Alteration of prefrontal functional connectivity in preclinical Alzheimer's disease: an fNIRS study

Abstract

Background: Early detection of Alzheimer's disease (AD) is vital for delaying its progression through timely intervention. The preclinical stage, the longest phase of AD, often goes undetected due to a lack of noticeable symptoms. Developing an accessible and quantitative screening method for AD is essential for enabling appropriate interventions during this stage. Methods: Functional near-infrared spectroscopy was used to investigate prefrontal functional connectivity in preclinical AD subjects. A total of 99 participants, including healthy controls and preclinical subjects who were amyloid beta (Aβ) positive (n = 45), were recruited. We designed a mixed phonemic and semantic verbal fluency task for the experimental protocol. Functional connectivity was then analyzed as z-values in the left, right, and interhemispheric prefrontal regions during a verbal fluency task. Finally, we assessed the correlation between the participants' z-values and clinical indices. Results: The preclinical AD group exhibited increased interhemispheric functional connectivity derived from oxygenated and deoxygenated hemoglobin during verbal tasks involving the first phonemic letter. Additionally, significant right and left functional connectivity differences were observed in the healthy control group during verbal tasks with the letter and categories, but not in the preclinical AD group. Lastly, the difference in interhemispheric functional connectivity of oxygenated hemoglobin between the first and second verbal trials was significantly greater in the preclinical AD group. These interhemispheric functional connectivity values were significantly correlated with Aβ results from positron emission tomography. Conclusion: The initial increase and subsequent reduction of interhemispheric functional connectivity in the preclinical AD group across task repetitions suggests that task-related prefrontal network alterations may occur during the preclinical phase of AD and shows its potential as a biomarker for screening preclinical AD. Copyright © 2025 Kim, Lee, Choi, Kim, Gwak, Lee and Kim.