Impact of diabetes on the progression of Alzheimer’s disease via trajectories of amyloid–tau–neurodegeneration (ATN) biomarkers - 29/11/24

Doi : 10.1016/j.jnha.2024.100444

Eun Woo Kim ^a,^b, Keun You Kim ^c,^d,⁎ , Eosu Kim ^a,^d,^e,^f,⁎
for the Alzheimer's Disease Neuroimaging Initiative^¹
Data used in preparation of this article were obtained from the Alzheimer’s Disease Neuroimaging Initiative (ADNI) database (adni.loni.usc.edu). As such, the investigators within the ADNI contributed to the design and implementation of ADNI and provided data but did not participate in analysis or writing of this report. A complete listing of ADNI investigators can be found at: ADNI_Acknowledgement_List.pdf.
^a Graduate School of Medicine, Yonsei University, Seoul 03722, Republic of Korea
^b Department of Nursing, Seoyeong University, Gwangju 61268, Republic of Korea
^c Department of Psychiatry, Seoul Metropolitan Government Seoul National University (SMG-SNU) Boramae Medical Center, Seoul National University College of Medicine, Seoul, 07061, Republic of Korea
^d Department of Psychiatry, Laboratory for Alzheimer’s Molecular Psychiatry, Institute of Behavioral Science in Medicine, Yonsei University College of Medicine, Seoul 03722, Republic of Korea
^e Graduate School of Medical Science, Brain Korea 21 Project, Yonsei University College of Medicine, Seoul 03722, Republic of Korea
^f Metabolism-Dementia Research Institute, Yonsei University College of Medicine, Seoul 03722, Republic of Korea

^⁎Corresponding authors.

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Abstract

Background

Alzheimer's disease (AD) is characterized by the accumulation of abnormal proteins, such as β-amyloid and tau, in the brain, which precedes cognitive impairment. Although diabetes mellitus (DM) is a well-established risk factor for AD, few studies have investigated how the presence of DM affects the sequential pathogenesis of AD, specifically within the amyloid-tau-neurodegeneration (ATN) and cognition framework.

Objectives

This study aims to investigate the trajectories of ATN biomarkers in relation to the presence of DM in the preclinical and prodromal stages of AD.

Design

Participants with normal cognition (CN) or mild cognitive impairment (MCI) at baseline were included. Subjects were followed for 12–192 months, with neuroimaging and cognitive assessments conducted at every 12 or 24 months.

Setting

This study utilized data from the Alzheimer's Disease Neuroimaging Initiative (ADNI) database.

Participants

A total of 603 participants aged 55–90 years were included, comprising 284 CN (25 with DM, 259 without DM) and 319 MCI (39 with DM, 280 without DM) individuals.

Measurements

ATN biomarkers were identified using florbetapir positron emission tomography (PET), flortaucipir PET, and magnetic resonance imaging (MRI), respectively. Cognition was assessed using the Clinical Dementia Rating-Sum of Boxes (CDR-SB) and Mini-Mental State Examination (MMSE). Moderation analysis was conducted to investigate the effect of DM on the association between ATN biomarkers of AD.

Results

Elevated amyloid standardized uptake value ratios (SUVRs) were associated with increased tau levels in the hippocampus, and this association was significantly enhanced by the presence of DM in MCI participants (p = 0.021). DM also strengthened the association between increased tau SUVR levels and neurodegeneration (indicated by decreased entorhinal cortical volumes; p = 0.005) in those with MCI. Furthermore, DM enhanced the association of decreased entorhinal (p = 0.012) and middle temporal cortex (p = 0.031) volumes with increased (worsened) CDR-SB scores in MCI participants. However, DM did not predict significant longitudinal changes in ATN pathology or cognitive decline in CN participants.

Conclusions

Our study suggests that DM may increase the risk of AD by accelerating each step of the A-T-N cascade in the prodromal stage of AD, underscoring the importance of DM management in preventing the MCI conversion to AD.

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Keywords : Alzheimer’s disease, Diabetes mellitus, Mild cognitive impairment, ATN framework

Abbreviations : AD, ADNI, ATN, CDR-SB, CN, DM, GSK-3β, MCI, MMSE, MRI, PET, ROI, SUVR