Hierarchical Development of Frailty and Cognitive Impairment: Clues into Etiological Pathways

Background: Frailty and cognitive impairment (CI) are associated and often coexist in older adults. Whether temporal patterns of occurrence reflect different etiologies remain unknown. Methods: Participants from the National Health and Aging Trends Study were assessed annually (2011-2016) for frailty (Fried's criteria) and CI (bottom quintile of clock drawing test or immediate and delayed recall; proxy-report of dementia diagnosis or AD8 ≥ 2). We used the Fine & Gray model to identify correlates of frailty onset before CI, CI onset before frailty, and frailty-CI co-occurrence, accounting for death as a competing risk. Results: Of 3,848 free of frailty, CI, and dementia at baseline, 2,183 (61.2%) developed neither frailty nor CI during the 5-year follow-up; 343 (8.3%) developed frailty first; 1,014 (24.4%) developed CI first; and 308 (6.0%) developed frailty-CI co-occurrence. Incident dementia, as a marker of underlying neuropathologies, was associated with greater likelihood of CI onset first (subdistribution hazard ratios [SHR] = 2.60, 95% confidence interval [ci] 2.09 to 3.24), and frailty-CI co-occurrence (SHR = 8.77, 95% ci 5.79 to 13.28), but lower likelihood of frailty onset first (SHR = 0.38, 95% ci 0.21 to 0.68). Number of comorbidities was only associated with frailty occurrence first (1 comorbidity: SHR = 2.51, 95% ci 1.15 to 5.47; 4+ comorbidities: SHR = 6.48, 95% ci 2.78 to 15.48). Conclusions: Different patterns of frailty and CI occurrence exist, and dementia-related pathologies and comorbidities may be important correlates of order of emergence, potentially reflecting different etiologies. Future investigation into relationships between these patterns and dementia subtypes and related pathologies is needed to elucidate etiologic pathways and to provide new targets for prevention, intervention, and risk screening.