Associations between Frailty, Neurodegenerative Biomarkers, and Neuorimaging Measures in Young-Onset Mild Cognitive Impairment

Mild Cognitive Impairment (MCI) is an early stage of cognitive impairment that may regress, remain stable, or progress to dementia. In parallel, frailty is a clinical condition characterised by an impaired ability to respond to physiological stressors, and its interactions with biomarkers of neurodegenerative pathology and brain alterations are not well defined in patients with young-onset MCI. This study aims to investigate the relationships between frailty, fluid biomarkers, and brain morphological and microstructural alterations in patients with MCI who have an onset before the age of 65. The present study included 146 patients with MCI from two neurological clinics, recruited between 2019 and 2021. Frailty was measured using a 40-item Frailty Index (FI). To calculate the FI, clinical history, objective examinations, and functional assessments in the medical reports were retrospectively examined. The biomarkers study included Aβ₁₋₄₂, Aβ₁₋₄₀, t-tau, p-tau, and NfL levels in cerebrospinal fluid and blood. Statistical analyses on the continuous variables were performed with Spearman's coefficient (ρ), calculated on the total sample, and further analysed within the AD and non-AD subgroups to explore subgroup-specific patterns. Neuroimaging analyses were based on structural MRI (VBM) and DTI, with the extraction of AF, MD, and RD, and were performed with correction for age, sex, and years of education. In the total sample, FI was positively associated with age and negatively with years of education. However, it showed no significant correlations with any neurodegenerative biomarkers, neither in the AD nor in the non-AD subgroup. The negative association with years of education was maintained in both subgroups, while the positive association with age was maintained only in the non-AD subgroup. Morphometric analysis in VBM showed an association between increased frailty and reduced brain volume in specific areas of the cerebellum and left peri-rolandic cortex, while DTI analysis showed extensive microstructural alteration of the white matter, in particular in cerebellar and fronto-temporal tracts, which is indicative of demyelination and axonal impairment. These results suggest that in patients with young-onset MCI, frailty is independent of AD biomarkers, but it correlates with demographic characteristics such as age and years of education, even at an early stage of MCI. Furthermore, frailty is already associated with cerebral alterations involving motor, executive, and visuospatial control networks. These changes thus seem to denote a distinct neuropathological process, which could be related to systemic or lifestyle vulnerability. In conclusion, this study demonstrated that frailty is an early and independent Alzheimer's disease index of brain alteration in patients with young-onset MCI. Furthermore, the results underscore the value of frailty as a complementary indicator of functional reserve, reinforcing its significance in understanding brain alterations in patients with young-onset MCI.