Early axonal degeneration linked to clinical decline in Alzheimer's disease progression revealed with diffusion MRI

Zhaoyuan Gong; John P. Laporte; Alexander Y. Guo; Murat Bilgel; Jonghyun Bae; Noam Y. Fox; Angelique de Rouen; Nathan Zhang; Aaliya Taranath; Rafael de Cabo; Josephine M. Egan; Luigi Ferrucci; Mustapha Bouhrara

doi:10.1172/JCI196638

Early axonal degeneration linked to clinical decline in Alzheimer's disease progression revealed with diffusion MRI

Zhaoyuan Gong,¹ John P. Laporte,¹ Alexander Y. Guo,¹ Murat Bilgel,¹ Jonghyun Bae,¹ Noam Y. Fox,¹ Angelique de Rouen,¹ Nathan Zhang,¹ Aaliya Taranath,¹ Rafael de Cabo,¹ Josephine M. Egan,¹ Luigi Ferrucci,¹ and Mustapha Bouhrara¹

Published November 27, 2025 - More info

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Abstract

BACKGROUND. Axonal degeneration is believed to be an early hallmark of Alzheimer’s disease (AD). This study investigated the temporal trajectory of axonal loss and its association with cognitive and functional decline using diffusion MRI-derived Axonal Density Index (dMRI-ADI).

METHODS. Longitudinal dMRI, CSF and PET data from the ADNI were analyzed, including 117 cognitively normal (CN) and 88 impaired (CI) subjects, consisting of 74 mild cognitive impairment (MCI) and 14 AD individuals. Linear mixed-effects models examined group differences as well as associations between baseline and longitudinal changes in ADI, CSF or PET biomarkers and clinical outcomes. Results derived from larger CSF (n=527) and PET (tau-PET: n=870; amyloid-PET: n=1581) data were also presented.

RESULTS. Compared to CN, the CI group exhibited significantly lower baseline ADI values and steeper longitudinal decline (p<10^–⁶). Lower baseline ADI predicted faster cognitive and functional decline in the CI group (MMSE: p=0.03; CDR-SB: p<10^–⁴), and longitudinal decreases in ADI were associated with worsening clinical outcomes (MMSE: p=0.001; CDR-SB: p<10^–¹²). Compared to CSF and PET biomarkers, ADI demonstrated superior sensitivity in tracking disease progression and matched these biomarkers in predicting future cognitive and functional decline. Furthermore, decreases in ADI were significantly associated with declines in clinical outcomes; an association observed only with amyloid-PET, but not CSF biomarkers.

CONCLUSION. Axonal degeneration is an early and clinically meaningful feature of AD. ADI is a promising noninvasive biomarker for early detection, prognosis, and disease monitoring.

TRIAL REGISTRATION. ClinicalTrials.gov NCT00106899.

FUNDING. This work was supported by the National Institute on Aging IRP.

Early axonal degeneration linked to clinical decline in Alzheimer's disease progression revealed with diffusion MRI

Zhaoyuan Gong,¹ John P. Laporte,¹ Alexander Y. Guo,¹ Murat Bilgel,¹ Jonghyun Bae,¹ Noam Y. Fox,¹ Angelique de Rouen,¹ Nathan Zhang,¹ Aaliya Taranath,¹ Rafael de Cabo,¹ Josephine M. Egan,¹ Luigi Ferrucci,¹ and Mustapha Bouhrara¹

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Early axonal degeneration linked to clinical decline in Alzheimer's disease progression revealed with diffusion MRI

Zhaoyuan Gong,1 John P. Laporte,1 Alexander Y. Guo,1 Murat Bilgel,1 Jonghyun Bae,1 Noam Y. Fox,1 Angelique de Rouen,1 Nathan Zhang,1 Aaliya Taranath,1 Rafael de Cabo,1 Josephine M. Egan,1 Luigi Ferrucci,1 and Mustapha Bouhrara1

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Zhaoyuan Gong,¹ John P. Laporte,¹ Alexander Y. Guo,¹ Murat Bilgel,¹ Jonghyun Bae,¹ Noam Y. Fox,¹ Angelique de Rouen,¹ Nathan Zhang,¹ Aaliya Taranath,¹ Rafael de Cabo,¹ Josephine M. Egan,¹ Luigi Ferrucci,¹ and Mustapha Bouhrara¹