Aims: Frailty is a risk factor for dementia as well as a cause and consequence of other modifiable dementia risk factors. Our objective was to investigate the degree to which frailty mediates the association between modifiable risk factors and dementia risk.
Methods: Data were from a prospective cohort of 7,510 participants attending US National Alzheimer’s Coordinating Center memory clinics (June 2005–May 2022). Included participants were at baseline cognitively unimpaired and aged 60 or over. Frailty was measured using a frailty index. Other risk factors included hearing loss, low education, smoking, depression, traumatic brain injury, hypertension, and diabetes. Analyses involved multivariable statistical models adjusted for age, sex and APOE ε4 status.
Results: During a total of 50,216 years of follow-up, 786 (10.5%) participants received a diagnosis of all-cause dementia. Longitudinally, each 10% increase in frailty was associated with higher dementia risk before (HR=1.57 [95% CI=1.39–1.78]) and after (HR=1.48 [95% CI=1.31–1.68]) adjustment for the other risk factors (relative change in HR=5.9%). Similarly, adjustment for frailty reduced the HRs for the other risk factors by between 0.9%–6.3%. The measure of explained variation for incident dementia increased by 1.5% when other risk factors were added to a model including covariates and frailty, and by 2.0% when frailty was added to a model including covariates and other risk factors.
Conclusions: Frailty plays a significant and unique role in explaining differences in dementia incidence. Even so, a comprehensive approach including all risk factors simultaneously provides the most accurate estimate of dementia risk.