Frailty and accelerated dementia onset in genetic, sociodemographic and neuropathologic subgroups

Quantifying how risk factors shape the timing of dementia onset can inform care and prevention strategies. We aimed to establish the degree to which and in whom frailty accelerates time to a diagnosis of dementia.

Longitudinal data came from community-dwelling participants of the Rush Memory and Aging Project in Northeastern Illinois. At baseline, participants had data on age, education, sex, APOE ε4 status and sufficient health/functional variables to calculate a frailty index score. In a subset of participants who underwent autopsy, neuropathologic burden was quantified using a 10-item index of markers of Alzheimer's disease and mixed brain pathology. Accelerated failure time models estimated associations of frailty and age at dementia diagnosis.

In 1614 participants (mean age 79.6 years, 75% female) over 23.9 years of follow-up, frailty (frailty index scores ≥0.25) was associated with 3.6% younger age at dementia diagnosis (time ratio, TR 0.96 (95% CI 0.95, 0.98)), equating to 2-3 years earlier. That association was stronger in males than females, but present across each sex, education and APOE ε4 subgroup. In the autopsy subset (n=906), frailty was associated with 9.8% younger dementia diagnosis among those who died with low neuropathologic burden (TR 0.90 (95% CI 0.85, 0.96)) but had no association in those with intermediate or high burden.

Frailty appears to independently accelerate dementia onset, particularly for individuals whose neurodegenerative lesions might be insufficient to explain their dementia diagnosis. Its routine measurement in clinical practice could hold benefit for risk stratification and care.