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. 2025 Apr-Jun;25(2):100588.
doi: 10.1016/j.ijchp.2025.100588. Epub 2025 Jun 4.

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

Pamela Chavarría-Elizondo  1   2   3 , Pablo Maturana-Quijada  4 , Ignacio Martínez-Zalacaín  5 , Inés Del Cerro  6   7 , Asier Juaneda-Seguí  1 , Andrés Guinea-Izquierdo  1 , Jordi Gascón-Bayarri  8 , Ramón Reñé-Ramírez  8 , Mikel Urretavizcaya  1   2   3   9 , Isidre Ferrer  10   11   12 , José M Menchón  1   2   3 , Virginia Soria  1   3   13   14 , Carles Soriano-Mas  1   3   15
Affiliations

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

Pamela Chavarría-Elizondo et al. Int J Clin Health Psychol. 2025 Apr-Jun.

Abstract

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.

Keywords: Amnestic mild cognitive impairment; Functional connectivity; Late-life depression; Resting-state.

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Conflict of interest statement

The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: Inés del Cerro reports a relationship with Worldwide Clinical Trials that includes: consulting or advisory. The author, Carles Soriano-Mas is an Advisory Board Member for International Journal of Clinical and Health Psychology and was not involved in the editorial review or the decision to publish this article. If there are other authors, they declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.

Figures

Fig. 1
Fig. 1
Group differences in functional connectivity in the precuneus cortex. (A) Baseline analysis reveals significantly decreased connectivity in the precuneus cortex in subjects with amnestic mild cognitive impairment (aMCI) compared to healthy controls (HCs); the color bar represents t-values. (B) Longitudinal changes in functional connectivity among HCs, individuals with aMCI, and patients with late-life depression (LLD) are presented at baseline and at the 2-year follow-up. *p < 0.05, **p Scheffé < 0.05.
Fig. 2
Fig. 2
Group differences in functional connectivity in the middle frontal and angular gyri. (A) At baseline, patients with late-life depression (LLD) exhibited reduced connectivity in the right middle frontal and right angular gyri relative to healthy controls (HCs); the color bar indicates t-values. (B) Longitudinal changes in right middle frontal gyrus connectivity are shown for HCs, individuals with amnestic mild cognitive impairment (aMCI), and patients with LLD, measured at baseline and at a 2-year follow-up. (C) Longitudinal changes in right angular gyrus connectivity are depicted for HCs, individuals with aMCI, and patients with LLD, measured at baseline and at a 2-year follow-up. *p < 0.05, **p Scheffé <0.05.
Fig. 3
Fig. 3
Group differences in functional connectivity in the posterior parietal and cuneal cortices. (A) Baseline increases in functional connectivity in the left posterior parietal cortex and left cuneal cortex in patients with late-life depression (LLD) compared to healthy controls (HCs). The color bar indicates t-values. (B) Longitudinal changes in functional connectivity in the left posterior parietal cortex across HCs, individuals with amnestic mild cognitive impairment (aMCI), and patients with LLD, measured at baseline and at the 2-year follow-up. (C) Longitudinal changes in functional connectivity in the left cuneal cortex across HCs, individuals with aMCI, and patients with LLD, measured at baseline and at the 2-year follow-up. *p < 0.05, **p Scheffé <0.05.
Fig. 4
Fig. 4
Group differences in functional connectivity in the insular cortex and postcentral gyrus. (A) Baseline decreased connectivity in the right insular cortex and left postcentral gyrus in patients with late-life depression (LLD) compared to healthy controls (HCs). The color bar represents t-values. (B) Longitudinal changes in functional connectivity in the right insular cortex across HCs, individuals with amnestic mild cognitive impairment (aMCI), and patients with LLD, measured at baseline and at the 2-year follow-up. (C) Longitudinal changes in functional connectivity in the left postcentral gyrus across HCs, individuals with aMCI, and patients with LLD, measured at baseline and at the 2-year follow-up. *p < 0.05, **p Scheffé <0.05.
Fig. 5
Fig. 5
Correlations between functional connectivity and clinical variables at baseline. (A) Depicts the correlation between left posterior parietal cortex connectivity and Long-Term Memory (age-adjusted scores). (B) Depicts the correlation between left cuneal cortex connectivity and GDS (age-adjusted scores).
Fig. 6
Fig. 6
Correlations between baseline functional connectivity and follow-up depression scores. (A) Depicts the correlation between baseline connectivity in the insular cortex and follow-up and baseline GDS age-adjusted scores. (B) Depicts the correlation between baseline connectivity in the insular cortex and follow-up and baseline HDRS17 age-adjusted scores. (C) Depicts the correlation between baseline connectivity in the left postcentral gyrus and follow-up baseline GDS age-adjusted scores. (D) Depicts the correlation between baseline connectivity in the left cuneal cortex and follow-up and baseline HDRS17 age-adjusted scores.
Fig. 7
Fig. 7
Correlations between baseline functional connectivity and follow-up cognitive performance. (A) Depicts the correlation between baseline connectivity in the precuneus cortex and follow-up and baseline MMSE age-adjusted scores. (B) Depicts the correlation between baseline connectivity in the precuneus cortex and follow-up and baseline age-adjusted Long-Term Memory scores.
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