Plasma neurofilament light mediates the effects of Apolipoprotein E on brain atrophy and cognitive decline in the comorbid Alzheimer's Disease and Cerebral Small Vessel Disease - 01/01/25

Doi : 10.1016/j.tjpad.2024.100054

Chunhua Zhang ^1,^2,^{^{†
These authors contributed equally to this work.}}, Bingyu Li ^3,^{^{†
These authors contributed equally to this work.}}, Kok Pin Ng ^4,⁵, Yaojun Tai ², Yuanming Tai ², Xicheng Song ^6,^⁎ , Min Kong ^7,^⁎ , Maowen Ba ^1,^6,^⁎
for Alzheimer's Disease Neuroimaging Initiative^{^‡}
Data used in the 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/or provided data but did not participate in the analysis or writing of this report. A complete listing of ADNI investigators can be found at: how to apply/ADNI Acknowledgement List.pdf
¹ Department of Neurology, Affiliated Yantai Yuhuangding Hospital of Qingdao University, Yantai 264000, Shandong, China
² Department of Neurology, Jiaozhou Branch of Shanghai East Hospital, Tongji University, Jiaozhou 266300, Shandong, China
³ Department of Neurology, Shanghai Tongji Hospital, School of Medicine, Tongji University, Shanghai 200000, China
⁴ Department of Neurology, National Neuroscience Institute, Singapore 308433, Singapore
⁵ Duke-NUS Medical School, Singapore 169857, Singapore
⁶ Shandong Provincial Key Laboratory of Neuroimmune Interaction and Regulation, Yantai 264000, Shandong, China
⁷ Department of Neurology, Yantaishan Hospital, Yantai 264000, Shandong, China

^∗Corresponding author: Maowen Ba, Department of Neurology, Affiliated Yantai Yuhuangding Hospital of Qingdao University, 20 Yuhuangding East Road, Zhifu District, Yantai 264000, Shandong, China. Tel.: +86 15949962216; Fax: +86535 6240341.Department of NeurologyAffiliated Yantai Yuhuangding Hospital of Qingdao University20 Yuhuangding East Road, Zhifu DistrictYantaiShandong264000China^⁎⁎Corresponding author: Min Kong, Department of Neurology, Yantaishan Hospital, 10087 Keji Avenue, Laishan District, Yantai 264000, Shandong, China. Tel.: +86 15266547949.Department of NeurologyYantaishan Hospital10087 Keji Avenue, Laishan DistrictYantaiShandong264000China^⁎⁎⁎Corresponding author: Xicheng Song, Shandong Provincial Key Laboratory of Neuroimmune Interaction and Regulation, 20 Yuhuangding East Road, Zhifu District, Shandong, China. Tel.: +86 18005350077.Shandong Provincial Key Laboratory of Neuroimmune Interaction and Regulation20 Yuhuangding East Road, Zhifu DistrictShandongChina

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Abstract

Background

Alzheimer's disease (AD) and cerebral small vessel disease (CSVD) often coexist in older adults and contribute to cognitive impairment. The Apolipoprotein E (APOE) ε4 allele and neuroaxonal injury, measured by plasma neurofilament light chain (NfL), are associated with an increased risk for both AD and CSVD. However, the relationship between APOE ε4, plasma NfL, and their association with the comorbidity of AD and CSVD remains unclear.

Objective

To investigate the longitudinal relationship among APOE ε4, elevated plasma NfL, brain atrophy, and cognitive decline in individuals with comorbid AD and CSVD.

Methods

We included 570 non-demented participants from the Alzheimer's Disease Neuroimaging Initiative (ADNI) study, categorizing them into four groups based on amyloid-β positivity and CSVD burden. Linear mixed-effects models examined the association among APOE ε4, plasma NfL, brain volume measured by magnetic resonance imaging, and cognition over 2 years. Mediation analyses assessed the role of elevated plasma NfL in the relationship between APOE ε4, brain atrophy, and cognitive decline.

Results

APOE ε4 carriers showed elevated plasma NfL levels, brain atrophy, and cognitive decline. Plasma NfL mediated the effects of APOE ε4 on brain atrophy and cognitive decline in participants with comorbid AD and CSVD.

Conclusion

Our findings suggest that neuroaxonal injury as a potential mechanism in the effects of APOE ε4 on brain atrophy and cognitive decline, highlighting the clinical utility of plasma NfL as a potential biomarker for disease progression and response to therapeutic intervention in comorbid AD and CSVD.

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Keywords : Alzheimer's disease, cerebral small vessel disease, neurofilament light, white matter hyperintensities, cognition