Frailty and prognosis of biomarker-confirmed Alzheimer's disease: a Swedish, register-based, retrospective cohort study

Background: This study aimed to examine the value of frailty status (defined by the frailty index) in informing the prognosis of people living with Alzheimer's disease. Methods: In this retrospective cohort study, we used the Swedish Registry for Cognitive/Dementia Disorders linked to other Swedish health-care registers to collect data from May 1, 2007, to Dec 31, 2020. We included people with mild cognitive impairment or Alzheimer's disease dementia, both with cerebrospinal fluid (CSF) biomarkers supporting Alzheimer's pathology. We excluded people living in an institution or those who did not have at least one Mini-Mental State Examination (MMSE). We constructed a 41-item frailty index, incorporating diseases, symptoms, polypharmacy, nutritional status, and care dependency. Individuals with frailty index scores of 0·25 or above were considered frail. The associations between frailty and MMSE trajectories, subsequent institutionalisation, and mortality were evaluated by jointly modelling longitudinal and survival data. We also examined whether frailty could modify the associations between CSF amyloid β42, phosphorylated tau181, and total tau and cognitive decline. Findings: The study included 7251 individuals (mean age 72·7 years, 4271 [58·9%] females, 2980 [41·1%] males). Frailty was associated with a 0·723-point (95% CI 0·250–1·196) lower baseline MMSE but not with the rate of MMSE decline. Frailty was associated with a hazard ratio of 1·91 (1·43–2·54) for institutionalisation and 2·41 (1·73–3·33) for mortality. Individuals living with frailty had a 1·3-year (0·9–1·7) shorter lifespan and a 1·0-year (0·8–1·3) shorter non-institutionalised lifespan. Associations between CSF biomarkers and MMSE trajectories did not differ by frailty status. Interpretation: Frailty, measured by the frailty index, predicted institutionalisation and mortality in people with Alzheimer's disease, but its absence of association with cognitive decline suggests neurodegeneration as the primary driver. Funding: Innovative Health Initiative Joint Undertaking and Vinnova.