Exploring the interplay between frailty, Alzheimer's disease biomarkers, and cognitive functioning in patients with...

BackgroundFrailty is characterized by declining homeostatic reserves and increased vulnerability to stressors, and has been associated with cognitive decline and dementia.ObjectiveTo examine the relationship between frailty, Alzheimer's disease (AD) biomarkers, and cognitive performance in individuals with mild cognitive impairment (MCI).MethodsWe enrolled 183 MCI patients from the Diagnostic Outpatient Service of the Neurodegenerative Diseases Unit at IRCCS Ca' Granda Ospedale Maggiore Policlinico, Milan. Cerebrospinal fluid (CSF) biomarkers amyloid-β42, total-tau, and phosphorylated-tau181were analyzed. Frailty was assessed using a 47-item frailty index (FI), and cognitive performance was measured with the Mini-Mental State Examination (MMSE).ResultsHigher FI scores were associated with lower MMSE scores, even after adjusting for amyloid and tau biomarkers (β = -0.72, 95% CI -1.20, -0.24). Compared to robust (FI ≤ 0.11) amyloid-negative subjects, individuals with higher FI (>0.11) and CSF amyloid positivity had significantly lower MMSE scores. Patients with lower FI had twice the odds ratio (OR 2.00, 95% CI 1.02-3.90) of presenting an amyloid-positive (A+) CSF profile compared to those with higher FI; similar trends were found for the amyloid and tau-positive (A + T+) profile (OR 2.29, 95% CI 1.14-4.61).ConclusionsFrailty modulates the phenotypic variability of AD, influencing its clinical expression in MCI. Specifically, it is associated with lower cognitive performance in MCI independently of AD biomarker status and contributes synergistically with amyloid pathology to cognitive decline. Moreover, lower frailty levels are associated with a higher likelihood of an AD-compatible CSF profile, suggesting that frailty assessment may aid in identifying patients at greater risk.