Frailty in Adults With Down Syndrome: Cognitive, Functional and Biomarker Associations

ABSTRACT Background Down syndrome (DS) entails widespread age‐related functional decline affecting multiple organ systems, including genetically determined early‐onset Alzheimer disease (DSAD), resulting in an increased vulnerability to frailty early in life. We investigated the relationship between frailty, cognition and intellectual disability (ID) in adults with DS and explored biomarkers associated with frailty. Methods This cross‐sectional study investigated 148 consecutive patients at a DSAD outpatient clinic. We applied correlation analyses and hierarchical linear models to determine associations of the Frailty Index for people with Intellectual Disabilities—short form (ID‐FI SF ) with measures of cognition (Cambridge cognitive assessment, CAMCOG‐DS), adaptive function (short adaptive behaviour scale, SABS), motor function (SPES/SCOPA), a screening tool (dementia screening questionnaire in individuals with intellectual disabilities, DSQIID‐G) for dementia‐related change in ADL (activities of daily living) performance, and ID severity (DSM‐5). Patients were stratified as cognitively healthy, DS‐MCI, DSAD dementia, secondary cognitive decline (CD) or CD of unknown cause. Exploratory analyses included blood biomarkers, bioimpedance measurements and indirect calorimetry. Results Both baseline ID severity ( β = 0.093, p = 0.014) and cognitive performance (CAMCOG‐DS, β = −0.0033, p < 0.001) were independently associated with ID‐FI SF scores. Acquired cognitive decline was associated with (pre)frailty irrespective of aetiology. After adjustment for ID severity and cognition, ID‐FI SF scores were associated with adaptive function (SABS: β = −0.0033, p < 0.001), motor function (SPES‐SCOPA: β = 0.015, p < 0.001), change in ADL performance (DSQIID‐G: β = 0.0061, p < 0.001) and medication burden ( β = 0.016, p < 0.001). Exploratory biomarker analyses identified associations with ID‐FI SF scores for markers of neurodegeneration, inflammation, body composition, cardiac function and cellular stress signalling. Conclusions Frailty in DS is associated with both ID severity and acquired cognitive decline. Future studies should determine whether severe baseline ID increases susceptibility to frailty or primarily influences frailty measurement through lower baseline functional abilities, potentially necessitating ID‐adapted frailty thresholds. Biomarker associations further support a multifactorial model of frailty involving neurodegeneration, inflammation and sarcopenia‐related processes.