Influence of APOE ε4 on performance of CSF biomarkers in differentiating clinical Alzheimer's disease

Yan Wang; Fangyu Li; Qi Qin; Tingting Li; Qi Wang; Yan Li; Ying Li; Jianping Jia; Alzheimer's Disease Neuroimaging Initiative

doi:10.1016/j.tjpad.2025.100065

Influence of APOE ε4 on performance of CSF biomarkers in differentiating clinical Alzheimer's disease

J Prev Alzheimers Dis. 2025 Jan 17:100065. doi: 10.1016/j.tjpad.2025.100065. Online ahead of print.

Authors

Yan Wang¹, Fangyu Li¹, Qi Qin¹, Tingting Li¹, Qi Wang¹, Yan Li¹, Ying Li¹, Jianping Jia²; Alzheimer's Disease Neuroimaging Initiative

Affiliations

¹ Innovation Center for Neurological Disorders and Department of Neurology, Xuanwu Hospital, Capital Medical University, National Clinical Research Center for Geriatric Diseases.
² Innovation Center for Neurological Disorders and Department of Neurology, Xuanwu Hospital, Capital Medical University, National Clinical Research Center for Geriatric Diseases; Beijing Key Laboratory of Geriatric Cognitive Disorders; Clinical Center for Neurodegenerative Disease and Memory Impairment, Capital Medical University; Center of Alzheimer's Disease, Beijing Institute of Brain Disorders, Collaborative Innovation Center for Brain Disorders, Capital Medical University; Key Laboratory of Neurodegenerative Diseases, Ministry of Education. Electronic address: jjp@ccmu.edu.cn.

PMID: 39827005
DOI: 10.1016/j.tjpad.2025.100065

Abstract

Introduction: Apolipoprotein E ε4 (APOE ε4) bring the higher risk of Alzheimer' Disease (AD). It is essential to evaluate whether the diagnostic performances and critical values of cerebrospinal fluid (CSF) biomarkers are influenced by APOE ε4, which has guiding significance for the clinical practical application.

Methods: The differences in CSF biomarkers and their performances between APOE ε4 carriers and non-carriers in distinguishing AD, mild cognitive impairment (MCI) and preclinical AD from normal controls (NCs) were analyzed. The receiver operating characteristic (ROC) curves were generated to compare the area under the curve (AUC) between APOE ε4 carriers and non-carriers, as well as the critical values corresponding Youden Index.

Results: In a cross sectional convenience sample of 1610 participants, lower Aβ42 and Aβ42/Aβ40 and higher p-Tau 181/Aβ42 in CSF were observed among APOE ε4 carriers than non-carriers in NC, MCI, and AD groups (P< 0.05). The performance of CSF p-tau/Aβ42 in distinguishing MCI from NC among APOE ε4 carriers was superior to non-carriers [AUC: 0.714 (95%CI: 0.673- 0.752) vs 0.600 (95%CI: 0.564- 0.634), P< 0.001], although it was similar in distinguishing AD from NC between APOE ε4 carriers and non-carriers [AUC: 0.874 (95%CI: 0.835-0.906) vs 0.876 (95%CI: 0.843- 0.904)]. In the longitudinal cohort of 254 participants, the association of CSF Aβ42, Aβ42/Aβ40 and p-Tau181/Aβ42 with cognitive decline were stronger in APOE ε4 carriers compared to non-carriers (P< 0.05). Meanwhile, the critical values were different depending on APOE genotype.

Discussion: The CSF level of p-Tau181/Aβ42 was significantly different between APOE ε4 carriers and non-carriers at different stages of AD. The results indicate that the performances of CSF biomarkers are influenced by APOE ε4, which should be considered in the practical application.

Keywords: Alzheimer's disease; Apolipoprotein E; Biomarker; Cognitive decline; Mild cognitive impairment.