD or a history of atrial fibrillation. The majority of cohort participants did not have significant renal impairment at baseline (99%) (Table 1).

In our study, higher serum FGF23 was associated with an increased risk of incident dementia and AD but was not associated with structural brain measures predictive of vascular brain injury or with performance on neurocognitive testing.

Higher serum FGF23 was associated with an increased risk of incident dementia, which was not accounted for by increased vascular risk factor burden or vascular measures of structural brain injury. FGF23-related biological pathways may play a role in the development of dementia.




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