Altered resting-state functional connectivity in individuals at risk for Alzheimer’s disease: a longitudinal study

Background: Resting-state functional connectivity magnetic resonance imaging (rs-fMRI) is a sensitive tool for detecting early brain changes associated with Alzheimer's disease, even in its preclinical stages. Amnestic mild cognitive impairment (aMCI) and late-life depression (LLD) are two prevalent conditions in older adults that significantly elevate the risk of cognitive decline and dementia. This study aimed to elucidate the underlying neurobiological substrates by longitudinally identifying and comparing distinct connectivity patterns in aMCI subjects and LLD patients, and by examining the associations between these patterns and clinical measures of cognitive and mood impairments. Methods: The study included three groups: 26 healthy controls (HCs), 15 individuals with aMCI, and 21 patients with LLD. All participants underwent rs-fMRI and neuropsychological assessments at baseline and at a 2-year follow-up. Functional connectivity was analyzed using a group Independent Component Analysis (ICA) model to investigate both group differences and longitudinal changes over time. Results: At baseline, individuals with aMCI exhibited reduced functional connectivity in the precuneus, whereas LLD patients showed decreased connectivity in frontal, insular, and postcentral regions alongside increased connectivity in posterior parietal and cuneal cortices. Correlation analyses revealed that lower baseline insular connectivity predicted higher depressive symptoms at follow-up in aMCI subjects. In LLD, reduced baseline precuneus connectivity was associated with better two-year outcomes in global cognition and long-term memory. Conclusions: This study provides evidence of distinct alterations in resting-state functional connectivity in individuals with aMCI and LLD, underscoring region-specific vulnerabilities that may contribute to cognitive decline and depressive symptomatology in older adults.