¹National Health Research Institutes, Center for Neuropsychiatric Research, Miaoli County, Taiwan, ²Chang Gung Memorial Hospital Linkou Medical Center and College of Medicine, Chang Gung University, Department of Neurology, Taoyuan, Taiwan, ³Taoyuan Chang Gung Memorial Hospital, Dementia Center, Taoyuan, Taiwan, ⁴National Health Research Institutes, Institute of Population Health Sciences, Miaoli County, Taiwan, ⁵National Health Research Institutes, National Center for Geriatrics and Welfare Research, Yunlin, Taiwan, ⁶National Health Research Institutes, Institute of Molecular and Genomic Medicine, Miaoli County, Taiwan, ⁷National Yang Ming Chiao Tung University, Department of Life Sciences and Institute of Genome Sciences, Taipei, Taiwan

Background: Elevated levels of C-C motif chemokine ligand 11 (CCL11, also known as eotaxin-1) have been reported in patients with Alzheimer’s disease (AD). However, the mechanism behind its increase during the pathological process remains unclear.

Aims & Objectives: The aim of this study is to use a pathway-based genome-wide association study (GWAS) to uncover the genetic mechanisms underlying the pathological processes.

Method: A total of 117 participants from the Healthy Aging Longitudinal Study in Taiwan (HALST) and 5 from Chang Gung Memorial Hospital were used as reference controls, along with age- and gender-matched dementia patients: 50 with mild cognitive impairment (MCI), 49 with mild dementia, and 23 with moderate dementia. Genetic DNA samples were extracted, and genome-wide genotyping was performed. Plasma CCL11 levels were analyzed using enzyme-linked immunosorbent assay (ELISA), and cognitive function was assessed using the Mini-Mental State Examination (MMSE).

Results: The age range for participants from HALST was 51 to 88 years, while the age range for Alzheimer's disease (AD) patients across different disease stages was 55 to 91 years. Cognitive function, as assessed by the Mini-Mental State Examination (MMSE), was reduced (Kruskal-Wallis test, p < 0.0001), while plasma CCL11 levels were increased (Kruskal-Wallis test, p < 0.0001) in AD patients. Pathway-based association analysis revealed statistically significant findings in the moderate dementia group of AD patients. Significant associations were found between plasma CCL11 levels and pathways related to the elongation of N-glycan antennae (pathway based p = 0.00004), the modification of N-glycans in cellular or biochemical contexts (such as in culture media or transfected cells) (pathway based p = 0.00006), and the N-glycosylation of proteins in the Golgi apparatus (pathway based p = 0.0001). These pathway genes of MGAT4C, B4GALT4, and SEC24C (p ≤ 0.0001) showed highly significant associations with the plasma CCL11 levels in moderate dementia.

Discussion & Conclusions: In summary, the moderate dementia stage is where post-translational modifications, glycosylation of CCL11, and genes associated with CCL11 elevation are most prominent. Further studies will use cellular models to verify the biological roles of these pathway genes.